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Effects of Nitric Oxide on Renal Proximal Tubular Na + Transport. BIOMED RESEARCH INTERNATIONAL 2017; 2017:6871081. [PMID: 29181400 PMCID: PMC5664255 DOI: 10.1155/2017/6871081] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 09/14/2017] [Indexed: 12/28/2022]
Abstract
Nitric oxide (NO) has a wide variety of physiological functions in the kidney. Besides the regulatory effects in intrarenal haemodynamics and glomerular microcirculation, in vivo studies reported the diuretic and natriuretic effects of NO. However, opposite results showing the stimulatory effect of NO on Na+ reabsorption in the proximal tubule led to an intense debate on its physiological roles. Animal studies have showed the biphasic effect of angiotensin II (Ang II) and the overall inhibitory effect of NO on the activity of proximal tubular Na+ transporters, the apical Na+/H+ exchanger isoform 3, basolateral Na+/K+ ATPase, and the Na+/HCO3− cotransporter. However, whether these effects could be reproduced in humans remained unclear. Notably, our recent functional analysis of isolated proximal tubules demonstrated that Ang II dose-dependently stimulated human proximal tubular Na+ transport through the NO/guanosine 3′,5′-cyclic monophosphate (cGMP) pathway, confirming the human-specific regulation of proximal tubular transport via NO and Ang II. Of particular importance for this newly identified pathway is its possibility of being a human-specific therapeutic target for hypertension. In this review, we focus on NO-mediated regulation of proximal tubular Na+ transport, with emphasis on the interaction with individual Na+ transporters and the crosstalk with Ang II signalling.
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Horita S, Nakamura M, Suzuki M, Satoh N, Suzuki A, Homma Y, Nangaku M. The role of renal proximal tubule transport in the regulation of blood pressure. Kidney Res Clin Pract 2017; 36:12-21. [PMID: 28428931 PMCID: PMC5331971 DOI: 10.23876/j.krcp.2017.36.1.12] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 10/18/2016] [Accepted: 12/05/2016] [Indexed: 12/15/2022] Open
Abstract
The electrogenic sodium/bicarbonate cotransporter 1 (NBCe1) on the basolateral side of the renal proximal tubule plays a pivotal role in systemic acid-base homeostasis. Mutations in the gene encoding NBCe1 cause severe proximal renal tubular acidosis accompanied by other extrarenal symptoms. The proximal tubule reabsorbs most of the sodium filtered in the glomerulus, contributing to the regulation of plasma volume and blood pressure. NBCe1 and other sodium transporters in the proximal tubule are regulated by hormones, such as angiotensin II and insulin. Angiotensin II is probably the most important stimulator of sodium reabsorption. Proximal tubule AT1A receptor is crucial for the systemic pressor effect of angiotensin II. In rodents and rabbits, the effect on proximal tubule NBCe1 is biphasic; at low concentration, angiotensin II stimulates NBCe1 via PKC/cAMP/ERK, whereas at high concentration, it inhibits NBCe1 via NO/cGMP/cGKII. In contrast, in human proximal tubule, angiotensin II has a dose-dependent monophasic stimulatory effect via NO/cGMP/ERK. Insulin stimulates the proximal tubule sodium transport, which is IRS2-dependent. We found that in insulin resistance and overt diabetic nephropathy, stimulatory effect of insulin on proximal tubule transport was preserved. Our results suggest that the preserved stimulation of the proximal tubule enhances sodium reabsorption, contributing to the pathogenesis of hypertension with metabolic syndrome. We describe recent findings regarding the role of proximal tubule transport in the regulation of blood pressure, focusing on the effects of angiotensin II and insulin.
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Affiliation(s)
- Shoko Horita
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Motonobu Nakamura
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Masashi Suzuki
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Nobuhiko Satoh
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Atsushi Suzuki
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
| | - Yukio Homma
- Department of Urology, The University of Tokyo Hospital, Tokyo, Japan
| | - Masaomi Nangaku
- Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan
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Seki G, Nakamura M, Suzuki M, Satoh N, Horita S. Species differences in regulation of renal proximal tubule transport by certain molecules. World J Nephrol 2015; 4:307-312. [PMID: 25949945 PMCID: PMC4419141 DOI: 10.5527/wjn.v4.i2.307] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 12/24/2014] [Accepted: 01/20/2015] [Indexed: 02/06/2023] Open
Abstract
Renal proximal tubules (PTs) play important roles in the regulation of acid/base, plasma volume and blood pressure. Recent studies suggest that there are substantial species differences in the regulation of PT transport. For example, thiazolidinediones (TZDs) are widely used for the treatment of type 2 diabetes mellitus, but the use of TZDs is associated with fluid overload. In addition to the transcriptional enhancement of sodium transport in distal nephrons, TZDs rapidly stimulate PT sodium transport via a non-genomic mechanism depending on peroxisome proliferator activated receptor γ/Src/epidermal growth factor receptor (EGFR)/MEK/ERK. In mouse PTs, however, TZDs fail to stimulate PT transport probably due to constitutive activation of Src/EGFR/ERK pathway. This unique activation of Src/ERK may also affect the effect of high concentrations of insulin on mouse PT transport. On the other hand, the effect of angiotensin II (Ang II) on PT transport is known to be biphasic in rabbits, rats, and mice. However, Ang II induces a concentration-dependent, monophasic transport stimulation in human PTs. The contrasting responses to nitric oxide/guanosine 3’,5’-cyclic monophosphate pathway may largely explain these different effects of Ang II on PT transport. In this review, we focus on the recent findings on the species differences in the regulation of PT transport, which may help understand the species-specific mechanisms underlying edema formation and/or hypertension occurrence.
