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Klemcke HG, Calderon ML, Ryan KL, Xiang L, Hinojosa-Laborde C. Effects of extremity trauma on physiological responses to hemorrhage in conscious rats. J Appl Physiol (1985) 2023; 134:203-215. [PMID: 36519571 PMCID: PMC9829477 DOI: 10.1152/japplphysiol.00191.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 12/09/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
Although physiological responses to hemorrhage are well-studied, hemorrhage is often accompanied by trauma, and it remains unclear how injury affects these responses. This study examined effects of extremity trauma on cardiorespiratory responses and survival to moderate (37%; H-37) or severe (50%; H-50) hemorrhage in rats. Transmitter and carotid catheter implantation and extremity trauma (fibular fracture and muscle injury) were conducted 2 wk, 24 h, and 90 min, respectively, before conscious hemorrhage. Mean arterial pressure (MAP) and heart rate (HR; via telemetry), and respiration rate (RR), minute volume (MV), and tidal volume (TV; via plethysmography) were measured throughout the 25 min hemorrhage and remainder of the 4 h observation period. There were four groups: 1) H-37, no trauma (NT; n = 17); 2) H-37, extremity trauma (T, n = 18); 3) H-50, NT (n = 20); and 4) H-50, T (n = 20). For H-37, during and after hemorrhage, T increased HR (P ≤ 0.031) and MV (P ≤ 0.048) compared with NT rats. During H-50, T increased HR (0.041) and MV (P = 0.043). After hemorrhage, T increased MV (P = 0.008) but decreased HR (P = 0.007) and MAP (P = 0.039). All cardiorespiratory differences between T and NT groups were intermittent. Importantly, both survival time (159.8 ± 78.2 min vs. 211.9 ± 60.3 min; P = 0.022; mean ± SD) and percent survival (45% vs. 80%; P = 0.048) were less in T versus NT rats after H-50. Trauma interacts with physiological systems in a complex manner and no single cardiorespiratory measure was sufficiently altered to indicate that it alone could account for increased mortality after H-50.NEW & NOTEWORTHY In both civilian and military settings, severe hemorrhage rarely occurs in the absence of tissue trauma, yet many animal models for the study of hemorrhage do not include significant tissue trauma. This study using conscious unrestrained rats clearly demonstrates that extremity trauma worsens the probability of survival after a severe hemorrhage. Although no single cardiorespiratory factor accounted for the increased mortality, multiple modest time-related cardiorespiratory responses to the trauma were observed suggesting that their combined dysfunction may have contributed to the reduced survival.
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Affiliation(s)
- Harold G Klemcke
- US Army Institute of Surgical Research, Joint Base San Antonio-Fort Sam Houston, San Antonio, Texas
| | - Mariam L Calderon
- US Army Institute of Surgical Research, Joint Base San Antonio-Fort Sam Houston, San Antonio, Texas
| | - Kathy L Ryan
- US Army Institute of Surgical Research, Joint Base San Antonio-Fort Sam Houston, San Antonio, Texas
| | - Lusha Xiang
- US Army Institute of Surgical Research, Joint Base San Antonio-Fort Sam Houston, San Antonio, Texas
| | - Carmen Hinojosa-Laborde
- US Army Institute of Surgical Research, Joint Base San Antonio-Fort Sam Houston, San Antonio, Texas
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2
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Khodadadi F, Ketabchi F, Khodabandeh Z, Tavassoli A, Lewis GF, Bahaoddini A. The effect of subdiaphragmatic vagotomy on heart rate variability and lung inflammation in rats with severe hemorrhagic shock. BMC Cardiovasc Disord 2022; 22:181. [PMID: 35439928 PMCID: PMC9020113 DOI: 10.1186/s12872-022-02594-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/28/2022] [Indexed: 11/10/2022] Open
Abstract
Background The influence of cutting the sub-diaphragmatic branch of the vagus nerve on heart rate variability (HRV) and inflammatory reaction to severe hemorrhagic shock has not been determined prior to this study. Methods Male Sprague–Dawley rats were divided into four groups of Sham, sub-diaphragmatic vagotomized (Vag), subacute (135 ± 2 min) hemorrhagic shock (SHS), and sub-diaphragmatic vagotomized with SHS (Vag + SHS). Hemodynamic parameters were recorded and HRV calculated during multiple phases in a conscious model of hemorrhagic shock. The expressions of TNF-α and iNOS were measured in the spleen and lung tissues at the conclusion of the protocol. Results Decreases in blood pressure during blood withdrawal were identical in the SHS and Vag + SHS groups. However, heart rate only decreased in the Nadir-1 phase of the SHS group. HRV indicated increased power in the very-low, low, and high (VLF, LF, and HF) frequency bands during the Nadir-1 phase of the SHS and Vag + SHS groups, albeit the values were higher in the SHS group. In the recovery phase, the HF bands were only lower in the SHS group. After hemorrhagic shock followed by resuscitation, the expression of TNF-α and iNOS increased in the spleen and lung of the SHS group, and the expression of these genes was significantly lower in the Vag + SHS group than in the SHS group. Conclusion Parasympathetic activity increases during the hypotensive phase of hemorrhagic shock, whereas the cardiac vagal tone decreases in the recovery phase. Sub-diapragmatic vagotomy blunts the cardiac vagal tone during hemorrhagic shock, but its effect is reversed in the recovery phase. The vagus nerve plays a role in proinflammatory responses in the lungs and spleen in subacute hemorrhagic shock followed by resuscitation.
