Renal dopaminergic system: Pathophysiological implications and clinical perspectives

Table 1 Renal dopaminergic system impairment in experimental hypertension

Animal experimental model	Renal dopaminergic system impairment	Principal findings	Ref.
Spontaneously hypertensive rats	D1-like receptor function impairment caused by a defective coupling of the receptor with AC	Increased sodium reabsorption as a mechanism of hypertension	Ohbu et al[61]
Dahl salt-sensitive rats	D1-like receptor function impairment caused by a defective coupling of the receptor with AC	Prehypertensive Dahl salt-sensitive rats exhibit a blunted natriuretic response to dopamine compared with Dahl salt-resistant rats	Nishi et al[62]
DOCA salt-sensitive rats	Decreased renal dopamine production	Renal dopaminergic system is dominantly supressed in this model of hypertension	Iimura et al[63]
Dopamine receptor knockout mice	Defective D1-D2 like receptor/signal transduction	Impaired D1 and D2-like receptor signal pathway associated with development of hypertension	Banday et al[64] Zeng et al[65] Albrecht et al[66]
C57BL/6 mice	D1-like receptor function impairment associated with increased expression of GRK4 upon salt loading	Impaired ability to excrete a salt load with a resultant increase in blood pressure levels	Escano et al[67]
Mice with selective proximal tubule AADC deletion	Deletion of the kidney’s ability to generate dopamine is associated with unbuffered response to angiotensin II that leads to hypertension and decreased longevity in mice	Increased expression of tubular sodium transporters, decreased natriuresis and diuresis in response to L-Dopa, decreased medullary COX-2 expression and urinary prostaglandin E2 excretion, increased renin and AT1 receptor expression, decreased AT2 and Mas receptor expression, and finally salt-sensitive hypertension.	Zhang et al[42]
Old FBN rats	Reduction of G-protein coupling in response to D1R activation associated with exaggerated AT1 receptor activity	Increase of oxidative stress	Chugh et al[68]
Renalase knockout mice	Alteration of urinary dopamine concentration in luminal fluid and proximal tubular transport	Impaired sodium excretion with increased blood pressure	Desir[18]
3/4 nephrectomized (3/4nx) rats	Decrease in urinary levels of dopamine and in renal AADC activity	A reduction in the natriuretic response to volume expansion with a time-dependent increase in both systolic and diastolic blood pressure	Moreira-Rodrigues et al[69]
Obese Zucker rats	Decrease in D1-like dopamine receptor binding sites and diminished activation of G proteins	Overproduction of ROS	Hussain et al[70]

GRK4: G protein receptor kinase 4; D1R: Dopamine receptor subtype 1; COX-2: Cyclooxygenase type 2; AT1: Angiotensin II receptor subtype 1; AT2: Angiotensin II receptor subtype 2; ROS: Reactive oxygen species; AC: Adenylate cyclase; FBN: Fischer 344 x Brown Norway F1.

Table 2 Clinical studies providing evidence against/in support of clinical use of low dose dopamine

	Study design	Results	Ref.
Against clinical use of low dose dopamine	The Australian and New Zealand Intensive Care Society (ANZICS): multicenter, randomized, double-blind, placebo-controlled	324 patients with at least two criteria for the systemic inflammatory response syndrome and clinical evidence of early renal dysfunction: continuous intravenous infusion of low-dose dopamine (2 µg/kg per minute) did not attenuate the peak serum creatinine compared with placebo. There was no statistical difference in mortality between dopamine and placebo arms	Bellomo et al[119]
	Meta-analysis study: 17 studies were randomized clinical trials (n = 854)	Low dose dopamine administration did not prevent mortality or the onset of acute renal failure, or the need for haemodialysis in clinically ill patients	Kellum and M Decker[120]
	Meta-analysis study: 15 randomized controlled studies	Dopamine administration did not present beneficial results in terms of serum creatinine changes and incidence of acute renal failure in clinically ill patients	Marik[121]
	Sepsis Occurrence in Acutely Ill Patients (SOAP): Cohort, multiple-center, observational study	Dopamine administration in shock patients, compared to patients who did not receive it, was associated with 20% increase in ICU and hospital mortality rates	Sakr et al[122]
	Renal Optimization Strategies Evaluation (ROSE) study: multicenter, double-blind, placebo-controlled randomized clinical trial	Low dose dopamine (2 µg/kg per minute) did not enhance decongestion or improved renal function when added to diuretic therapy in 360 patients with acute heart failure and renal dysfunction	Chen et al[123]
In support of clinical use of low dose dopamine	Dopamine in Acute Decompensated Heart Failure (DAD-HF) Trial: randomized clinical trial	The addition of low-dose dopamine (5 μg/kg per minute) to low-dose furosemide (5 mg/h) was associated with improvement in renal function profile and potassium homeostasis at 24 h and it was equally effective as high-dose furosemide (20 mg/h) alone on subjective perception of dyspnoea in 60 patients with acute decompensated heart failure	Giamouzis et al[124]
	Retrospective clinical study	Continuous infusion of furosemide in addition to low-dose dopamine compared to intermittent boluses of furosemide was less nephrotoxic and carried a lower readmission rate at 30 d in 116 patients with acute decompensated heart failure	Aziz et al[125]
	A prospective single-center randomized double-blind placebo controlled trial	The treatment with high-dose fenoldopam at 1 μg/kg per minute (short-acting D1 agonist) during cardiopulmonary bypass in 80 pediatric patients undergoing cardiac surgery for congenital heart disease significantly decreased urinary biomarkers of acute kidney injury (urinary neutrophil gelatinase-associated lipocaline and cystatin C levels) and also reduced the incidence of acute kidney injury in the postoperative period and the use of diuretics and vasodilators	Ricci et al[126]
	Clinical case finding	Low doses of ANP (0.0125 μg/kg per minute) with low dose dopamine (1.0 μg/kg per minute) in acute decompensated heart failure increased urine output, decreased heart rate, improved congestion with a reduced brain natriuretic peptide level, reduced serum creatinine and the levels of urinary liver-type fatty acid binding protein -a novel reno-tubular stress marker- and 8-hydroxydeoxyguanosine -an oxidative stress marker	Kamiya[127]
	Prospective randomized clinical study	Low dose dopamine infusion reduces renal tubular injury following cardiopulmonary bypass in 48 patients with normal or near normal baseline renal function	Sumeray et al[128]