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Shirai A, Yamazaki O, Horita S, Nakamura M, Satoh N, Yamada H, Suzuki M, Kudo A, Kawakami H, Hofmann F, Nishiyama A, Kume H, Enomoto Y, Homma Y, Seki G. Angiotensin II dose-dependently stimulates human renal proximal tubule transport by the nitric oxide/guanosine 3',5'-cyclic monophosphate pathway. J Am Soc Nephrol 2014; 25:1523-32. [PMID: 24511122 DOI: 10.1681/asn.2013060596] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Stimulation of renal proximal tubule (PT) transport by angiotensin II (Ang II) is critical for regulation of BP. Notably, in rats, mice, and rabbits, the regulation of PT sodium transport by Ang II is biphasic: transport is stimulated by picomolar to nanomolar concentrations of Ang II but inhibited by nanomolar to micromolar concentrations of Ang II. However, little is known about the effects of Ang II on human PT transport. By functional analysis with isolated PTs obtained from nephrectomy surgery, we found that Ang II induces a dose-dependent profound stimulation of human PT transport by type 1 Ang II receptor (AT1)-dependent phosphorylation of extracellular signal-regulated kinase (ERK). In PTs of wild-type mice, the nitric oxide (NO) /cGMP/cGMP-dependent kinase II (cGKII) pathway mediated the inhibitory effect of Ang II. In PTs of cGKII-deficient mice, the inhibitory effect of Ang II was lost, but activation of the NO/cGMP pathway failed to phosphorylate ERK. Conversely, in human PTs, the NO/cGMP pathway mediated the stimulatory effect of Ang II by phosphorylating ERK independently of cGKII. These contrasting responses to the NO/cGMP pathway may largely explain the different modes of PT transport regulation by Ang II, and the unopposed marked stimulation of PT transport by high intrarenal concentrations of Ang II may be an important factor in the pathogenesis of human hypertension. Additionally, the previously unrecognized stimulatory effect of the NO/cGMP pathway on PT transport may represent a human-specific therapeutic target in hypertension.
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Affiliation(s)
| | | | | | | | | | | | | | - Akihiko Kudo
- Department of Anatomy, Kyorin University School of Medicine, Tokyo, Japan
| | - Hayato Kawakami
- Department of Anatomy, Kyorin University School of Medicine, Tokyo, Japan
| | - Franz Hofmann
- Forschergruppe 923, Institut für Pharmakologie und Toxikologie der Technischen Universität München, München, Germany; and
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Haruki Kume
- Urology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yutaka Enomoto
- Urology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yukio Homma
- Urology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
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Caixeta A, Dogan O, Weisz G. Contrast-induced nephropathy: Protective role of fenoldopam. Clin Exp Pharmacol Physiol 2012; 39:497-505. [DOI: 10.1111/j.1440-1681.2012.05707.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- Adriano Caixeta
- Center for Interventional Vascular Therapy; New York Presbyterian Hospital; Columbia University Medical Center; New York; NY; USA
| | - Ozgen Dogan
- Center for Interventional Vascular Therapy; New York Presbyterian Hospital; Columbia University Medical Center; New York; NY; USA
| | - Giora Weisz
- Center for Interventional Vascular Therapy; New York Presbyterian Hospital; Columbia University Medical Center; New York; NY; USA
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Abstract
Approximately 72 million people in the US experience hypertension. Worldwide, hypertension may affect as many as 1 billion people and be responsible for approximately 7.1 million deaths per year. It is estimated that approximately 1% of patients with hypertension will, at some point, develop a hypertensive crisis. Hypertensive crises are further defined as either hypertensive emergencies or urgencies, depending on the degree of blood pressure elevation and presence of end-organ damage. Immediate reduction in blood pressure is required only in patients with acute end-organ damage (i.e. hypertensive emergency) and requires treatment with a titratable, short-acting, intravenous antihypertensive agent, while severe hypertension without acute end-organ damage (i.e. hypertensive urgency) is usually treated with oral antihypertensive agents. The primary goal of intervention in a hypertensive crisis is to safely reduce blood pressure. The appropriate therapeutic approach of each patient will depend on their clinical presentation. Patients with hypertensive emergencies are best treated in an intensive care unit with titratable, intravenous, hypotensive agents. Rapid-acting intravenous antihypertensive agents are available, including labetalol, esmolol, fenoldopam, nicardipine and sodium nitroprusside. Newer agents, such as clevidipine and fenoldopam, may hold considerable advantages to other available agents in the management of hypertensive crises. Sodium nitroprusside is an extremely toxic drug and its use in the treatment of hypertensive emergencies should be avoided. Similarly, nifedipine, nitroglycerin and hydralazine should not to be considered first-line therapies in the management of hypertensive crises because these agents are associated with significant toxicities and/or adverse effects.
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Affiliation(s)
- Joseph Varon
- The University of Texas Health Science Center at Houston, Houston, Texas, USA.
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Abstract
Hypertension affects > 65 million people in the United States and is one of the leading causes of death. One to two percent of patients with hypertension have acute elevations of BP that require urgent medical treatment. Depending on the degree of BP elevation and presence of end-organ damage, severe hypertension can be defined as either a hypertensive emergency or a hypertensive urgency. A hypertensive emergency is associated with acute end-organ damage and requires immediate treatment with a titratable short-acting IV antihypertensive agent. Severe hypertension without acute end-organ damage is referred to as a hypertensive urgency and is usually treated with oral antihypertensive agents. This article reviews definitions, current concepts, common misconceptions, and pitfalls in the diagnosis and management of patients with acutely elevated BP as well as special clinical situations in which BP must be controlled.
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Affiliation(s)
- Paul E Marik
- Department of Pulmonary and Critical Care, Thomas Jefferson University, Philadelphia, PA USA.
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Abstract
The appropriate and timely evaluation and treatment of patients with severely elevated blood pressure is essential to avoid serious adverse outcomes. Most importantly, the distinction between a hypertensive emergency (crisis) and urgency needs to be made. A sudden elevation in systolic (SBP) and/or diastolic blood pressure (DBP) that is associated with acute end organ damage (cardiovascular, cerebrovascular, or renal) is defined as a hypertensive crisis or emergency. In contrast, acute elevation in SBP and/or DBP not associated with evidence of end organ damage is defined as hypertensive urgency. In patients with a hypertensive emergency, blood pressure control should be attained as expeditiously as possible with parenteral medications to prevent ongoing and potentially permanent end organ damage. In contrast, with hypertensive urgency, blood pressure control can be achieved with the use of oral medications within 24-48 hours. This paper reviews the management of hypertensive emergencies.
