Renal sympathetic antidiuretic, antinatriuretic, and vasoconstrictor responses are mediated by a,-adrenergic receptors in the normal rat. Since the renal nerve has been implicated in the pathogenesis of rat genetic hypertension, we investigated renal <x,-adrenergic receptor coupling to phosphoinositide turnover in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). In cortical slices from adult (13-week-oM) SHR and WKY, stimulation with norepinephrine (l0 M 0−3M) caused a concentrationdependent increase in accumulation of [3H]inositol phosphates. However, dose-response curves for SHR characteristically displayed a depression of the maximum response as compared with those for WKY. Baseline accumulation of [3H]inositol phosphates was not different between strains (39.4 ± 2.2 cpm/mg tissue/hr for WKY and 34.4 ± 2.1 cpm/mg tissue/hr for SHR slices;n= 5 rats/group, determined in triplicate). Antagonist competition studies revealed that norepinephrine-stimulated (10∼4M) [3H] inositol phosphate accumulation was mediated by a,-adrenergic receptors (ICj,) for prazosin: 65 ± 11 nM for SHR and 64 ± 5 nM for WKY). The reduction in norepinephrine-stimulated [3H]inositol phosphate accumulation in SHR cortex was not the result of the hypertension, since it was also present in cortical slkes from young (4-week-old) SHR in which the blood pressure was not yet significantly different from that in WKY and since [3H]inositol phosphate accumulation was unchanged from control values in rats made hypertensive by treatment with deoxycorticosterone acetate. Scatchard analysis of [3H]prazosin binding in renal cortical membranes of young and adult SHR and WKY revealed no significant differences in aradrenergk receptor density or affinity between strains at either age. Our results suggest that renal o,-adrenergic receptor coupling to phospholipase C is less efficient in SHR than in WKY. This unpaired response is not the result of hypertension or changes in receptor density; this defect may play a role in increased renal sympathetic nerve activity and in the development or maintenance of hypertension in SHR.