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

Agonist desensitisation of responses coupled to phosphatidylinositol m etabolism were studied. Responses mediated by two different agonists, endothelin-1 and noradrenaline were investigated. In vivo pressor resp onses were examined in conscious male New Zealand white rabbits, while effects on inositol phosphate formation were studied in rings of fres hly isolated aorta and in cultured aortic vascular smooth muscle cells . No desensitisation of responses to noradrenaline were observed in vi vo despite a 10-day infusion under conditions which cause desensitisat ion of alpha2 and beta-adrenoceptor mediated responses. In contrast, r esponses to endothelin-1 were attenuated within 5 min of commencing en dothelin-1 infusions. No reduction in noradrenaline stimulated inosito l phosphate was observed in cultured vascular smooth muscle cells afte r pre-incubation with noradrenaline up to 10(-4)M, whereas with endoth elin-1 pre-incubation a dose and time-related reduction in endothelin- 1 stimulated inositol phosphate formation was observed. Thus, differen ces in the pattern of desensitisation of both pressor responses and ph osphatidylinositol metabolism were observed for noradrenaline and endo thelin-1 suggesting that the nature of the 2nd messenger involved in s ignal transduction is not the only determinant of agonist desensitisat ion. In addition, differences in the rate of desensitisation and sensi tivity to endothelin-1, but not noradrenaline, were observed when resp onses in cultured cells were compared with in vivo responses or respon ses to freshly isolated tissues. These differences are discussed in re lation to possible modifications of the endothelin receptor or its cou pling to phosphatidylinositol metabolism during culture.