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Affiliation(s)
- Andrew R Haas
- Division of Critical Care, Pulmonary, Allergy and Immunologic Disease, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA
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Oliver WC, Nuttall GA, Cherry KJ, Decker PA, Bower T, Ereth MH. A Comparison of Fenoldopam with Dopamine and Sodium Nitroprusside in Patients Undergoing Cross-Clamping of the Abdominal Aorta. Anesth Analg 2006; 103:833-40. [PMID: 17000789 DOI: 10.1213/01.ane.0000237273.79553.9e] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Fenoldopam, a selective dopamine-1-receptor agonist, decreases arterial blood pressure rapidly, with a brief duration of action similar to sodium nitroprusside (SNP), but in contrast to SNP, it increases renal blood flow. We compared the hemodynamic and renal effects of fenoldopam in patients undergoing abdominal aortic surgery requiring cross-clamping of the aorta with another therapeutic option, dopamine and SNP. Fenoldopam or 2 mcg x kg(-1) x min(-1) of dopamine and SNP was infused before incision in 60 randomly selected patients in a double-blind fashion. Hemodynamic variables were recorded before incision, immediately before clamping the aorta, 5 min after cross-clamp release and upon completion of surgery. Urine output, serum creatinine, and creatinine clearance were measured intraoperatively and postoperatively. Characteristics were compared between groups using two-sample rank sum test for continuous variables and Fisher's exact test for discrete variables. The occurrence of severe hypotension, maximum systolic blood pressure, and need for additional antihypertensive drugs were not different between the groups. Most intraoperative hemodynamic variables and all indices of renal function did not differ according to treatment. Therefore, fenoldopam has no therapeutic advantage compared with similar therapies in patients undergoing major vascular surgery involving cross-clamping of the aorta.
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Affiliation(s)
- William C Oliver
- Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
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Ng TMH, Shurmur SW, Silver M, Nissen LR, O'Leary EL, Rigmaiden RS, Cieciorka M, Porter LL, Ineck BA, Kline ME, Puumala SE. Comparison of N-acetylcysteine and fenoldopam for preventing contrast-induced nephropathy (CAFCIN). Int J Cardiol 2006; 109:322-8. [PMID: 16039733 DOI: 10.1016/j.ijcard.2005.06.038] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2005] [Accepted: 06/10/2005] [Indexed: 11/19/2022]
Abstract
BACKGROUND N-acetylcysteine and fenoldopam are commonly prescribed for prevention of contrast mediated nephropathy, however, comparative superiority of either agent is unknown. METHODS In a prospective, randomized, parallel-group trial, adult cardiac catheterization patients at the university and veterans' hospitals with pre-existing stable renal insufficiency were randomized to N-acetylcysteine 600 mg orally twice daily for 4 doses or fenoldopam 0.1 mcg/kg/min intravenously for a minimum of 8 h. All patients received intravenous hydration with normal saline (5% dextrose in normal saline for diabetics on insulin). Randomization was stratified for diabetes. The primary endpoint was mean change in Scr at 72 h. Secondary endpoint was the incidence of contrast-induced nephropathy (25% increase above baseline Scr or absolute increase of 0.5 mg/dL). RESULTS Study termination occurred after ninety-five patients (mean age 68+/-10 years, female 25%, diabetic 42%, mean baseline Scr 1.5+/-0.4 mg/dL) were randomized, with 84 completing follow-up (44 N-acetylcysteine, 40 fenoldopam). Overall, there were no significant differences in mean change in Scr at 72 h (N-acetylcysteine 0.20+/-0.72 vs. fenoldopam 0.08+/-0.48 mg/dL, p=0.4) or incidence of contrast-induced nephropathy (N-acetylcysteine 5 vs fenoldopam 8, p=0.4). No differences were detected in subgroup analyses for diabetes, baseline Scr >1.7 or 2.0 mg/dL, gender, age >70 years, or contrast volume >150 mL. Results were similar after multivariate adjustment for diabetes, contrast volume, heart failure and gender. CONCLUSIONS Our randomized comparison failed to demonstrate a significant difference in the abilities of N-acetylcysteine and fenoldopam to prevent the decline in renal function or the incidence of contrast-induced nephropathy during cardiac catheterization.
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Affiliation(s)
- Tien M H Ng
- Department of Pharmacy Practice, University of Nebraska Medical Center, 986045 Nebraska Medical Center, Omaha, Nebraska 68198-6045, USA.
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Bove T, Landoni G, Calabrò MG, Aletti G, Marino G, Cerchierini E, Crescenzi G, Zangrillo A. Renoprotective Action of Fenoldopam in High-Risk Patients Undergoing Cardiac Surgery. Circulation 2005; 111:3230-5. [PMID: 15967861 DOI: 10.1161/circulationaha.104.509141] [Citation(s) in RCA: 137] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background—
Acute renal failure is a serious complication of cardiac surgery causing high morbidity and mortality. The aim of this study was to evaluate the usefulness of fenoldopam, a specific agonist of the dopamine-1 receptor, in patients at high risk of perioperative renal dysfunction.
Methods and Results—
A prospective single-center, randomized, double-blind trial was performed after local ethical committee approval and after written consent was obtained from 80 patients undergoing cardiac surgery. Patients received either fenoldopam at 0.05 μg/kg per minute or dopamine at 2.5 μg/kg per minute after the induction of anesthesia for a 24-hour period. All these patients were at high risk of perioperative renal dysfunction as indicated by Continuous Improvement in Cardiac Surgery Program score >10. Primary end point was defined as 25% creatinine increase from baseline levels after cardiac surgery. The 2 groups (fenoldopam versus dopamine) were homogeneous cohorts, and no difference in outcome was observed. Acute renal failure was similar: 17 of 40 (42.5%) in the fenoldopam group and 16 of 40 (40%) in the dopamine group (
P
=0.9). Peak postoperative serum creatinine level, intensive care unit and hospital stay, and mortality were also similar in the 2 groups.
Conclusions—
Despite an increasing number of reports of renal protective properties from fenoldopam, we observed no difference in the clinical outcome compared with dopamine in a high-risk population undergoing cardiac surgery.
