Dopamine receptor signaling defects in spontaneous hypertension

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 (2%-10%) expansion may be mediated by D-1-like receptors. The renal paracrine effect of dopamine is impaired in genetic hypertension; this is due to defects in renal dopamine production or transduction of the dopamine signal. The Dahl salt sensitive rat and the spontaneously hypertensive rat (SHR), which have normal renal dopamine production and expression of dopamine receptors, have a defect in the coupling of a D-1-like receptor to G-protein/effector enzyme complex. A consequence of the defective D-1-like receptor/effector enzyme coupling in SHR is a decreased ability of D-1 agonists to inhibit Na+/H+ exchange and Na+/K+-ATPase activity. The defect is 1) genetic, since it precedes the onset of and cosegregates with the hypertension; 2) receptor specific, since it is not shared by other humoral agents; and 3) confined to the renal proximal tubule. Two of the cloned dopamine receptors in mammals are D-1-like (D-1A and D-1B). The D-1A receptor gene is expressed to a greater extent in renal proximal tubules than the D-1B receptor gene. The D-1-like receptor is important in the pathogenesis of hypertension. Chronic blockade of dopamine receptors accelerates the development of hypertension in normotensive and hypertensive rats. Moreover, disruption of the D-1A receptor gene in mice increases systolic blood pressure and results in diastolic hypertension. The abnormal D-1-like receptor in SHR may be the D-1A receptor; its uncoupling from the G-protein/effector enzyme complex in renal proximal tubules of SHR may be due to mistargeting, The mechanism for this ''mistargeting'' of the D-1A receptor is not due to a mutation in the primary sequence and remains to be determined.