ROLE OF DOPAMINE D3 RECEPTORS IN THE PATHOGENESIS OF GENETIC HYPERTENSION• 1635

Abstract

Abnormalities of the dopaminergic control of cardiovascular function have been implicated in human and animal models of genetic hypertension. Uncoupling of a D1-like receptor from its G-protein/effector enzyme complex in renal proximal tubules resuls in a decreased ability to excrete a sodium load; this abnormality cosegregates with hypertension in spontaneously hypertensive rats. Since the natriuretic effect of dopamine involves a synergism between D1-like and D2-like receptors, an abnormality of one or both these receptors may be involved in genetic hypertension. We, therefore, studied the cardiovascular consequences of the disruption of the D3 receptor, a member of the family of D2-like receptors, expressed in renal proximal tubules. In 3 mo old F2 mice, body weights (BW) were similar among wild type (WT),heterozygous (HE), and homozygous (HO) mice. However, systolic (SBP) and diastolic (DBP) blood pressures were higher in HE (SBP= 120±2, DBP=94±3 mmHg, n=10) and HO(SBP=120±2, DBP=96±3 mmHg, n=11) than in WT (SBP=101±4, DBP=79±4 mmHg, n=9) mice. An acute saline load (SL) (5% BW) did not affect BP. Glomerular filtration rates were similar among the groups before and after SL; SL increased urine flow (WT=1.7±0.5, HE=1.2±0.3, HO=0.9±0.1μl/min) and Na excretion (WT=253±196, HE=338±107, HO=124±28 nEq/min) to a similar extent in WT and HE but the increase was attenuated in HO. Adrenergic nerve activity was not increased in HO since renal norepinephrine content was not greater in HO than in WT or HE (WT=82±14, HE=75±14, HO=60±10 ng/g kidney). Since D3 receptors negatively regulate renin secretion, we examined the role of the renin-angiotensin system in the higher BP in HO than in WT mice by observing the effect on SBP of a bolus injection of the AT1 antagonist, losartan (3mg/kg). Losartan, decreased SBP to a greater (HO=-37%, n=5, WT=-23%, n=5) and longer extent in HO (greater than 70 min) than in WT(≤40min). We conclude that disruption of the D3 receptor increases BP in HE and HO mice. The mechanism of the increase in BP in HE remains to be determined; in HO, it appears to be mainly due to a failure to suppress the renin-angiotensin system.