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Affiliation(s)
- Tiziana Bove
- Department of Cardiovascular Anesthesia, Vita-Salute University of Milan, IRCCS San Raffaele Hospital, Milan, Italy
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Ranucci M, Soro G, Barzaghi N, Locatelli A, Giordano G, Vavassori A, Manzato A, Melchiorri C, Bove T, Juliano G, Uslenghi MF. Fenoldopam Prophylaxis of Postoperative Acute Renal Failure in High-Risk Cardiac Surgery Patients. Ann Thorac Surg 2004; 78:1332-7; discussion 1337-8. [PMID: 15464494 DOI: 10.1016/j.athoracsur.2004.02.065] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/18/2004] [Indexed: 11/24/2022]
Abstract
BACKGROUND Acute renal failure requiring replacement therapy occurs in 1% to 2% of patients who have undergone cardiac surgery with cardiopulmonary bypass and is associated with a very high mortality rate. The aim of this study was to determine if prophylactic treatment with fenoldopam mesylate of patients at high risk of postoperative acute renal failure reduced the incidence of this event. METHODS This was a multicenter, prospective, cohort study in which 108 patients at high risk of postoperative acute renal failure and undergoing cardiac surgery with cardiopulmonary bypass were treated with fenoldopam mesylate (0.08 microg x kg(-1) x min(-1)) starting at the induction of anesthesia and throughout at least the next 24 hours. A homogeneous control group of 108 patients was created using a propensity-score analysis. RESULTS Fenoldopam prophylaxis was significantly associated with a reduction in acute renal failure incidence (from 22% to 11%, p = 0.028), a less pronounced creatinine clearance decrease (p = 0.05), and a lower mortality rate (6.5% versus 15.7%, p = 0.03) by the univariate analysis, but these results were not confirmed by a multivariable analysis. Within the subgroup of patients who suffered a postoperative low output syndrome, fenoldopam prophylaxis was an independent protective factor for postoperative renal failure (odds ratio, 0.14; 95% confidence interval, 0.03 to 0.7; p = 0.017). CONCLUSIONS Given the limitations of a nonrandomized prospective trial, our results support the hypothesis that fenoldopam may reduce the risk of acute renal failure in patients in whom endogenous and exogenous cathecolamines action may induce a renal vascular constrictive condition.
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Affiliation(s)
- Marco Ranucci
- Cardiothoracic Anesthesia and Intensive Care, Istituto Policlinico S. Donato, Milan, Italy
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Devlin JW, Seta ML, Kanji S, Somerville AL. Fenoldopam Versus Nitroprusside for the Treatment of Hypertensive Emergency. Ann Pharmacother 2004; 38:755-9. [PMID: 15039472 DOI: 10.1345/aph.1d363] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND While sodium nitroprusside remains first-line therapy for hypertensive emergency (HEM), fenoldopam is increasingly being used because of its benign safety profile and potential renal protective effects. OBJECTIVE To compare the efficacy, safety, and cost of sodium nitroprusside versus fenoldopam for the treatment of HEM. METHODS This study was a retrospective analysis of consecutive patients with HEM admitted to a university-affiliated, level 1 trauma center from 1999 to 2001 and treated with either nitroprusside (n = 21) or fenoldopam (n = 22) for >30 minutes. Time to reach mean arterial pressure (MAP) goal, change in MAP over time, time to initiation of oral antihypertensive therapy, change in renal function, incidence of cyanide toxicity, and cost of therapy were compared between groups. RESULTS Demographic parameters were similar between groups, except renal failure, which was more prevalent in the fenoldopam group (10% vs 46%; p = 0.009). Neither the mean ± SD pretreatment MAP (nitroprusside 168 ± 19; fenoldopam 163 ± 19; p = 0.45), time to reach MAP goal (3.6 [0.4–30] vs 4 [1–22] h; p = 0.51), nor infusion duration (18 [0.7–113] vs 18 [3–74] h; p = 0.45) differed between the patient groups. Time to initiation of oral antihypertensive therapy was similar between nitroprusside- (4.5 h [0.5–22] and fenoldopam- (6.5 h [1–100] treated patients; p = 0.65). Additional intravenous antihypertensives were administered to 16 patients in each group (p = 0.80). Change in creatinine clearance and incidence of tachycardia did not differ between groups. No symptoms of cyanide toxicity were detected. Cost of drug therapy was greater with fenoldopam ($597.60, $199.20–6675.20); than nitroprusside ($2.66, $1.68–3.48; p < 0.001). CONCLUSIONS Treatment of HEM with fenoldopam appears to result in patient outcomes equivalent to those with nitroprusside but at a substantially higher cost. Further study is required to delineate the exact role of fenoldopam for treatment of HEM.
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Affiliation(s)
- John W Devlin
- School of Pharmacy, Northeastern University, Boston, MA 02115-5001, USA.
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Garwood S, Swamidoss CP, Davis EA, Samson L, Hines RL. A case series of low-dose fenoldopam in seventy cardiac surgical patients at increased risk of renal dysfunction. J Cardiothorac Vasc Anesth 2003; 17:17-21. [PMID: 12635055 DOI: 10.1053/jcan.2003.5] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To evaluate the usefulness of low-dose fenoldopam mesylate in patients at risk of developing renal dysfunction after cardiac surgery requiring cardiopulmonary bypass. DESIGN A prospective, single-center, observational study. SETTING University teaching hospital. PARTICIPANTS Seventy patients scheduled for elective cardiac surgery with one or more predefined risk factors for renal dysfunction. INTERVENTIONS After induction of anesthesia, fenoldopam (0.03 microg/kg/min) was administered throughout surgery and into the postoperative period, until the patient was stable and weaned from all other vasoactive agents. Perioperatively, fenoldopam was also used as a second-line antihypertensive agent as required. MEASUREMENTS AND MAIN RESULTS No patient developed renal failure that required dialysis, whereas 7.1% (5/70) developed non-dialysis-dependent renal dysfunction. Four out of these 5 patients had 2 or more risk factors (9.5%). Higher preoperative creatinine levels, a history of hypertension, myocardial infarction within 5 days of surgery, and a preoperative diagnosis of chronic renal insufficiency were all good predictors of postoperative non-dialysis-dependent renal dysfunction. Discharge serum creatinine levels were lower than preoperative levels (1.16 +/- 0.36 mg/dL v 1.26 +/- 0.34 mg/dL, p < 0.05). CONCLUSION These findings suggest that renal function was preserved in patients at increased risk for renal dysfunction after cardiac surgery when low-dose fenoldopam was used in the perioperative period. However, a randomized, controlled trial is required to establish efficacy.
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Affiliation(s)
- Susan Garwood
- Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06520, USA.
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16
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Abstract
Resistant hypertension, secondary hypertension, and hypertensive crises are uncommon but potentially dangerous forms of hypertension that are associated with an increased risk of complications such as myocardial infarction, heart failure, stroke, and renal failure. Appropriate diagnostic screening and selective drug or surgical management can reduce the risk of these complications dramatically. In compliant patients, resistant hypertension occurs most often in obese patients receiving inadequate diuretic therapy. In patients with clinical clues to the diagnosis, the best current screening test for renovascular hypertension is probably the ACE-inhibitor renal scintiscan. Angioplasty is considerably more successful in younger patients with fibrous dysplasia than in older patients with the atherosclerotic variety. Hypertensive crises are divided into BP urgencies and emergencies. In both settings, the reduction in BP should generally be gradual rather than abrupt, with no intent to acutely normalize the BP.
