ALTERED PROTEIN-KINASE-C REGULATION OF PHOSPHOINOSITIDE-COUPLED RECEPTORS IN DEOXYCORTICOSTERONE ACETATE SALT HYPERTENSIVE RATS

This study examined the contribution of phosphatidylinositol metabolis m and the efficacy of protein kinase C-mediated desensitization in the exaggerated alpha(1b)-adrenergic receptor-mediated inositol phosphate response in the aorta of the deoxycorticosterone acetate (DOCA)-salt rat model of hypertension. The basal accumulation of inositol phosphat es and the basal incorporation of [H-3]myo-inositol in the phosphatidy linositol lipid pool were significantly higher in the aorta of these h ypertensive rats. A positive correlation (r=.88, P<.01) was demonstrat ed between basal inositol phosphate levels and the [H-3]myo-inositol-l abeled phosphatidylinositol lipid pool. In hypertensive rats, alpha(1b )-adrenergic receptor-mediated inositol phosphate production in respon se to phenylephrine was significantly higher compared with normotensiv e rats. Despite the normalization of phenylephrine-mediated inositol p hosphate production to the [H-3]myo-inositol-labeled phosphatidylinosi tol lipid pool, the alpha(1b)-adrenergic response remained significant ly higher in the hypertensive rats. Phorbol ester activation of protei n kinase C attenuated to a lesser extent phenylephrine-mediated inosit ol phosphate production (40%) in the aorta of hypertensive rats compar ed with the 80% attenuation observed in the aorta of normotensive rats . This desensitization was inhibited in both groups by the protein kin ase C inhibitor staurosporine. The blunted desensitization of the alph a(1b)-adrenergic receptor by protein kinase C activation was not assoc iated with a decrease in protein kinase C activity in the hypertensive rats, because aortic strips from these animals were more responsive t o phorbol ester activation than aortic strips from normotensive animal s. 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 recepto r-mediated inositol phosphate production was significantly reduced, an d in contrast to the normotensive rats, in which a 50% decrease was ob served, the endothelin-l receptor was unresponsive to protein kinase C -mediated desensitization. From these results one can conclude that du ring the development of DOCA-salt hypertension, an increase in both ba sal phosphatidylinositol turnover and alpha(1b)-adrenergic receptor re activity could contribute to an enhanced vascular smooth muscle tone. These observations provide further evidence for an important role of t he sympathetic nervous system and for the existence of an impaired reg ulation of the cu,,-adrenergic reactivity of vascular tissues in the d evelopment and/or maintenance of hypertension in DOCA-salt-treated rat s.