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Affiliation(s)
- Fateme Khodadadi
- Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
| | - Farzaneh Ketabchi
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Khodabandeh
- Stem Cell Technology Research Center, Shiraz University of Medical Science, Shiraz, Iran
| | - Alireza Tavassoli
- Department of Pathology, Fasa University of Medical Sciences, Fasa, Iran
| | - Gregory F Lewis
- Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA.,The Traumatic Stress Research Consortium at the Kinsey Institute, Indiana University, Bloomington, IN, USA
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N-Methyl-D-aspartate Glutamate Receptor Modulates Cardiovascular and Neuroendocrine Responses Evoked by Hemorrhagic Shock in Rats. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1156031. [PMID: 34423030 PMCID: PMC8378978 DOI: 10.1155/2021/1156031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/12/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022]
Abstract
Here, we report the participation of N-methyl-D-aspartate (NMDA) glutamate receptor in the mediation of cardiovascular and circulating vasopressin responses evoked by a hemorrhagic stimulus. In addition, once NMDA receptor activation is a prominent mechanism involved in nitric oxide (NO) synthesis in the brain, we investigated whether control of hemorrhagic shock by NMDA glutamate receptor was followed by changes in NO synthesis in brain supramedullary structures involved in cardiovascular and neuroendocrine control. Thus, we observed that intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK801, 0.3 mg/kg) delayed and reduced the magnitude of hemorrhage-induced hypotension. Besides, hemorrhage induced a tachycardia response in the posthemorrhage period (i.e., recovery period) in control animals, and systemic treatment with MK801 caused a bradycardia response during hemorrhagic shock. Hemorrhagic stimulus increased plasma vasopressin levels during the recovery period and NMDA receptor antagonism increased concentration of this hormone during both the hemorrhage and postbleeding periods in relation to control animals. Moreover, hemorrhagic shock caused a decrease in NOx levels in the paraventricular nucleus of the hypothalamus (PVN), amygdala, bed nucleus of the stria terminalis (BNST), and ventral periaqueductal gray matter (vPAG). Nevertheless, treatment with MK801 did not affect these effects. Taken together, these results indicate that the NMDA glutamate receptor is involved in the hemorrhagic shock by inhibiting circulating vasopressin release. Our data also suggest a role of the NMDA receptor in tachycardia, but not in the decreased NO synthesis in the brain evoked by hemorrhage.
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Convertino VA, Koons NJ, Suresh MR. Physiology of Human Hemorrhage and Compensation. Compr Physiol 2021; 11:1531-1574. [PMID: 33577122 DOI: 10.1002/cphy.c200016] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hemorrhage is a leading cause of death following traumatic injuries in the United States. Much of the previous work in assessing the physiology and pathophysiology underlying blood loss has focused on descriptive measures of hemodynamic responses such as blood pressure, cardiac output, stroke volume, heart rate, and vascular resistance as indicators of changes in organ perfusion. More recent work has shifted the focus toward understanding mechanisms of compensation for reduced systemic delivery and cellular utilization of oxygen as a more comprehensive approach to understanding the complex physiologic changes that occur following and during blood loss. In this article, we begin with applying dimensional analysis for comparison of animal models, and progress to descriptions of various physiological consequences of hemorrhage. We then introduce the complementary side of compensation by detailing the complexity and integration of various compensatory mechanisms that are activated from the initiation of hemorrhage and serve to maintain adequate vital organ perfusion and hemodynamic stability in the scenario of reduced systemic delivery of oxygen until the onset of hemodynamic decompensation. New data are introduced that challenge legacy concepts related to mechanisms that underlie baroreflex functions and provide novel insights into the measurement of the integrated response of compensation to central hypovolemia known as the compensatory reserve. The impact of demographic and environmental factors on tolerance to hemorrhage is also reviewed. Finally, we describe how understanding the physiology of compensation can be translated to applications for early assessment of the clinical status and accurate triage of hypovolemic and hypotensive patients. © 2021 American Physiological Society. Compr Physiol 11:1531-1574, 2021.
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Affiliation(s)
- Victor A Convertino
- Battlefield Healthy & Trauma Center for Human Integrative Physiology, United States Army Institute of Surgical Research, JBSA San Antonio, Texas, USA
| | - Natalie J Koons
- Battlefield Healthy & Trauma Center for Human Integrative Physiology, United States Army Institute of Surgical Research, JBSA San Antonio, Texas, USA
| | - Mithun R Suresh
- Battlefield Healthy & Trauma Center for Human Integrative Physiology, United States Army Institute of Surgical Research, JBSA San Antonio, Texas, USA
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5
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Mendonça MM, Costa AN, Moraes GCA, Martins GM, Almeida AF, Rincon GCN, Siqueira JPR, Padilha DM, Moya MI, Ferreira-Neto ML, Gomes RM, Pedrino GR, Fontes MAP, Colombari E, Crestani CC, Fajemiroye JO, Xavier CH. Centrally acting antihypertensives change the psychogenic cardiovascular reactivity. Fundam Clin Pharmacol 2021; 35:892-905. [PMID: 33465820 DOI: 10.1111/fcp.12648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/21/2020] [Accepted: 01/15/2021] [Indexed: 11/27/2022]
Abstract
Clonidine (CL) and Rilmenidine (RI) are among the most frequently prescribed centrally acting antihypertensives. Here, we compared CL and RI effects on psychogenic cardiovascular reactivity to sonant, luminous, motosensory, and vibrotactile stimuli during neurogenic hypertension. The femoral artery and vein of Wistar (WT - normotensive) and spontaneously hypertensive rats (SHR) were catheterized before (24 h interval) i.p. injection of vehicle (NaCl 0.9%, control - CT group), CL (10 µg/kg), or RI (10 µg/kg) and acute exposure to luminous (5000 lm), sonant (75 dB sudden tap), motor (180° cage twist), and air-jet (10 L/min - restraint and vibrotactile). Findings showed that: (i) CL or RI reduced the arterial pressure of SHR, without affecting basal heart rate in WT and SHR; (ii) different stimuli evoked pressor and tachycardic responses; (iii) CL and RI reduced pressor response to sound; (iv) CL or RI reduced pressor responses to luminous stimulus without a change in peak tachycardia in SHR; (v) cage twist increased blood pressure in SHR, which was attenuated by CL or RI; (vi) air-jet increased pressure and heart rate; (vii) CL or RI attenuated the pressor responses to air-jet in SHR while RI reduced the chronotropic reactivity in both strains. Altogether, both antihypertensives relieved the psychogenic cardiovascular responses to different stimuli. The RI elicited higher cardioprotective effects through a reduction in air-jet-induced tachycardia.
