Kinetics of vasoconstrictor action of endothelins.

Endothelin peptides (Et) induce slowly developing and long-lasting contractions of rat aortic strips with a rank order of potency (Et-1 = Et-2 greater than sarafotoxin S6b greater than Et-3) consistent with the involvement of an EtA-like receptor subtype. A similar profile of action is observed for Et-induced intracellular [Ca2+]i mobilization in cultured aortic myocytes. Modeling the association of Et-1 to its receptor shows that, at concentrations which produce large increases in tension, Et-1 associates rapidly to its receptors and that a slow rate of association is not responsible for the slow rate of tension development. Action of endothelins on [Ca2+]i was studied using isolated cultured aortic myocytes and compared with that of angiotensin II and vasopressin. Results show that three vasoconstrictors produce similar and rapid changes in [Ca2+]i. The rate-limiting step for the contractile action of Et is a postreceptor event probably distal to early changes in [Ca2+]i. Biological responses to Et are usually characterized by a relative insensitivity to the peptide as compared with Kd values determined in binding experiments. Data presented show that insensitivity of the early [Ca2+]i responses to Et could be accounted for by the fact that the responses develop under nonequilibrium conditions. Tension amplitude seems also to be determined by non-equilibrium binding conditions. It correlates with the fraction of the Et-1 binding sites occupied 20 s after addition of the peptide and not to the fractional site occupancy at the time of maximum tension development.(ABSTRACT TRUNCATED AT 250 WORDS)