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Affiliation(s)
- W Dallas Hall
- Emory University School of Medicine, 1100 Parker Place, Atlanta, GA 30324-5402, USA.
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Hypertensive Crises. Intensive Care Med 2002. [DOI: 10.1007/978-1-4757-5551-0_77] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Garwood S. New pharmacologic options for renal preservation. ANESTHESIOLOGY CLINICS OF NORTH AMERICA 2000; 18:753-71. [PMID: 11094689 DOI: 10.1016/s0889-8537(05)70193-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The understanding of the cause and pathophysiology of renal failure has guided the rational development of pharmacologic renoprotective strategies. Although traditionally anesthesiologists have focused on renal hemodynamic derangements, newer information suggests that cellular interactions amplify and perpetuate the insult. Consequently, the potential renoprotective armamentarium not only encompasses the more traditional vasoactive agents but also therapeutic approaches that may modify the cellular response to injury. Although few of these agents have reached the clinical arena, preliminary work suggests that this new approach to renal injury and protection may be promising.
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Affiliation(s)
- S Garwood
- Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut, USA.
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Abstract
Severe hypertension is a common clinical problem in the United States, encountered in various clinical settings. Although various terms have been applied to severe hypertension, such as hypertensive crises, emergencies, or urgencies, they are all characterized by acute elevations in BP that may be associated with end-organ damage (hypertensive crisis). The immediate reduction of BP is only required in patients with acute end-organ damage. Hypertension associated with cerebral infarction or intracerebral hemorrhage only rarely requires treatment. While nitroprusside is commonly used to treat severe hypertension, it is an extremely toxic drug that should only be used in rare circumstances. Furthermore, the short-acting calcium channel blocker nifedipine is associated with significant morbidity and should be avoided. Today, a wide range of pharmacologic alternatives are available to the practitioner to control severe hypertension. This article reviews some of the current concepts and common misconceptions in the management of patients with acutely elevated BP.
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Affiliation(s)
- J Varon
- Department of Medicine, Baylor College of Medicine, Houston TX, USA.
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20
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Abstract
OBJECTIVE To review studies and drug therapy relating to the treatment of hypertension in perioperative patients. DATA SOURCES Articles were selected from a MEDLINE search (1966-August 1998), and several textbooks on hypertension and surgery were reviewed. In addition, bibliographies of all articles and textbook chapters were studied for articles not found in the computerized searches. STUDY SELECTION Clinical studies involving hypertension in the perioperative setting were included. The initial search was limited to studies conducted in humans and published in English. DATA EXTRACTION Information regarding drug therapy was reviewed and guidelines were constructed for managing surgical patients with acute blood pressure elevations. DATA SYNTHESIS Although nitroprusside and nitroglycerin, with their short onset of action and duration of effect, are indicated for hypertensive emergencies, a variety of agents are available for hypertensive urgencies. An algorithm that can be used as a template for the development of intrainstitutional guidelines is provided. CONCLUSIONS Due to the scarcity of comparative trials, decisions involving agents for the treatment of perioperative hypertension must often be made based on combined efficacy, toxicity, cost, and convenience considerations.
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Affiliation(s)
- B L Erstad
- College of Pharmacy, University of Arizona, Tucson 85721, USA.
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21
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Mathur VS, Swan SK, Lambrecht LJ, Anjum S, Fellmann J, McGuire D, Epstein M, Luther RR. The effects of fenoldopam, a selective dopamine receptor agonist, on systemic and renal hemodynamics in normotensive subjects. Crit Care Med 1999; 27:1832-7. [PMID: 10507606 DOI: 10.1097/00003246-199909000-00021] [Citation(s) in RCA: 125] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Acute renal failure, frequently a consequence of renal vasoconstriction and subsequent renal ischemia, is a common problem for which no proven preventive or therapeutic agents exist. Fenoldopam is a new, selective, dopamine-1 receptor agonist that causes both systemic and renal arteriolar vasodilation. In hypertensive patients, fenoldopam rapidly decreases blood pressure, increases renal blood flow, and maintains or improves the glomerular filtration rate. We sought to determine a dose of fenoldopam that increases renal blood flow without inducing hypotension in normotensive patients and to explore the role of volume status (sodium replete vs. deplete) in these effects. DESIGN Randomized, double-blind, placebo-controlled, cross-over study. SETTING Clinical research unit. PATIENTS Fourteen normal male volunteers. INTERVENTIONS Renal plasma flow (para-aminohippurate clearance) and glomerular filtration rate (inulin clearance) were measured during three fixed, escalating doses of fenoldopam (0.03, 0.1, and 0.3 Lg/kg/min) on both a high-sodium and a low-sodium diet. MEASUREMENTS AND MAIN RESULTS Fenoldopam significantly increased renal plasma flow in a dose-dependent manner compared with placebo: 670 + 148 vs. 576 + 85 mUmin at 0.03 iLg/kg/min; 777 + 172 vs. 579 + 80 mUmin at 0.1 tig/kg/min; and 784 + 170 vs. 592 + 165 mUmin at 0.3 ilg/kg/min (p < .05 fenoldopam vs. placebo at all three doses). Glomerular filtration rate was maintained. At the lowest dose (i.e., 0.03 ILg/kg/min), significant renal blood flow increases occurred without changes in systemic blood pressure or heart rate. At 0.1 and 0.3 Lgl/kg/ min, systolic blood pressure did not change, but diastolic blood pressure was slightly lower in the fenoldopam group than in the placebo group: 62.5 + 6.4 vs. 63.6 + 2.6 mm Hg, respectively, at 0.3 tg/kg/min (p < .05). None of the effects of fenoldopam were altered by volume status. CONCLUSIONS Fenoldopam increased renal blood flow in a dose-dependent manner compared with placebo, and, at the lowest dose, significantly increased renal blood flow occurred without changes in systemic blood pressure or heart rate. These findings will be useful in designing future studies exploring the role of fenoldopam in preventing or treating renal failure in patients who are not hypertensive.
