Dopamine receptor defect in hypertension.

Dopamine, an endogenous catecholamine, regulates many cellular activities by occupation of D1-like and D2-like receptors. Two of the cloned dopamine receptors are D1-like (D1A and D1B or D5) and 3 are D2-like (D2, D3, and D4). Dopamine receptors affect adenylyl cyclase (AC), phospholipase C (PLC), PLA2, K+ and Ca2+ channels. D1- and D2-like receptors are expressed differentially in renal microvessels and tubules (proximal tubule > cortical collecting duct > medullary thick ascending limb of Henle). Dopamine produced by renal proximal tubules acts as an intrarenal natriuretic factor by direct tubular action; this paracrine effect is influenced by the state of sodium balance. Up to 60% of sodium excretion with volume (5-10%) expansion may be mediated by D1-like receptors. The renal paracrine effect of dopamine is impaired in genetic hypertension; this is due to defects in renal dopamine production and/or transduction of the dopamine signal. The Dahl salt sensitive rat and the spontaneously hypertensive rat (SHR), which have no limitation in renal dopamine production or expression of dopamine receptors, have a defect in the coupling of a D1-like receptor to G protein/effector complex resulting in an impaired ability of dopamine and D1 agonists to stimulate AC or PLC activity. A consequence of the defective D1-like receptor/effector enzyme coupling in SHR is a decreased ability of D1 agonists to inhibit exchange and ATPase activity. The defect is: (1) genetic, since it precedes the onset of and co-segregates with hypertension, (2) receptor specific, since it is not shared by other humoral agents, (3) organ and nephron segment selective, since it occurs in proximal tubules but not in cortical collecting ducts or the brain striatum. The abnormal D1-like receptor in SHR is the D1A receptor; its uncoupling from the G-protein/effector enzyme complex in renal proximal tubules of SHR may due to mistargeting. The mechanism for this “mistargeting” of the D1A receptor is not due to a mutation in the primary sequence and remains to be determined.