The physiological role of the endothelin system in the maintenance of vascular tone in man

• Main Author: Strachan, Fiona Elizabeth
• Published: University of Edinburgh 2001
• Subjects: 616.9
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.662535

Constriction in capacitance and resistance vessels was demonstrated in response to locally active infusion of the non-selective ET receptor agonist ET-1 and the ETB receptor selective agonists sarafotoxin S6c (SFTX6c) and BQ-3020, supporting a potential role for the ETB receptor in ET-1 mediated vasoconstriction. In capacitance vessels, constriction to ET-1 but not SFTX6c was attenuated during co-infusion of the ETA receptor selective antagonist BQ-123, in contrast constriction to SFTX6c but not ET-1 was attenuated during co-infusion of the ETB receptor selective antagonist BQ-788. In addition to the vasoconstriction described with low dose infusion of ETB receptor selective antagonists, vasodilatation , which appeared to be mediated largely by nitric oxide through ETB receptor stimulation, was demonstrated with high dose intra-arterial infusion of the ETB agonist SFTX6c. The repeatability of the forearm blood flow response to intra-arterial infusion of ET-1 was assessed and using this response as a model, a pharmacologically active dose range of the ETA receptor selective antagonist BMS-193884 and the non-selective ETA/ETB receptor antagonist MSD L-753,037 was identified. Although ETB receptor mediated pharmacological effects can be demonstrated by administration of ETB receptor agonists, the endogenous physiological effects of the ETB receptor are perhaps better demonstrated by ETB receptor selective antagonists. Local and systemic vasoconstriction were demonstrated in response to locally and systemically active infusion of the ETB receptor selective antagonist BQ-788. Both ETA receptor selective and combined ETA/ETB receptor antagonism resulted in significant forearm vasodilatation. However, the local vasodilator effects of the ETA receptor selective antagonist BQ-123 were attenuated in the presence of the selective ETB receptor antagonist BQ-788. These results confirm the importance of ET-1 in the maintenance of vascular tone and indicate that, in healthy blood vessels at least the vasodilator effects of non-selective ETA/ETB receptor antagonism are less than those of ETA receptor selective antagonism.