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Affiliation(s)
- V S Mathur
- Neurex Corporation, Menlo Park, CA 94025-1012, USA
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22
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Taylor AA, Mangoo‐Karim R, Ballard KD, Luther RR, Pool JL. Sustained Hemodynamic Effects of the Selective Dopamine‐1 Agonist, Fenoldopam, during 48‐Hour Infusions in Hypertensive Patients: A Dose‐Tolerability Study. J Clin Pharmacol 1999. [DOI: 10.1177/009127009903900506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Addison A. Taylor
- Section on Hypertension and Clinical Pharmacology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Roberto Mangoo‐Karim
- Section on Hypertension and Clinical Pharmacology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Kevin D. Ballard
- Section on Hypertension and Clinical Pharmacology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | | | - James L. Pool
- Section on Hypertension and Clinical Pharmacology, Department of Medicine, Baylor College of Medicine, Houston, Texas
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23
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Post JB, Frishman WH. Fenoldopam: a new dopamine agonist for the treatment of hypertensive urgencies and emergencies. J Clin Pharmacol 1998; 38:2-13. [PMID: 9597553 DOI: 10.1002/j.1552-4604.1998.tb04369.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Fenoldopam is a selective dopamine agonist that is being considered for the parenteral treatment of systemic hypertension. In both an oral and parenteral form, the drug causes peripheral vasodilation by stimulating dopamine-1 adrenergic receptors. Its pharmaco-dynamics are reviewed in this article, along with the clinical experiences in patients with hypertensive urgencies and emergencies. Intravenous fenoldopam may provide advantages over sodium nitroprusside because it can induce both a diuresis and natriuresis, is not light sensitive, and is not associated with cyanide toxicity. There is no evidence for rebound hypertension after discontinuation of fenoldopam influsion.
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Affiliation(s)
- J B Post
- Department of Medicine, Albert Einstein College of Medicine/Montefiore-Medical Center, Bronx, New York, USA
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24
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25
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Panacek EA, Bednarczyk EM, Dunbar LM, Foulke GE, Holcslaw TL. Randomized, prospective trial of fenoldopam vs sodium nitroprusside in the treatment of acute severe hypertension. Fenoldopam Study Group. Acad Emerg Med 1995; 2:959-65. [PMID: 8536121 DOI: 10.1111/j.1553-2712.1995.tb03122.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVE To compare the safeties and efficacies of IV fenoldopam (FNP) vs sodium nitroprusside (NTP) in severe acute hypertension. METHODS A prospective, randomized, open-label, multicenter international trial, at 24 academic medical centers, was conducted. The participants were adult patients (21-80 years of age) who had supine diastolic blood pressures (DBPs) > or = 120 mm Hg, were capable of written informed consent, and did not have selected exclusion criteria. The subjects were randomized to either FNP or NTP therapy; DBP was titrated to 95-110 mm Hg, or a maximum reduction of 40 mm Hg for very high pressures. Infusions were maintained for at least six hours, then the patients were weaned off the IV therapy and oral medication was started. Measurements included BP, heart rate, and duration of study drug infusion and frequency of side effects or complications. RESULTS A total of 183 patients (90 FNP, 93 NTP) were enrolled. Fifteen patients from each arm were excluded from efficacy analysis due to protocol violation. There was no significant difference in baseline characteristics. The two antihypertensive agents were equivalent in controlling and maintaining DBP. Systolic blood pressure (SBP) was reduced to a slightly greater degree for the NTP-treated patients during the initial (0.5-1-hr) study period, and both SBP and DBP were reduced more for the FNP-treated patients in the subset receiving infusions during the 12-24-hour period. The adverse effect profiles of the drugs were similar, as were the times to achieve target pressure, with no clinically relevant difference. CONCLUSIONS For patients who had acute severe hypertension, FNP and NTP were equivalent in terms of efficacy and acute adverse events. Because of a unique mechanism of action, FNP may have advantages in selected subsets of patients. Further studies may be indicated in patient populations with pure "hypertensive emergencies."
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26
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Shusterman NH, Elliott WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function. Am J Med 1993; 95:161-8. [PMID: 8102835 DOI: 10.1016/0002-9343(93)90256-o] [Citation(s) in RCA: 107] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE Patients with hypertensive crises often experience reduced renal function that may worsen as the elevated blood pressure is treated. Fenoldopam, a novel, peripherally acting dopamine-1 agonist, lowers blood pressure through arteriolar vasodilation, with particularly prominent effects on the renal vascular bed. This study was conducted to examine the effects of fenoldopam on blood pressure and renal function compared to those of sodium nitroprusside in severely hypertensive patients with impaired renal function. PATIENTS AND METHODS Renal function and systemic hemodynamics were studied in 19 severely hypertensive patients (diastolic blood pressure greater than or equal to 120 mm Hg) with impaired renal function (creatinine clearance less than or equal to 70 mL/min) enrolled in clinical trials of fenoldopam and sodium nitroprusside. For comparison, an additional 22 severely hypertensive patients with nonimpaired renal function were studied under the same conditions. Blood pressure and heart rate were measured at baseline before treatment and periodically during treatment. Renal function was determined before and during drug infusion by collection of timed urine specimens and blood samples. Creatinine clearance, urine flow rate, and sodium and potassium excretions were measured and compared. RESULTS In patients with impaired renal function, blood pressure (mean +/- SEM) was reduced successfully in both groups (fenoldopam: 214 +/- 8/139 +/- 6 mm Hg to 176 +/- 8/107 +/- 3 mm Hg, p < 0.001 for systolic and diastolic comparisons; nitroprusside: 226 +/- 4/145 +/- 5 mm Hg to 171 +/- 6/108 +/- 2 mm Hg, p < 0.001 for systolic and diastolic comparisons). Results of renal function studies showed significant increases in creatinine clearance (from 39 +/- 7 mL/min to 75 +/- 16 mL/min, p < 0.05), urine flow (from 119 +/- 37 mL/h to 275 +/- 84 mL/h, p < 0.01), and sodium excretion (from 75 +/- 22 microEq/min to 227 +/- 60 microEq/min, p < 0.01) in patients with impaired renal function treated with fenoldopam. No significant changes were seen in patients treated with nitroprusside. In patients with nonimpaired renal function, blood pressure was reduced by both agents, but only patients who received fenoldopam experienced significant increases in creatinine clearance, urine flow rate, and sodium excretion. CONCLUSION Fenoldopam, but not nitroprusside, improved renal function in severely hypertensive patients at all levels of baseline renal function while lowering blood pressure. Because of these effects, fenoldopam may be particularly useful in treating severely hypertensive patients with impaired renal function.