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Affiliation(s)
- Michelle M Mendonça
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil
| | - Amanda N Costa
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil
| | - Gean C A Moraes
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil
| | - Gustavo M Martins
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil.,School of Medicine, Federal University of Goias, Goiania, Brazil
| | - Aline F Almeida
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil.,School of Medicine, Federal University of Goias, Goiania, Brazil
| | - Gabriel C N Rincon
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil.,School of Medicine, Federal University of Goias, Goiania, Brazil
| | - João P R Siqueira
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil.,School of Medicine, Federal University of Goias, Goiania, Brazil
| | - Daniella M Padilha
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil.,School of Medicine, Federal University of Goias, Goiania, Brazil
| | - Marcela I Moya
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil.,School of Medicine, Federal University of Goias, Goiania, Brazil
| | | | - Rodrigo Mello Gomes
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil
| | | | | | - Eduardo Colombari
- School of Dentistry, São Paulo State University (UNESP), Araraquara, Brazil
| | - Carlos C Crestani
- School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil
| | - James O Fajemiroye
- Institute of Biological Sciences, Federal University of Goias, Goiania, Brazil
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Khodadadi F, Bahaoddini A, Tavassoli A, Ketabchi F. Heart rate variability and pulmonary dysfunction in rats subjected to hemorrhagic shock. BMC Cardiovasc Disord 2020; 20:331. [PMID: 32652932 PMCID: PMC7353764 DOI: 10.1186/s12872-020-01606-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 06/29/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The activity of autonomic nervous system and its association with organ damage have not been entirely elucidated in hemorrhagic shock. The aim of this study was to investigate heart rate variability (HRV) and pulmonary gas exchange in hemorrhagic shock during unilateral subdiaphragmatic vagotomy. METHODS Male Sprague Dawley rats were randomly assigned into groups of Sham, vagotomized (Vag), hemorrhagic shock (HS) and Vag + HS. HS was induced in conscious animals by blood withdrawal until reaching to mean arterial blood pressure (MAP) of 40 ± 5 mmHg. Then, it was allowed to MAP returning toward the basal values. MAP and heart rate (HR) were recorded throughout the experiments, HRV components of low (LF, sympathetic index), high (LH, parasympathetic index), and very low (VLF, injury index) frequencies and the LF/HF ratio calculated, and the lung histological and blood gas parameters assessed. RESULTS In the initial phases of HS, the increase in HR with no change in MAP were observed in both HS and Vag + HS groups, while LF increased only in the HS group. In the second phase, HR and MAP decreased sharply in the HS group, whereas, only MAP decreased in the Vag + HS group. Meanwhile, LF and HF increased relative to their baselines in the HS and Vag + HS groups, even though the values were much pronounced in the HS group. In the third phase, HR, MAP, LF, HF, and the LF/HF ratio were returned back to their baselines in both HS and Vag + HS groups. In the Vag + HS group, the VLF was lower and HR was higher than those in the other groups. Furthermore, blood gas parameters and lung histology indicated the impairment of gas exchange in the Vag + HS group. CONCLUSIONS The sympathetic activity is predominant in the first phase, whereas the parasympathetic activity is dominant in the second and third phases of hemorrhagic shock. There is an inverse relationship between the level of VLF and lung injury in vagotomized animals subjected to hemorrhagic shock.
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Affiliation(s)
- Fateme Khodadadi
- Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
| | | | - Alireza Tavassoli
- Department of Pathology, Fasa University of Medical Sciences, Fasa, Iran
| | - Farzaneh Ketabchi
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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Chen Y, Yoon JH, Pinsky MR, Ma T, Clermont G. Development of hemorrhage identification model using non-invasive vital signs. Physiol Meas 2020; 41:055010. [PMID: 32325439 PMCID: PMC7894612 DOI: 10.1088/1361-6579/ab8cb2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Early detection and timely management of bleeding is critical as failure to recognize physiologically significant bleeding is associated with significant morbidity and mortality. Many such instances are detected late, even in highly monitored environments, contributing to delay in recognition and intervention. We propose a non-invasive early identification model to detect bleeding events using continuously collected photoplethysmography (PPG) and electrocardiography (ECG) waveforms. APPROACH Fifty-nine York pigs undergoing fixed-rate, controlled hemorrhage were involved in this study and a least absolute shrinkage and selection operator regression-based early detection model was developed and tested using PPG and ECG derived features. The output of the early detection model was a risk trajectory indicating the future probability of bleeding. MAIN RESULTS Our proposed models were generally accurate in predicting bleeding with an area under the curve of 0.89 (95% CI 0.87-0.92) and achieved an average time of 16.1 mins to detect 16.8% blood loss when a false alert rate of 1% was tolerated. Models developed on non-invasive data performed with similar discrimination and lead time to hemorrhage compared to models using invasive arterial blood pressure as monitoring data. SIGNIFICANCE A bleed detection model using only non-invasive monitoring performs as well as those using invasive arterial pressure monitoring.
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Affiliation(s)
- Yang Chen
- Department of Electronic and Information Engineering, Harbin Institute of Technology at Shenzhen, Shenzhen, China
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Joo Heung Yoon
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, U.S.A
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Michael R. Pinsky
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, U.S.A
| | - Ting Ma
- Department of Electronic and Information Engineering, Harbin Institute of Technology at Shenzhen, Shenzhen, China
- Pengcheng Laboratory, Shenzhen, China
| | - Gilles Clermont
- Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, U.S.A
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Scully CG, Daluwatte C, Marques NR, Khan M, Salter M, Wolf J, Nelson C, Salsbury J, Enkhbaatar P, Kinsky M, Kramer GC, Strauss DG. Effect of hemorrhage rate on early hemodynamic responses in conscious sheep. Physiol Rep 2016; 4:4/7/e12739. [PMID: 27044850 PMCID: PMC4831318 DOI: 10.14814/phy2.12739] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 02/19/2016] [Indexed: 11/24/2022] Open
Abstract
Physiological compensatory mechanisms can mask the extent of hemorrhage in conscious mammals, which can be further complicated by individual tolerance and variations in hemorrhage onset and duration. We assessed the effect of hemorrhage rate on tolerance and early physiologic responses to hemorrhage in conscious sheep. Eight Merino ewes (37.4 ± 1.1 kg) were subjected to fast (1.25 mL/kg/min) and slow (0.25 mL/kg/min) hemorrhages separated by at least 3 days. Blood was withdrawn until a drop in mean arterial pressure (MAP) of >30 mmHg and returned at the end of the experiment. Continuous monitoring included MAP, central venous pressure, pulmonary artery pressure, pulse oximetry, and tissue oximetry. Cardiac output by thermodilution and arterial blood samples were also measured. The effects of fast versus slow hemorrhage rates were compared for total volume of blood removed and stoppage time (when MAP < 30 mmHg of baseline) and physiological responses during and after the hemorrhage. Estimated blood volume removed when MAP dropped 30 mmHg was 27.0 ± 4.2% (mean ± standard error) in the slow and 27.3 ± 3.2% in the fast hemorrhage (P = 0.47, paired t test between rates). Pressure and tissue oximetry responses were similar between hemorrhage rates. Heart rate increased at earlier levels of blood loss during the fast hemorrhage, but hemorrhage rate was not a significant factor for individual hemorrhage tolerance or hemodynamic responses. In 5/16 hemorrhages MAP stopping criteria was reached with <25% of blood volume removed. This study presents the physiological responses leading up to a significant drop in blood pressure in a large conscious animal model and how they are altered by the rate of hemorrhage.
