Dopamine, the kidney, and hypertension.
ABSTRACT There is increasing evidence that the intrarenal dopaminergic system plays an important role in the regulation of blood pressure, and defects in dopamine signaling appear to be involved in the development of hypertension. Recent experimental models have definitively demonstrated that abnormalities in intrarenal dopamine production or receptor signaling can predispose to salt-sensitive hypertension and a dysregulated renin-angiotensin system. In addition, studies in both experimental animal models and in humans with salt-sensitive hypertension implicate abnormalities in dopamine receptor regulation due to receptor desensitization resulting from increased G-protein receptor kinase 4 (GRK4) activity. Functional polymorphisms that predispose to increased basal GRK4 activity both decrease dopamine receptor activity and increase angiotensin II type 1 (AT1) receptor activity and are associated with essential hypertension in a number of different human cohorts.
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ABSTRACT: Exogenous dopamine inhibits insulin secretion from pancreatic β-cells, but the lack of dopaminergic neurons in pancreatic islets has led to controversy regarding the importance of this effect. Recent data, however, suggest a plausible physiologic role for dopamine in the regulation of insulin secretion. We review the literature underlying our current understanding of dopaminergic signaling that can down-regulate glucose-stimulated insulin secretion from pancreatic islets. In this negative feedback loop, dopamine is synthesized in the β-cells from circulating l-dopa, serves as an autocrine signal that is cosecreted with insulin, and causes a tonic inhibition on glucose-stimulated insulin secretion. On the whole animal scale, l-dopa is produced by cells in the gastrointestinal tract, and its concentration in the blood plasma increases following a mixed meal. By reviewing the outcome of certain types of bariatric surgery that result in rapid amelioration of glucose tolerance, we hypothesize that dopamine serves as an "antiincretin" signal that counterbalances the stimulatory effect of glucagons-like peptide 1.Molecular Endocrinology 06/2013; · 4.20 Impact Factor
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ABSTRACT: Salt sensitivity of blood pressure, whether in hypertensive or normotensive subjects, is associated with increased cardiovascular risk and overall mortality. Salt sensitivity can be treated by reducing NaCl consumption. However, decreasing salt intake in some may actually increase cardiovascular risk, including an increase in blood pressure, that is, inverse salt sensitivity. Several genes have been associated with salt sensitivity and inverse salt sensitivity. Some of these genes encode proteins expressed in the kidney that are needed to excrete a sodium load, for example, dopamine receptors and their regulators, G protein-coupled receptor kinase 4 (GRK4). We review here research in this field that has provided several translational opportunities, ranging from diagnostic tests to gene therapy, such as (1) a test in renal proximal tubule cells isolated from the urine of humans that may determine the salt-sensitive phenotype by analyzing the recruitment of dopamine D1 receptors to the plasma membrane; (2) the presence of common GRK4 gene variants that are not only associated with hypertension but may also be predictive of the response to antihypertensive therapy; (3) genetic testing for polymorphisms of the dopamine D2 receptor that may be associated with hypertension and inverse salt sensitivity and may increase the susceptibility to chronic kidney disease because of loss of the antioxidant and anti-inflammatory effects of the renal dopamine D2 receptor, and (4) in vivo renal selective amelioration of renal tubular genetic defects by a gene transfer approach, using adeno-associated viral vectors introduced to the kidney by retrograde ureteral infusion.Translational Research 07/2014; · 4.04 Impact Factor
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ABSTRACT: Vascular smooth muscle cells (VSMCs) proliferation and migration, which are central in the development of vascular diseases, are regulated by numerous hormones and humoral factors. Activation of the insulin receptor stimulates VSMCs proliferation while dopamine receptors, via D1 and D3 receptors, inhibit the stimulatory effects of norepinephrine on VSMCs proliferation. We hypothesize that activation of the D4 dopamine receptor may also inhibit the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. Our current study found that insulin increased the proliferation and migration of A10 cells, an effect that was reduced in the presence of a D4 receptor agonist, PD168077. The negative effect of the D4 receptor on insulin's action may be via decreasing insulin receptor expression, because activation of the D4 receptor inhibited insulin receptor protein and mRNA expressions, indicating that the regulation occured at the transcriptional or post-transcriptional levels. To determine whether or not the inhibition of D4 receptor on insulin-mediated proliferation and migration of VSMCs has physiological significance, hyper-insulinemic Sprague-Dawley rats with balloon-injured carotid artery were treated with a D4 agonist, PD168077, (6 mg/kg/d) for 14 days. We found that PD168077 significantly inhibited neointimal formation by inhibition of VSMC proliferation. This study suggests that activation of the D4 receptor suppresses the proliferation and migration of VSMCs, therefore, inhibit atherosclerosis. The D4 receptor may be a potential therapeutic target to reduce the effects of insulin on artery remodeling.Cardiovascular Diabetology 06/2014; 13(1):97. · 3.71 Impact Factor