D3 Dopamine Receptor and Essential Hypertension

Abstract

Dopamine receptors are expressed in a number of organs and tissues; the peripheral dopamine receptors influence cardiovascular and renal function by decreasing preload and afterload and by regulating fluid and electrolyte transport. Most of the knowledge on these actions of dopamine has been garnered from studies of D 1 -like dopamine receptors. The D 3 dopamine receptor subtype, which belongs to the D 2 -like receptor subfamily, has been extensively studied in the neurosciences. Recently, the peripheral actions of the D 3 receptor have also raised considerable interest. Previous studies showed that the D 3 receptor is expressed in organs outside the central nervous system such as the kidneys and blood vessels. Activation of the D 3 receptor, alone or in synergism with D 1 receptor induces diuresis and natriuresis and dilates resistance vessels. The D 3 receptor also interacts positively with endothelin type B receptors and negatively with the renin-angiotensin-aldosterone system. For example, the D 3 receptor-mediated natriuresis can be blocked by ETB receptor antagonists and stimulation of the D 3 receptor decreases AT 1 receptor expression in renal proximal tubule cells and inhibits renin and aldosterone secretion. The high blood pressure observed in spontaneously hypertensive rats and D 3 receptor deficient mice, may, in part, be caused by impaired D 3 receptor-mediated renal sodium excretion, impaired interaction with D 1 and ETB receptors and impaired inhibition of the renin-angiotensin-aldosterone system. In this review, we examine the role of the peripheral D 3 receptor in the regulation of renal sodium excretion and vascular resistance, and its interaction with the renin-angiotensin system and other dopamine receptor subtypes. We also present our current understanding of the role of D 3 receptor in the pathophysiology of human essential hypertension.

Potential Dopamine-1 Receptor Stimulation in Hypertension Management

“…During conditions of moderate sodium balance, more than 50% of renal sodium excretion is regulated by endogenously produced dopamine via D1-like receptors [2,3,[36][37][38]. Although the natriuresis induced by exogenously administered D1-like receptor agonists is caused by both an increase in renal blood flow and a decrease in sodium transport, endogenous dopamine can exert its natriuretic effect independent of renal blood flow [36].…”

“…Dopamine acting on dopamine receptors is now recognized as important in the regulation of systemic blood pressure [1][2][3][4], which is achieved by direct action of dopamine on arterial and venous vessels to alter renal hemodynamics, and in regulating fluid and electrolyte balance via effects on renal and gastrointestinal epithelial ion transport [1][2][3][4]. The affinity of dopamine for its receptors ranges from the low nanomolar to the low micromolar level.…”

“…At higher concentrations, dopamine also stimulates α-adrenergic, β-adrenergic, and serotonin receptors. Although circulating concentrations of dopamine (picomolar range) are not sufficiently high to activate dopamine receptors, a high nanomolar to micromolar range can be attained in dopamine-producing tissues [1][2][3].…”

“…D1, but not D5, also couples to Gαq and stimulates phospholipase C [7][8][9][10]. The D2-like receptors are composed of the D2, D3, and D4 receptor subtypes, which couple to the inhibitory G proteins Gi and Go and modulate ion channel activity, inhibit adenylate cyclase activity, or both [1][2][3][4]. Each subtype has been implicated in the regulation of renal sodium transport and blood pressure control, and members of both classes are expressed in the kidney [11].…”

“…All of the dopamine receptor subtypes have been shown to directly or indirectly regulate renal sodium transport (in the proximal and distal nephron) and blood pressure [1][2][3][4]. The aim of this review is to present experimental evidence in the light of recent findings that D1-like receptors, especially D1 receptors, are a major regulator of blood pressure either by themselves or by interaction with other blood pressure regulating systems.…”