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MESH Headings
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/therapeutic use
- Adult
- Creatinine/metabolism
- Female
- Fenoldopam
- Hemodynamics/drug effects
- Humans
- Hypertension/complications
- Hypertension/drug therapy
- Hypertension/physiopathology
- Kidney/drug effects
- Kidney/physiology
- Kidney Function Tests
- Male
- Middle Aged
- Nitroprusside/pharmacology
- Nitroprusside/therapeutic use
- Renal Insufficiency/complications
- Renal Insufficiency/drug therapy
- Renal Insufficiency/metabolism
- Renal Insufficiency/physiopathology
- Severity of Illness Index
- Vasodilator Agents/pharmacology
- Vasodilator Agents/therapeutic use
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Affiliation(s)
- N H Shusterman
- SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939
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27
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Hill AJ, Feneck RO, Walesby RK. A comparison of fenoldopam and nitroprusside in the control of hypertension following coronary artery surgery. J Cardiothorac Vasc Anesth 1993; 7:279-84. [PMID: 8100152 DOI: 10.1016/1053-0770(93)90005-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
A prospective trial to compare the effects of the synthetic dopaminergic (DA1) agonist, fenoldopam (FEN), with sodium nitroprusside (SNP) for control of blood pressure following coronary artery bypass graft surgery was carried out in 20 patients. Patients were randomly allocated to receive either FEN or SNP when the systolic arterial blood pressure (SAP) rose above 130 mmHg. The goal of therapy was to achieve a stable control of blood pressure below 130 mmHg at a level at least 25 mmHg below the pretreatment value. Treatment was then continued for 2 hours. Hemodynamic measurements were made before treatment, after stable control of blood pressure had been achieved, and thereafter at 30, 60, and 120 minutes. Urine output, sodium, potassium, and creatinine clearance were also measured during the study. Both SNP and FEN caused a rapid and significant fall in SAP (P < 0.001) and a fall in systemic vascular resistance (P < 0.001). FEN caused an increase in cardiac index (P < 0.001) and in stroke volume (P < 0.001) in contrast to SNP. Urine output and potassium clearance fell with SNP (P < 0.05) in contrast to FEN. Thus, FEN would appear to control SAP as effectively as SNP, but may have more beneficial effects on cardiac output and some aspects of renal function.
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Affiliation(s)
- A J Hill
- Department of Anesthesia, London Chest Hospital, England
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28
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Pilmer BL, Green JA, Panacek EA, Elliot WJ, Murphy MB, Rutherford W, Nara AR. Fenoldopam mesylate versus sodium nitroprusside in the acute management of severe systemic hypertension. J Clin Pharmacol 1993; 33:549-53. [PMID: 8103527 DOI: 10.1002/j.1552-4604.1993.tb04702.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Thirty-three patients with severe systemic hypertension defined as a diastolic blood pressure (DBP) > or = 120 mm Hg were randomized in a single-blind fashion to be treated with either intravenous fenoldopam mesylate (FNP) or sodium nitroprusside (NTP). Fenoldopam mesylate and NTP infusion rates began at 0.1 microgram/kg/minute and 0.5 microgram/kg/minute, respectively and were titrated to achieve a goal DBP of between 95 and 110 mm Hg; or a reduction of at least 40 mm Hg if the baseline DBP was > 150 mm Hg. Fenoldopam mesylate (n = 15) reduced blood pressure from 217/145 +/- 6/5 to 187/112 +/- 6/3 mm Hg (P < .001) at an average infusion rate of 0.5 +/- 0.1 microgram/kg/minute. The average time to achieve goal DBP with FNP was 1.5 +/- 1.4 hours. Nitroprusside (n = 18) reduced blood pressure from 210/136 +/- 5/2 to 172/103 +/- 6/2 mm Hg (P < .001) at an average infusion rate of 1.2 +/- .24 micrograms/kg/minute. Nitroprusside response time averaged 2 +/- 2.5 hours. There was no significant difference between the magnitude of effect seen with either FNP or NTP; nor was there any difference observed in the adverse effect rates of the two agents. Fenoldopam mesylate and NTP demonstrate similar overall efficacy in the treatment of severe systemic hypertension.
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Affiliation(s)
- B L Pilmer
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio
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29
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Effects of intravenous fenoldopam (SK&F 82526-J) on blood pressure in severe hypertension. Cardiovasc Drugs Ther 1992; 6:445-6. [DOI: 10.1007/bf00054195] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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30
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Jorkasky DK, Audet P, Shusterman N, Ilson B, Dafoe D, Hedrich D, Stote RM. Fenoldopam Reverses Cyclosporine-Induced Renal Vasoconstriction in Kidney Transplant Recipients. Am J Kidney Dis 1992; 19:567-72. [PMID: 1350709 DOI: 10.1016/s0272-6386(12)80836-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Cyclosporine causes renal vasoconstriction and reduced renal blood flow that may contribute to chronic nephrotoxicity. This effect has not been consistently reversed by available pharmacologic agents. The efficacy of orally administered fenoldopam, a dopamine-1 (DA-1) agonist with renal vasodilator properties, was evaluated in six patients whose condition was stable 3 to 6 months following renal transplantation. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and p-aminohippurate (PAH) clearances, respectively, at baseline, after the acute oral administration of 100 mg of fenoldopam, and following 3 weeks of chronic oral fenoldopam therapy (100 mg thrice daily). Mean ERPF increased from 3.15 +/- 0.17 mL/s/1.73 m2 (189 +/- 10 mL/min/1.73 m2) at baseline to 3.48 +/- 0.17 mL/s/1.73 m2 (209 +/- 10 mL/min/1.73 m2) 4 hours after acute administration of fenoldopam (P = 0.04). Urine flow rate and fractional excretion of sodium also increased after acute administration, but not significantly. Mean systolic (SBP) and diastolic blood pressure (DBP) decreased maximally by 18 and 6 mm Hg, respectively, and mean pulse rate increased maximally by 8 bpm between 75 and 90 minutes after both acute and chronic administration. GFR was unchanged following both acute and chronic administration. The increase in ERPF was not maintained to the end of the dosing interval during chronic administration, probably due to the short half-life of fenoldopam. However, the renal vasodilatory response was still observed 3 to 4 hours after readministration of the drug following 3 weeks of oral dosing. Thus, fenoldopam significantly reverses the renal vasoconstriction caused by cyclosporine in renal transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)
