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It has been demonstrated that endogenous kidney dopamine (DA) contributes to the natriuretic response to acute volume expansion (VE). Several studies suggest that a defect in renal DA-ergic mechanism may play a role in genetic hypertension in humans and rats. The present study was designed to determine the role of renal DA and tubular DA-1 receptors in the natriuretic response to VE in age-matched spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats of 10-12 weeks of age. In pentobarbital-anesthetized rats, VE was carried out by intravenously infusing isotonic sodium chloride (5% body weight) over a period of 60 min. This maneuver evoked pronounced increases in urine output, urinary sodium excretion and urinary DA excretion. However, the natriuretic and diuretic response to VE was significantly reduced in SHR, although the increase in urinary DA excretion was similar in both SHR and WKY rats. During VE no significant changes in glomerular filtration rate or blood pressure were noted in either strain of animals, indicating the involvement of renal tubular mechanisms in the natriuretic response. In a separate group of SHR and WKY rats, pretreatment with DA-1 receptor antagonist SCH 23390 caused significant attenuation of the natriuretic and diuretic response to VE in WKY rats but not in SHR, suggesting that unlike WKY rats kidney DA was not contributing to the natriuretic response to VE in SHR. In another group of animals, the renal effects of exogenously administered DA-1 receptor agonist fenoldopam were examined. Fenoldopam (1 microgram/kg/min) produced significant increases in urine output and urinary sodium excretion without causing any alterations in blood pressure or glomerular filtration rate in both SHR and WKY rats. However, the interesting observation was that fenoldopam-induced diuresis and natriuresis were significantly attenuated in SHR compared to the WKY rats. These results show that SHR are not able to eliminate an acute increase in sodium load as efficiently as WKY rats, which may be at least in part due to a defect in renal tubular DA-1 receptor function.

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It is reported that a defect in dopamine-1 (DA-1) receptor adenylate cyclase coupling in the proximal convoluted tubule in the spontaneously hypertensive rat may contribute to the diminished natriuretic response to DA-1 receptor agonists. Since the tubular DA-1 receptor is also coupled to phospholipase C, and both of these cellular signaling processes are involved in DA-1 receptor-mediated diuresis and natriuresis, it is important to know whether a similar defect is also present in DA-1 receptor-coupled phospholipase C pathway. The present study was therefore designed to determine the functional status of DA-1 receptor-phospholipase C coupling system of adult spontaneously hypertensive rats using a renal cortical slice preparation. In addition, the renal response to exogenously administered dopamine (1 /ig/kg/min i.v.) was also determined. We found that basal phospholipase C activity was significantly higher in hypertensive rats than in age-matched Wistar-Kyoto rats (7J6±0J2% versus 5.61±0.27%, p<0.05). However, compared with the normotensive controls, dopamine-induced increases in phospholipase C activity were significantly attenuated in the preparations of hypertensive rats in a concentration-dependent manner (13±6% versus 38±6% for 1 mM dopamine, p<0.05; 49±6% versus 71±9% for 3 mM dopamine, p<0.05; 50±16% versus 106±22%, p<0.05 for 10 mM dopamine). The diminished dopamine-induced phospholipase C activation was due to a deficiency in dopamine receptor-phospholipase coupling since the DA-1 receptor antagonist SCH 23390 (30 /iM), which blocked 50% of dopamine-induced inositol phosphate production in the Wistar-Kyoto rats, did not exert such an effect in the spontaneously hypertensive rats. The in vivo functional study showed that the diuretic and natriuretic responses to intravenous administration of dopamine were significantly diminished in spontaneously hypertensive rats compared with Wistar-Kyoto rats (urine output, 34± 1 versus 63±10 fil/30 min,p<0.05; urinary sodium excretion, 1.8±0.1 versus 3.2±0.2 ^teq/30 min,/x0.05). These results suggest that there is a defect in the tubular DA-1 receptor-phospholipase C coupling process in spontaneously hypertensive rats that may contribute to a diminished natiiuretic response to DA-1 receptor activation. (Hypertension 1992;19:102-108) I t is generally accepted that an abnormality in renal handling of sodium is one of the factors in the pathogenesis and/or maintenance of high blood pressure in genetic hypertension. Central to this assumption are the observations that spontaneously hypertensive rats (SHR), as opposed to their normotensive Wistar-Kyoto (WKY) counterparts, retain sodium avidly before the development of hypertension 1 and that urinary sodium excretion (U Na V) in SHR is normal or subnormal despite the presence of elevated blood pressure.2 Furthermore, dietary sodium restriction retards the development of hypertension in SHR.