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Affiliation(s)
- Christopher G Scully
- Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland
| | - Chathuri Daluwatte
- Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland
| | - Nicole R Marques
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas
| | - Muzna Khan
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas
| | - Michael Salter
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas
| | - Jordan Wolf
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas
| | - Christina Nelson
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas
| | - John Salsbury
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas
| | - Perenlei Enkhbaatar
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas
| | - Michael Kinsky
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas
| | - George C Kramer
- Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas
| | - David G Strauss
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
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Busnardo C, Crestani CC, Fassini A, Resstel LBM, Corrêa FMA. NMDA and non-NMDA glutamate receptors in the paraventricular nucleus of the hypothalamus modulate different stages of hemorrhage-evoked cardiovascular responses in rats. Neuroscience 2016; 320:149-59. [PMID: 26861418 DOI: 10.1016/j.neuroscience.2016.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 01/18/2016] [Accepted: 02/01/2016] [Indexed: 10/22/2022]
Abstract
Here we report the involvement of N-Methyl-d-Aspartate (NMDA) and non-NMDA glutamate receptors from the paraventricular nucleus of the hypothalamus (PVN) in the mediation of cardiovascular changes observed during hemorrhage and post-bleeding periods. In addition, the present study provides further evidence of the involvement of circulating vasopressin and cardiac sympathetic activity in cardiovascular responses to hemorrhage. Systemic treatment with the V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP (50 μg/kg, i.v.) increased the latency to the onset of hypotension during hemorrhage and slowed post-bleeding recovery of blood pressure. Systemic treatment with the β1-adrenergic receptor antagonist atenolol (1 mg/kg, i.v.) also increased the latency to the onset of hypotension during hemorrhage. Moreover, atenolol reversed the hemorrhage-induced tachycardia into bradycardia. Bilateral microinjection of the selective NMDA glutamate receptor antagonist LY235959 (2 nmol/100 nL) into the PVN blocked the hypotensive response to hemorrhage and reduced the tachycardia during the post-hemorrhage period. Systemic treatment with dTyr(CH2)5(Me)AVP inhibited the effect of LY235959 on hemorrhage-induced hypotension, without affecting the post-bleeding tachycardia. PVN treatment with the selective non-NMDA receptor antagonist NBQX (2 nmol/100 nL) reduced the recovery of blood pressure to normal levels in the post-bleeding phase and reduced hemorrhage-induced tachycardia. Combined blockade of both NMDA and non-NMDA glutamate receptors in the PVN completely abolished the hypotensive response in the hemorrhage period and reduced the tachycardiac response in the post-hemorrhage period. These results indicate that local PVN glutamate neurotransmission is involved in the neural pathway mediating cardiovascular responses to hemorrhage, via an integrated control involving autonomic nervous system activity and vasopressin release into the circulation.
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Affiliation(s)
- C Busnardo
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
| | - C C Crestani
- School of Pharmaceutical Sciences, Univ. Estadual Paulista-UNESP, Araraquara, SP, Brazil
| | - A Fassini
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - L B M Resstel
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - F M A Corrêa
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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10
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The hemodynamic response to blood loss in the conscious rat: contributions of cardiac vagal and cardiac spinal signals. Shock 2014; 41:282-91. [PMID: 24365884 DOI: 10.1097/shk.0000000000000106] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The hemodynamic response to progressive blood loss passes through three distinct phases: an initial normotensive compensatory phase, a secondary hypotensive decompensatory phase, and a posthemorrhage recompensatory phase. The role of cardiac vagal and cardiac spinal signals in triggering the different phases of the response to hemorrhage was evaluated in the unanesthetized, freely moving rat by observing the effects on the response to 30% blood loss of prior cardiac vagal deafferentation (bilateral vagal rhizotomy) or prior cardiac spinal deafferentation (bilateral stellate ganglionectomy). In comparison to control animals, it was found that (i) cardiac spinal deafferentation significantly delayed the onset of the decompensatory phase, and (ii) cardiac vagal deafferentation slightly potentiated the decompensatory phase and impaired the recompensatory phase. These results indicate that it is cardiac spinal signals, rather than cardiac vagal signals, which in the conscious rat contribute to the triggering and progression of the decompensatory response to blood loss.
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11
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Ahlgren JK, Hayward LF. Role of lateral parabrachial opioid receptors in exercise-induced modulation of the hypotensive hemorrhage response in conscious male rats. Behav Brain Res 2012; 226:404-10. [PMID: 21985861 PMCID: PMC3221778 DOI: 10.1016/j.bbr.2011.09.036] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 09/02/2011] [Accepted: 09/26/2011] [Indexed: 01/03/2023]
Abstract
Some of the benefits of exercise appear to be mediated through modulation of neuronal excitability in central autonomic control circuits. Previously, we identified that six weeks of voluntary wheel running had a protective effect during hemorrhage (HEM), limiting both the hypotensive phase of HEM and enhancing recovery. The present study was undertaken to evaluate the role of opioid release in the lateral parabrachial nucleus (LPBN) on the response to severe HEM in chronically exercised (EX, voluntary) versus sedentary (SED) controls. Male Sprague Dawley rats were allowed either free access to running wheels (EX) or normal cage conditions (SED). After 6 weeks of "training" animals were instrumented with a bilateral cannula directed toward the dorsolateral pons and arterial catheters. After a recovery period, animals underwent central microinjection of either vehicle (VEH; n=3/group) or the opioid receptor antagonist naloxone (NAL; n=6/group) followed by withdrawal of 30% of their total estimated blood volume. Following VEH injection, the drop in MAP during and following HEM was significantly attenuated in the EX vs SED animals. Alternatively, NAL microinjection in the dorsolateral pons (20 μM, 200-500 nl) reversed the beneficial effect of EX on the HEM response. NAL microinjection in SED rats did not significantly alter the response to HEM. These data suggest chronic voluntary EX has a beneficial effect on the autonomic response to severe HEM which is mediated, in part, via EX-induced plasticity of the opioid system within the dorsolateral pons.
