DOPAMINERGIC DEFECT IN HYPERTENSION

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 hyperte nsion. Because some forms of hypertension are sodium dependent or aggr avated by sodium loading and because dopamine is important in aiding t he organism to eliminate ''excess'' sodium, an abnormality in the rena l dopaminergic system may be responsible for the sodium retention in h ypertension. Both human and animal models of hypertension are associat ed with renal dopamine production and/or post first messenger defects. The Dahl salt-sensitive rat, which has a decreased ability to generat e renal dopamine, and the spontaneously hypertensive rat (SHR), which has no such Limitation, have a defective coupling of a D-1 receptor to a G protein/adenylyl cyclase complex. This coupling defect is: (1) ge netic, since it precedes the onset of hyper tension and co-segregates with the hypertensive phenotype, (2) receptor specific, since it is no t shared by other humoral agents, and (3) organ and nephron segment se lective, since it occurs in proximal tubules but not in cortical colle cting ducts or the brain striatum. A consequence of the defective dopa mine receptor/adenylyl cyclase coupling in the SHR is a decreased abil ity of D-1 agonists to inhibit Na+/H+ exchange activity. A resistance to the natriuretic effect of dopamine and D-1 agonists in the SHR is d ue mainly to decreased cyclic AMP production, although with maturation a post cyclic AMP defect is acquired. Radioligand binding studies sug gest a ''loss'' of the high-affinity D-1 binding site in the SHR. Howe ver, sequencing of a limited segment of the D-1 receptor genes express ed in renal proximal tubule has not shown any difference between and t he SHR and the normotensive Wistar Kyoto strain. Whether the defect is in the primary or tertiary structure of the receptor that has not yet been cloned remains to be demonstrated.