Dopaminergic defect in hypertension

Abstract

Reverse genetics and the candidate gene approach have been utilized to identify the genetic defect(s) in hypertension. We have proposed the dopamine receptor gene as one candidate in the pathogenesis of hypertension. Because some forms of hypertension are sodium dependent or aggravated by sodium loading and because dopamine is important in aiding the organism to eliminate "excess" sodium, an abnormality in the renal dopaminergic system may be responsible for the sodium retention in hypertension. Both human and animal models of hypertension are associated with renal dopamine production and/or post first messenger defects. The Dahl salt-sensitive rat, which has a decreased ability to generate renal dopamine, and the spontaneously hypertensive rat (SHR), which has no such limitation, have a defective coupling of a D1 receptor to a G protein/adenylyl cyclase complex. This coupling defect is: (1) genetic, since it precedes the onset of hypertension and co-segregates with the hypertensive phenotype, (2) receptor specific, since it is not shared by other humoral agents, and (3) organ and nephron segment selective, since it occurs in proximal tubules but not in cortical collecting ducts or the brain striatum. A consequence of the defective dopamine receptor/adenylyl cyclase coupling in the SHR is a decreased ability of D1 agonists to inhibit Na+/H+ exchange activity. A resistance to the natriuretic effect of dopamine and D1 agonists in the SHR is due mainly to decreased cyclic AMP production, although with maturation a post cyclic AMP defect is acquired. Radioligand binding studies suggest a "loss" of the high-affinity D1 binding site in the SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine, the Kidney, and Hypertension

“…Studies indicate decreased dopamine production in some experimental models of hypertension such as DOCA-salt hypertension [44]. In addition, dopamine receptor expression is decreased in some experimental models of hypertension [1].…”

Dopamine, kidney, and hypertension: studies in dopamine receptor knockout mice

“…The impaired ability of D1-like receptors to stimulate cAMP production in renal proximal tubules is receptor specific, since the ability of parathyroid hormone to stimulate cAMP production or stimulate G proteins is intact [153, 155, 156] and, at least in young SHRs, β-adrenergic function is also intact [157]. Increased serine phosphorylation and decreased expression of D1 receptors at the plasma membrane [71, 158], are responsible for the impaired ability of D1-like receptors to stimulate cAMP production in renal proximal tubules in genetic hypertension.…”

Genetic Determinants of Dopaminergic Activity: Potential Role in Blood Pressure Regulation

“…The determinants of DA action, additional to DA release and inactivation, i. e. the genes of multiple DA receptors, have also been impressively explored. Their expression in the brain and other tissues, particularly the kidney, has led to the recognition of a potential DA receptor defect in experimental hypertension (3).…”