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Affiliation(s)
- Joslyn K Ahlgren
- University of Florida, College of Veterinary Medicine, Dept. of Physiological Sciences, Gainesville, FL 32610, United States
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Ahlgren JK, Hayward LF. Daily voluntary exercise alters the cardiovascular response to hemorrhage in conscious male rats. Auton Neurosci 2011; 160:42-52. [PMID: 21215710 PMCID: PMC3034809 DOI: 10.1016/j.autneu.2010.11.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 08/30/2010] [Accepted: 11/19/2010] [Indexed: 01/03/2023]
Abstract
The present study tested the hypothesis that voluntary wheel-exercised rats would better tolerate severe hemorrhage (HEM) compared to age matched sedentary (SED) controls. Conscious rats housed with (EX, n = 8) or without (SED, n = 8) a running wheel for 6 weeks underwent a 30% total blood volume HEM over 15 min and were euthanized 90 min later and brain tissue was processed for Fos-like immunoreactivity (FLI). Both EX and SED groups displayed typical responses to HEM (initial tachycardia followed by decreased HR and MAP) but at the end of HEM, mean arterial pressure (93 ± 6 vs 58 ± 3 mm Hg) and heart rate (316 ± 17 vs. 247 ± 22 bpm,) were higher in the EX vs. SED animals and 60 min following the end of HEM, HR remained significantly elevated in the EX vs SED animals. The altered HR response to HEM in the EX animals was linked to a significant difference in sympatho-vagal drive identified by heart rate variability analysis and an augmented baroreflex response to hypotension tested in a separate group of animals (n = 4-5/group). In many of the brain regions analyzed, EX rats displayed lower levels of FLI compared to SED rats. Significantly lower levels of FLI in the EX vs SED rats were identified in the middle and caudal external lateral subnucleus of the lateral parabrachial nucleus and the dorsal cap of the hypothalamic paraventricular nucleus. These results suggest that enhanced tolerance to HEM following daily exercise may result from an EX-induced reduction in excitation or exaggerated inhibition in central circuits involved in autonomic control.
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Affiliation(s)
- Joslyn K Ahlgren
- Department of Physiological Sciences, University of FL, Gainesville, 32610, United States
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13
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Experimental trauma models: an update. J Biomed Biotechnol 2011; 2011:797383. [PMID: 21331361 PMCID: PMC3035380 DOI: 10.1155/2011/797383] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2010] [Accepted: 12/17/2010] [Indexed: 01/31/2023] Open
Abstract
Treatment of polytrauma patients remains a medical as well as socioeconomic challenge. Although diagnostics and therapy improved during the last decades, multiple injuries are still the major cause of fatalities in patients below 45 years of age. Organ dysfunction and organ failure are major complications in patients with major injuries and contribute to mortality during the clinical course. Profound understanding of the systemic pathophysiological response is crucial for innovative therapeutic approaches. Therefore, experimental studies in various animal models are necessary. This review is aimed at providing detailed information of common trauma models in small as well as in large animals.
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Boku A, Sugimura M, Morimoto Y, Hanamoto H, Niwa H. Hemodynamic and autonomic response to acute hemorrhage in streptozotocin-induced diabetic rats. Cardiovasc Diabetol 2010; 9:78. [PMID: 21106105 PMCID: PMC3004820 DOI: 10.1186/1475-2840-9-78] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 11/25/2010] [Indexed: 02/04/2023] Open
Abstract
Background The various autonomic control systems lead to characteristic changes in heart rate (HR) and blood pressure (BP) during acute hemorrhage. However, cardiovascular autonomic neuropathy due to diabetes mellitus may interfere with the normal compensation for hemorrhage. Materials and methods A controlled graded bleeding (6 - 36% loss of estimated total blood volume: ETBV) was performed in streptozotocin-induced diabetic rats (STZ rats) under a conscious state. Hemodynamic and autonomic responses to acute hemorrhage were examined using analysis of BP-HR variability. The effects of dextran treatment after hemorrhage were also examined. Results A significant reduction in mean arterial pressure began at 12% ETBV loss in STZ rats and 18% in the control rats, respectively. When blood loss reached 18% of TEBV, the decrease in HR was prominent in STD rats due to the activation of a parasympathetic drive, as indicated by the increase in high frequency (HF; 0.75~3.0 Hz) power in HR variability, while in the control rats this response was not observed. The administration of dextran prevented the activation of the parasympathetic drive in STZ rats during hemorrhaging. In the control rats, the dextran treatment sustained the initial increase in HR with reduced HF power in HR variability. Conclusion STZ rats showed different hemodynamic and autonomic responses to acute hemorrhage from the control rats. STZ rats were prone to develop bradycardiac hypotension characterized by marked parasympathetic activation during hemorrhaging. This finding suggests enhancement of the Bezold-Jarisch reflex in STZ rats. Dextran treatment to maintain a normovolemic hemorrhage state inhibits this reflex.
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Affiliation(s)
- Aiji Boku
- Department of Dental Anesthesiology Osaka University Graduate School of Dentistry, Suita, Japan.
