This study examined the contribution of phosphatidylinositol metabolism and the efficacy of protein kinase C-mediated desensitization in the exaggerated alb-adrenergic receptor-mediated inositol phosphate response in the aorta of the deoxycorticosterone acetate (DOCA)-salt rat model of hypertension. The basal accumulation of inositol phosphates and the basal incorporation of [3H]myo-inositol in the phosphatidylinositol lipid pool were significantly higher in the aorta of these hypertensive rats. A positive correlation (r=.88,P<.01) was demonstrated between basal inositol phosphate levels and the [3H]myo-inositol-labeled phosphatidylinositol lipid pool. In hypertensive rats, α1b-adrenergic receptor-mediated inositol phosphate production in response to phenylephrine was significantly higher compared with normotensive rats. Despite the normalization of phenylephrine-mediated inositol phosphate production to the [3H]myo-inositol-labeled phosphatidylinositol lipid pool, the α1b-adrenergic response remained significantly higher in the hypertensive rats. Phorbol ester activation of protein kinase C attenuated to a lesser extent phenylephrinemediated inositol phosphate production (40%) in the aorta of hypertensive rats compared with the 80% attenuation observed in the aorta of normotensive rats. This desensitization was inhibited in both groups by the protein kinase C inhibitor staurosporine. The blunted desensitization of the α1b-adrenergic receptor by protein kinase C activation was not associated with a decrease in protein kinase C activity in the hypertensive rats, because aortic strips from these animals were more responsive to phorbol ester activation than aortic strips from normotensive animals. Moreover, the in vivo administration of staurosporine reduced mean arterial pressure to a greater extent in the hypertensive rats. In the same vascular tissue of these hypertensive rats, endothelin-1 receptor-mediated inositol phosphate production was significantly reduced, and in contrast to the nonnotensive rats, in which a 50% decrease was observed, the endothelin-1 receptor was unresponsive to protein kinase C-mediated desensitization. From these results one can conclude that during the development of DOCA-salt hypertension, an increase in both basal phosphatidylinositol turnover and alb-adrenergic receptor reactivity could contribute to an enhanced vascular smooth muscle tone. These observations provide further evidence for an important role of the sympathetic nervous system and for the existence of an impaired regulation of the alb-adrenergic reactivity of vascular tissues in the development and/or maintenance of hypertension in DOCA-salttreated rats.