AGONIST DESENSITIZATION OF ALPHA(1) ADRENOCEPTORS AND ENDOTHELIN-1 RECEPTORS COUPLED TO PHOSPHATIDYLINOSITOL METABOLISM

Agonist desensitisation of responses coupled to phosphatidylinositol metabolism were studied. Responses mediated by two different agonists, endothelin-1 and noradrenaline were investigated. In vivo pressor responses were examined in conscious male New Zealand white rabbits, while effects on inositol phosphate formation were studied in rings of freshly isolated aorta and in cultured aortic vascular smooth muscle cells. No desensitisation of responses to noradrenaline were observed in vivo despite a 10-day infusion under conditions which cause desensitisation of alpha2 and beta-adrenoceptor mediated responses. In contrast, responses to endothelin-1 were attenuated within 5 min of commencing endothelin-1 infusions. No reduction in noradrenaline stimulated inositol phosphate was observed in cultured vascular smooth muscle cells after pre-incubation with noradrenaline up to 10(-4)M, whereas with endothelin-1 pre-incubation a dose and time-related reduction in endothelin-1 stimulated inositol phosphate formation was observed. Thus, differences in the pattern of desensitisation of both pressor responses and phosphatidylinositol metabolism were observed for noradrenaline and endothelin-1 suggesting that the nature of the 2nd messenger involved in signal transduction is not the only determinant of agonist desensitisation. In addition, differences in the rate of desensitisation and sensitivity to endothelin-1, but not noradrenaline, were observed when responses in cultured cells were compared with in vivo responses or responses to freshly isolated tissues. These differences are discussed in relation to possible modifications of the endothelin receptor or its coupling to phosphatidylinositol metabolism during culture.