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15
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Porter K, Ahlgren J, Stanley J, Hayward LF. Modulation of heart rate variability during severe hemorrhage at different rates in conscious rats. Auton Neurosci 2009; 150:53-61. [PMID: 19482559 PMCID: PMC2739247 DOI: 10.1016/j.autneu.2009.04.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Revised: 04/27/2009] [Accepted: 04/28/2009] [Indexed: 10/20/2022]
Abstract
This study was undertaken to evaluate heart rate (HR) regulation during severe hemorrhage (HEM) at different rates of blood loss. Chronically instrumented male rats underwent HEM at one of three rates: slow (0.5 ml/min/kg; S-HEM), intermediate (1.0 ml/min/kg I-HEM), or 2.0 ml/min/kg (fast; F-HEM) until 30% of the estimated total blood volume (ETBV) was withdrawn. Heart rate variability analysis was performed and the absolute power within the low frequency (LF; 0.16-0.6 Hz) and high frequency (HF; 0.6-3 Hz) ranges was evaluated. During the first 15% of ETBV loss, arterial pressure (AP) was maintained while HR increased. The increase in HR was greatest in the S-HEM and I-HEM groups and was associated with a significant reduction in HF power in the S-HEM group only. As blood loss progressed, AP and HR declined in all treatment groups. The decrease in HR was associated with a significant increase in HF power in the F-HEM and I-HEM groups only. Parasympathetic blockade with atropine methyl bromide eliminated all decreases in HR, independent of the rate of hemorrhage. Blockade of parasympathetic activity also significantly increased the AP at ETBV losses > or =20% independent of the rate of hemorrhage. The effect of atropine on AP was most noticeable in the S-HEM and F-HEM groups. These results demonstrate that rate of blood loss has an important impact on autonomic regulation during severe HEM and support previous findings that neural strategies underlying autonomic control may vary depending on the rate of blood loss.
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Affiliation(s)
- Karen Porter
- Department of Physiological Sciences, University of Florida, Gainesville, FL 32610, USA
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16
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Beacher FDCC, Gray MA, Mathias CJ, Critchley HD. Vulnerability to simple faints is predicted by regional differences in brain anatomy. Neuroimage 2009; 47:937-45. [PMID: 19464376 PMCID: PMC2726440 DOI: 10.1016/j.neuroimage.2009.05.038] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2009] [Revised: 05/01/2009] [Accepted: 05/12/2009] [Indexed: 01/21/2023] Open
Abstract
Neurocardiogenic syncope (NCS, simple fainting) is a common and typically benign familial condition, which rarely may result in traumatic injury or hypoxic convulsions. NCS is associated with emotional triggers, anxiety states and stress. However, the etiology of NCS, as a psychophysiological process, is poorly understood. We therefore investigated the relationship between NCS and brain anatomy. We studied a non-clinical sample of eighteen individuals with histories characteristic of NCS, and nineteen matched controls who had never fainted. We recorded fainting frequency, resting heart rate variability measures and anxiety levels. Structural T1-weighted magnetic resonance images (MRI) were acquired at 1.5 T. Associations between brain morphometry (regional gray and white matter volumes) and NCS, resting physiology and anxiety were tested using voxel-based morphometry (VBM). Compared to controls, NCS participants had lower regional brain volume within medulla and midbrain (a priori regions of interest). Moreover, across NCS individuals, lower gray matter volume in contiguous regions of left caudate nucleus predicted enhanced parasympathetic cardiac tone, fainting frequency and anxiety levels. Our findings provide preliminary evidence for a hierarchical anatomical basis to NCS. First, differences in the volume of brainstem centers supporting cardiovascular homeostasis may relate to constitutional predisposition to NCS. Second, differences in the structural organization of the caudate nucleus in NCS individuals may relate to fainting frequency via interactions between emotional state and parasympathetic control of the heart. These observations highlight the application of VBM to the identification of neurovisceral mechanisms relevant to psychosomatic medicine and the neuroscience of emotion.
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Affiliation(s)
- Felix D C C Beacher
- Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, Brighton, BN1 9RY, UK.
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17
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Rutten M, Govindaswami M, Oeltgen P, Sonneborn JS. Post-treatment with the novel deltorphin E, a delta2-opioid receptor agonist, increases recovery and survival after severe hemorrhagic shock in behaving rats. Shock 2008; 29:42-8. [PMID: 17621254 DOI: 10.1097/shk.0b013e31805cdb70] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Deltorphin E was investigated as a pharmaceutical intervention in the ischemic hemorrhagic model. To monitor the hemodynamic biomarkers mean arterial pressure (MAP) and heart rate (HR) and to facilitate i.v. injections, rats were surgically fitted with femoral artery and vein catheters under anesthesia. After removal of 48% of total blood volume (range, 12-15 mL), posthemorrhage i.v. injections of 5.5-mg/kg deltorphin E were found to significantly (P < 0.05) increase maximum MAP, pulse pressure, and survival after hemorrhage, whereas lactic acid concentration was decreased when compared with saline injections. The results for the 5.5-mg/kg deltorphin E-treated animals versus saline controls showed the following values (expressed as mean +/- SEM): maximum MAP, 58 +/- 7 vs. 35 +/- 9 mmHg, respectively; lactic acid, 6.5 +/- 1.25 vs. 8.9 +/- 0.12 mmol/L, respectively; pulse pressure, 47.9 +/- 0.55 vs. 38.3 +/- 0.44 mmHg, respectively; and at least a fourfold increase in survival, 331 +/- 18 vs. 50 +/- 8 min, respectively. Heart rate in deltorphin E-treated groups was not significantly different from that in saline-treated groups (maximum HR, 396 +/- 40 vs. 425 +/- 94 bpm, respectively). Using logistic analysis, deltorphin E did not significantly alter the baroreflex sensitivity. However, a significant deltorphin E dose-dependent correlation was found between survival time and lactic acid production. Increased pulse pressure was also correlated with survival. Glibenclamide, a potassium-sensitive adenosine triphosphate-sensitive channel blocker, did not interfere with the positive effects of deltorphin E. Only the antagonists tested, known to affect delta(2)-opioid receptors, interfered with the deltorphin E survival benefit after hemorrhage. As a conclusion, deltorphin E is an effective pharmaceutical intervention in severe hemorrhagic shock and, perhaps, in other ischemic shock scenarios when administered after the onset of stress. Therefore, deltorphin E may have clinical potential.
