DOPAMINE-RECEPTOR SIGNALING DEFECTS IN SPONTANEOUS HYPERTENSION

Dopamine produced by renal proximal tubules acts as an intrarenal natr iuretic factor by direct tubular action; this paracrine effect is infl uenced by the state of sodium balance. Up to 60% of sodium excretion w ith volume (2%-10%) expansion may be mediated by D-1-like receptors. T he renal paracrine effect of dopamine is impaired in genetic hypertens ion; this is due to defects in renal dopamine production or transducti on of the dopamine signal. The Dahl salt sensitive rat and the spontan eously hypertensive rat (SHR), which have normal renal dopamine produc tion and expression of dopamine receptors, have a defect in the coupli ng of a D-1-like receptor to G-protein/effector enzyme complex. A cons equence 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 preced es the onset of and cosegregates with the hypertension; 2) receptor sp ecific, since it is not shared by other humoral agents; and 3) confine d to the renal proximal tubule. Two of the cloned dopamine receptors i n mammals are D-1-like (D-1A and D-1B). The D-1A receptor gene is expr essed to a greater extent in renal proximal tubules than the D-1B rece ptor gene. The D-1-like receptor is important in the pathogenesis of h ypertension. Chronic blockade of dopamine receptors accelerates the de velopment of hypertension in normotensive and hypertensive rats. Moreo ver, disruption of the D-1A receptor gene in mice increases systolic b lood 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 ma y be due to mistargeting, The mechanism for this ''mistargeting'' of t he D-1A receptor is not due to a mutation in the primary sequence and remains to be determined.