REGIONAL HEMODYNAMIC-EFFECTS OF PROLONGED INFUSIONS OF HUMAN ALPHA-CALCITONIN GENE-RELATED PEPTIDE IN CONSCIOUS, LONG EVANS RATS

1 Haemodynamic measurements were made in conscious, Long Evans rats chronically instrumented for the assessment of changes in regional blood flows (renal, mesenteric and hindquarters, or internal and common carotid) and systemic arterial blood pressure and heart rate, before, during and after 3 day infusions of vehicle or human alpha-calcitonin gene-related peptide (CGRP) (1.5 or 15 nmol kg-1 h-1). 2 In animals with renal, mesenteric and hindquarters flow probes (n = 8), during the first day of infusion of human alpha-CGRP (1.5 nmol kg-1 h-1) there was sustained tachycardia and hypotension, a sustained reduction in renal flow, a transient reduction in mesenteric flow and a relatively well-maintained increase in hindquarters flow. All these effects were significantly different from the changes seen in vehicle-infused rats (n = 8), but calculation of vascular conductances showed only the late mesenteric vasodilatation and the sustained hindquarters vasodilatation were different from the changes in vehicle-infused rats. However, by the second day of infusion and thereafter cardiovascular variables in the animals receiving vehicle and those receiving human alpha-CGRP were not different. 3 Nine animals instrumented with probes to monitor changes in internal and common carotid haemodynamics initially received human alpha-CGRP infused at a rate of 1.5 nmol kg-1 h-1. Three of these animals still showed some response to the human alpha-CGRP (tachycardia, hypotension, hyperaemic vasodilatation) throughout the second day of infusion and hence were taken through the 3 day infusion protocol. When the infusion was stopped on the fourth day all these animals showed reversal of the effects of human alpha-CGRP. The other 6 animals in the original group showed complete desensitization to the effects of human alpha-CGRP by the end of the second day of infusion (as seen in the group instrumented with renal, mesenteric and hindquarter probes). Therefore, in order to assess the extent of desensitization, at the beginning of the third day the dose of human alpha-CGRP was increased to 15 nmol kg-1 h-1. The resulting tachycardia, hypotension and hyperaemia in the carotid vascular beds were significant, (but no greater than the initial responses to human alpha-CGRP at 1.5 nmol kg-1 h-1). These effects were maintained throughout the third infusion day, but there was some desensitization to the effects of this higher dose of human alpha-CGRP by the beginning of the fourth infusion day. However, when the infusion was stopped there was clear reversal of the effects of human alpha-CGRP. 4 The results indicate substantial inter-individual variation in the haemodynamic effects of prolonged infusions of human alpha-CGRP in conscious, Long Evans rats. However, since increasing the dose of human alpha-CGRP overcame the desensitization, it is feasible that, in the clinical setting, maintained increases in internal carotid blood flow could be achieved by individually-adjusted infusions of human alpha-CGRP.