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Affiliation(s)
- Mikal Rutten
- Zoology and Physiology Department Graduate Program, University of Wyoming, Laramie, Wyoming 8207, USA
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18
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Vagg DJ, Bandler R, Keay KA. Hypovolemic shock: critical involvement of a projection from the ventrolateral periaqueductal gray to the caudal midline medulla. Neuroscience 2008; 152:1099-109. [PMID: 18343586 DOI: 10.1016/j.neuroscience.2007.10.070] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2006] [Revised: 09/17/2007] [Accepted: 10/10/2007] [Indexed: 11/24/2022]
Abstract
Previous research has suggested that the ventrolateral column of the periaqueductal gray (vlPAG) plays a crucial role in triggering a decompensatory response (sympathoinhibition, hypotension, bradycardia) to severe blood loss. vlPAG excitation triggers also quiescence, decreased vigilance and decreased reactivity, the behavioral response which usually accompanies hypovolemic shock. The aim of this study was to identify, in unanesthetized rats, the main descending pathway(s) via which vlPAG neurons trigger sympathoinhibition and bradycardia in response to severe blood loss. Firstly, immediate early gene (c-Fos) expression was used to identify vlPAG neurons selectively activated by severe blood loss. Subsequently, the specific medullary projections of these vlPAG neurons were defined by combined c-Fos, retrograde tracing (double-label) experiments. It was found that vlPAG neurons selectively activated by severe hemorrhage project overwhelmingly to the vasodepressor portion of the caudal midline medulla (CMM). Previous studies indicate that this CMM region mediates behaviorally-coupled cardiovascular adjustments and the findings described here fit with the idea that CMM neurons are uniquely recruited by salient challenges, the adaptive responses to which require more than reflexive homeostatic cardiovascular adjustments.
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Affiliation(s)
- D J Vagg
- School of Medical Sciences (Anatomy and Histology), Anderson Stuart Building, The University of Sydney, NSW, Australia
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19
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Ahlgren J, Porter K, Hayward LF. Hemodynamic responses and c-Fos changes associated with hypotensive hemorrhage: standardizing a protocol for severe hemorrhage in conscious rats. Am J Physiol Regul Integr Comp Physiol 2007; 292:R1862-71. [PMID: 17218446 DOI: 10.1152/ajpregu.00325.2006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The central mechanisms underlying the transition from compensation to decompensation during severe hemorrhage (HEM) are poorly understood. Furthermore, a lack of consistency in HEM protocols exists in the current literature. This study assessed the cardiovascular response and Fos-like immunoreactivity (FLI) in specific brain regions following severe HEM at three rates (2, 1, or 0.5 ml.kg(-1).min(-1)) in conscious rats. Heart rate (HR) and arterial pressure were recorded during the withdrawal of 30% of total blood volume (TBV). Data from animals hemorrhaged at the fast (F-HEM, n = 6), intermediate (I-HEM, n = 7), or slow (S-HEM, n = 7) rates were compared with saline (SAL, n = 5) and hypotensive (hydrazaline-induced, HYDRAZ, n = 5) controls. All HEM rates produced similar degrees of hypotension at the time of 30% TBV withdrawal. All HEM rates also produced bradycardia, but the change in HR was only significant in the F-HEM and I-HEM groups. Associated with I-HEM and F-HEM, but not HYDRAZ treatment were significant increases in FLI in the caudal ventrolateral periaqueductal gray (PAG), the central lateral nucleus of the rostral parabrachial nucleus, and locus coeruleus compared with SAL treatment. I-HEM also induced significant increases in FLI in the dorsomedial PAG, A7 region, and the cuneiform nucleus compared with SAL. S-HEM did not induce any significant change in FLI. Our results suggest that HEM at a rate of 1 ml.kg(-1).min(-1) may be most useful for investigating the potential role of the rostral brainstem regions in mediating hemorrhagic decompensation in conscious rats.
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Affiliation(s)
- Joslyn Ahlgren
- Dept of Physiological Sciences, HSC, Univ of Florida, Gainesville, FL 32610, USA.
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20
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Abstract
Shock resulting from life-threatening blood loss (hemorrhage) remains a common complication of traumatic injury. Intensive experimental efforts are needed if we are to understand the pathological effect(s) of hemorrhagic shock, alone or in association with traumatic tissue injury, and to reverse this deleterious process in trauma patients. Here, we overview selected studies that are representative of the different hemorrhagic shock models, considering their advantages and disadvantages from a scientific and clinical perspective. Fixed-pressure versus fixed-volume versus uncontrolled hemorrhage models, with or without tissue injury, will be discussed, as well as small versus large animal models. Most of these models are nonlethal in nature, and allow the researcher to understand the changes that contribute to increased susceptibility to subsequent infection or the development of multiple organ failure. We also consider some of the confounders in these models, including anesthesia, the nature of resuscitation, and the use of anticoagulants. The selection of model must take into consideration not only the need for experimental control but must also adequately reflect the clinical pathobiology of shock if we are to develop better pharmacological interventions.
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Affiliation(s)
- J L Lomas-Niera
- Division of Surgical Research/Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903, USA
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21
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Brown HJ, Henderson LA, Keay KA. Hypotensive but not normotensive haemorrhage increases tryptophan hydroxylase-2 mRNA in caudal midline medulla. Neurosci Lett 2006; 398:314-8. [PMID: 16483717 DOI: 10.1016/j.neulet.2006.01.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2005] [Revised: 01/10/2006] [Accepted: 01/11/2006] [Indexed: 10/25/2022]
Abstract
Severe blood loss triggers shock, a precipitous hypotension and bradycardia. The integrity of (i) neurons in the vasodepressor region of the caudal midline medulla and (ii) central 5-HT neurotransmission are critical for the expression of haemorrhagic shock. This study investigated whether progressive blood loss triggers altered synthesis of 5-HT in the vasodepressor region of the caudal midline medulla by measuring changes in relative expression levels of tryptophan hydroxylase 2 (TpH 2) mRNA, the rate-limiting enzyme in the synthesis of neuronal 5-HT. Hypotensive but not normotensive haemorrhage triggered a significant increase in TpH 2 mRNA in the vasodepressor region of the caudal midline medulla, identifying an important role for 5-HT-containing caudal midline medullary neurons in haemorrhagic shock.
