DIMINISHED PHOSPHOLIPASE-C ACTIVATION BY DOPAMINE IN SPONTANEOUSLY HYPERTENSIVE RATS

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-mu-g/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 (7.36 +/- 0.32% 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-mu-M), 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-mu-l/30 min, p < 0.05; urinary sodium excretion, 1.8-0.1 versus 3.2 +/- 0.2-mu-eq/30 min, p < 0.05). 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 natriuretic response to DA-1 receptor activation.