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 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)
Jose
P A
PA
Department of Pediatrics and Physiology and Biophysics, Georgetown University School of Medicine, Washington, District of Columbia.
Eisner
G M
GM
Felder
R A
RA
D000818:Animals; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D011954:Receptors, Dopamine / Q000235:genetics*
D011954:Receptors, Dopamine; D004298:Dopamine