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Affiliation(s)
- Heidi J Brown
- Pain Management Research Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia
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22
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Göktalay G, Cavun S, Levendusky MC, Resch GE, Veno PA, Millington WR. Hemorrhage activates proopiomelanocortin neurons in the rat hypothalamus. Brain Res 2006; 1070:45-55. [PMID: 16403465 DOI: 10.1016/j.brainres.2005.11.076] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2005] [Revised: 11/11/2005] [Accepted: 11/12/2005] [Indexed: 11/29/2022]
Abstract
Severe blood loss lowers arterial pressure through a central mechanism that is thought to include opioid neurons. In this study, we investigated whether hemorrhage activates proopiomelanocortin (POMC) neurons by measuring Fos immunoreactivity and POMC mRNA levels in the medial basal hypothalamus. Hemorrhage (2.2 ml/100 g body weight over 20 min) increased the number of Fos immunoreactive neurons throughout the rostral-caudal extent of the arcuate nucleus, the retrochiasmatic area and the peri-arcuate region lateral to the arcuate nucleus where POMC neurons are located. Double label immunohistochemistry revealed that hemorrhage increased Fos expression by beta-endorphin immunoreactive neurons significantly. The proportion of beta-endorphin immunoreactive neurons that expressed Fos immunoreactivity increased approximately four-fold, from 11.7+/-1.4% in sham-operated control animals to 42.0+/-5.2% in hemorrhaged animals. Hemorrhage also increased POMC mRNA levels in the medial basal hypothalamus significantly, consistent with the hypothesis that blood loss activates POMC neurons. To test whether activation of arcuate neurons contributes to the fall in arterial pressure evoked by hemorrhage, we inhibited neuronal activity in the caudal arcuate nucleus by microinjecting the local anesthetic lidocaine (2%; 0.1 or 0.3 microl) bilaterally 2 min before hemorrhage was initiated. Lidocaine injection inhibited hemorrhagic hypotension and bradycardia significantly although it did not influence arterial pressure or heart rate in non-hemorrhaged rats. These results demonstrate that hemorrhage activates POMC neurons and provide evidence that activation of neurons in the arcuate nucleus plays an important role in the hemodynamic response to hemorrhage.
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Affiliation(s)
- Gökhan Göktalay
- Department of Basic and Pharmaceutical Sciences, Albany College of Pharmacy, Union University, 106 New Scotland Avenue, Albany, NY 12208-3492, USA
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Schadt JC, Shafford HL, McKown MD. Neuronal activity within the ventrolateral periaqueductal gray during simulated hemorrhage in conscious rabbits. Am J Physiol Regul Integr Comp Physiol 2005; 290:R715-25. [PMID: 16195496 DOI: 10.1152/ajpregu.00374.2004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The ventrolateral (vl) periaqueductal gray (PAG) has been proposed as a site responsible for the active process triggering the onset of hypotension (i.e., phase 2) during blood loss in conscious animals (Cavun S and Millington WR. Am J Physiol Regul Integr Comp Physiol 281: R747-R752, 2001). We recorded the extracellular activity of PAG neurons in conscious rabbits to test the hypothesis that vlPAG neurons change their firing frequency before the onset of hypotension during simulated hemorrhage. Arterial and venous catheters, an intrathoracic vena caval occluder, and midbrain microelectrodes on a microdrive were implanted in 10 rabbits. During simulated hemorrhage, the occluder was inflated until arterial pressure < or = 40 mmHg. We compared changes in neuronal activity during simulated hemorrhage with those during a similar length control period for 64 vlPAG and 29 dorsolateral (dl) PAG neurons. Arterial pressure pulse modulation of neuronal activity was present in 45 and 76% of vlPAG and dlPAG neurons, respectively. When we evaluated the absolute change in activity, thus accounting for both increases and decreases, simulated hemorrhage had a significant effect on activity of vlPAG but not dlPAG neurons. The majority (56%) of vlPAG neurons did not appear to respond to simulated hemorrhage. Of the 28 responsive vlPAG neurons, 11 showed an abrupt change in firing frequency during the time interval preceding the onset of hypotension; 13 responded after the onset of hypotension; and 4 showed a consistent direction of change across the entire simulated hemorrhage. Thus 24 (38%) of the vlPAG neurons recorded responded at a time consistent with a contribution to the hypotension associated with simulated hemorrhage.
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Affiliation(s)
- James C Schadt
- Dalton Cardiovascular Research Center and Department of Biomedical Sciences, University of Missouri, Columbia, Missouri 65211, USA.
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Jin XL, Zheng Y, Shen HM, Jing WL, Zhang ZQ, Huang JZ, Tan QL. Analysis of the mechanisms of rabbit’s brainstem hemorrhage complicated with irritable changes in the alvine mucous membrane. World J Gastroenterol 2005; 11:1610-5. [PMID: 15786536 PMCID: PMC4305940 DOI: 10.3748/wjg.v11.i11.1610] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the dynamic changes in the pressure of the lateral ventricle during acute brainstem hemorrhage and the changes of neural discharge of vagus nerve under the load of intracranial hypertension, so as to analyze their effects on the congestive degree of intestinal mucous membrane and the morphologic changes of intestinal mucous membrane.
METHODS: An operation was made to open the skull to obtain an acute brainstem hemorrhage animal model. Microcirculatory microscope photography device and video recording system were used to determine the changes continuously in the caliber of jejunal mesenteric artery during brainstem hemorrhage and the changes with time in the congestion of jejunal mucosal villi. We used HE stain morphology to analyze the changes of duodenal mucosal villi. A recording electrode was used to calculate and measure the electric discharge activities of cervical vagus nerve.
RESULTS: (1) We observed that the pressure of lateral cerebral ventricle increased transiently during acute brainstem hemorrhage; (2) The caliber of the jejunal mesenteric artery increased during brainstem hemorrhage. Analysis of red color coordinate values indicated transient increase in the congestion of jejunal mucous membrane during acute brainstem hemorrhage; (3) Through the analysis of the pathologic slice, we found enlarged blood vessels, stagnant blood, and transudatory red blood cells in the duodenal submucous layer; (4) Electric discharge of vagus nerve increased and sporadic hemorrhage spots occurred in duodenal mucous and submucous layer, when the lateral ventricle was under pressure.
CONCLUSION: Brainstem hemorrhage could cause intracranial hypertension, which would increase the neural discharge of vagus nerve and cause the transient congestion of jejunal mucous membrane. It could cause hyperemia and diffused hemorrhage in the duodenal submucous layer 48 h after brainstem hemorrhage.
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Affiliation(s)
- Xue-Long Jin
- Department of Physiology, Tianjin Medical University, Tianjin 300070, China.
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