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MESH Headings
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/administration & dosage
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/therapeutic use
- Administration, Oral
- Adult
- Cyclosporine/adverse effects
- Cyclosporine/antagonists & inhibitors
- Cyclosporine/therapeutic use
- Dopamine Agents/administration & dosage
- Dopamine Agents/therapeutic use
- Fenoldopam
- Glomerular Filtration Rate/drug effects
- Humans
- Immunosuppression Therapy
- Kidney Transplantation/physiology
- Male
- Renal Circulation/drug effects
- Vasoconstriction/drug effects
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Affiliation(s)
- D K Jorkasky
- Presbyterian Medical Center of Philadelphia, PA 19104
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31
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Hackman BB, Griffin B, Mills M, Ramanathan KB. Comparative effects of fenoldopam mesylate and nitroprusside on left ventricular performance in severe systemic hypertension. Am J Cardiol 1992; 69:918-22. [PMID: 1347965 DOI: 10.1016/0002-9149(92)90793-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
To compare the effects of fenoldopam (n = 15), a selective dopamine-1 agonist, and nitroprusside (n = 14) on left ventricular (LV) function in severely hypertensive subjects (diastolic blood pressure (BP) greater than 120 mm Hg), both agents were infused to reduce diastolic BP by 40 mm Hg (or less than 110 mm Hg). Indexes of LV systolic and diastolic functions were obtained using gated radionuclide angiography before the initiation of treatment and after targeted BP was achieved. Both fenoldopam and nitroprusside effectively reduced systolic and diastolic BP to target levels. Changes in heart rate, peak filling rate and relative end-diastolic volume were similar with both agents. Baseline ejection fraction increased after infusion of both drugs. The magnitude of the increase in ejection fraction was far greater with fenoldopam than with nitroprusside (+22% vs +8%; p = 0.04), despite a lesser reduction in systolic BP (-12 vs -22%, p = 0.002). Furthermore, the reduction in relative end-systolic volume (-35 vs -20%; p = 0.04), and increase in the ratio of peak systolic pressure to relative end-systolic volume (+43 vs +6%; p = 0.007) were greater after fenoldopam than after nitroprusside. The greater increment in parameters of LV systolic function produced by fenoldopam than by nitroprusside suggests an effect on LV performance that is independent of afterload reduction.
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MESH Headings
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/therapeutic use
- Adult
- Analysis of Variance
- Blood Pressure/drug effects
- Chi-Square Distribution
- Female
- Fenoldopam
- Heart Rate/drug effects
- Humans
- Hypertension/diagnostic imaging
- Hypertension/drug therapy
- Infusions, Intravenous
- Male
- Middle Aged
- Nitroprusside/pharmacology
- Nitroprusside/therapeutic use
- Radionuclide Ventriculography
- Vasodilator Agents/pharmacology
- Vasodilator Agents/therapeutic use
- Ventricular Function, Left/drug effects
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Affiliation(s)
- B B Hackman
- Department of Medicine, University of Tennessee Center for the Health Sciences, Memphis
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32
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Elliott WJ, Weber RR, Nelson KS, Oliner CM, Fumo MT, Gretler DD, McCray GR, Murphy MB. Renal and hemodynamic effects of intravenous fenoldopam versus nitroprusside in severe hypertension. Circulation 1990; 81:970-7. [PMID: 1968368 DOI: 10.1161/01.cir.81.3.970] [Citation(s) in RCA: 98] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The renal and hemodynamic effects of intravenously administered fenoldopam mesylate, a novel dopamine-1 receptor agonist, were compared with those of sodium nitroprusside in 28 patients (18 male; 26 black, two white; average age, 49 +/- 3 years) with an average blood pressure of 219/137 mm Hg, most of whom presented with acute target organ damage. Fenoldopam and nitroprusside lowered blood pressure safely to an average pressure of 176/105 mm Hg; highly significant dose-response relations were found for the 13 patients receiving fenoldopam and the 15 receiving nitroprusside. Volume and sodium, potassium, and creatinine concentrations were measured in freely voided urine specimens both before and during intravenous therapy. In the fenoldopam-treated patients, there were significant increases in urinary flow (92 +/- 21 to 168 +/- 37 ml/hr, p less than 0.003), sodium excretion (227 +/- 73 to 335 +/- 90 mu eq/min, p less than 0.001), and creatinine clearance (70 +/- 11 to 93 +/- 13 ml/hr, p less than 0.003). In the nitroprusside-treated group, however, all these parameters decreased, but not significantly. For direct comparison of the two agents, the increments in urinary flow rate (+76 +/- 20 vs. -16 +/- 15 ml/hr, fenoldopam vs. nitroprusside), sodium excretion (+109 +/- 28 vs. -39 +/- 28 mu eq/min), and creatinine clearance (+23 +/- 6 vs. -11 +/- 7 ml/min) were significantly greater (p less than 0.001 for each) in the fenoldopam-treated group. Significant differences were also obtained when these parameters were calculated as percentage increase over baseline. Fenoldopam and nitroprusside are effective therapies for severe, accelerated, or malignant hypertension, but fenoldopam had additional salutary renal effects in these patients.
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MESH Headings
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives
- 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/therapeutic use
- Dopamine Agents/therapeutic use
- Dose-Response Relationship, Drug
- Female
- Fenoldopam
- Ferricyanides/therapeutic use
- Hemodynamics/drug effects
- Humans
- Hypertension/drug therapy
- Hypertension, Malignant/drug therapy
- Kidney/drug effects
- Kidney Function Tests
- Male
- Middle Aged
- Nitroprusside/therapeutic use
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Affiliation(s)
- W J Elliott
- Committee on Clinical Pharmacology, University of Chicago, IL 60637
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33
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Bednarczyk EM, White WB, Munger MA, Gonzalez FM, Panacek EA, Weed SG, Rutherford WF, Nara AR, Green JA. Comparative acute blood pressure reduction from intravenous fenoldopam mesylate versus sodium nitroprusside in severe systemic hypertension. Am J Cardiol 1989; 63:993-6. [PMID: 2564726 DOI: 10.1016/0002-9149(89)90157-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- E M Bednarczyk
- Division of Cardiology, University Hospitals of Cleveland, Ohio 44106
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