Haemodynamic effects of human α‐calcitonin gene‐related peptide following administration of endothelin‐1 or NG‐nitro‐l‐arginine methyl ester in conscious rats

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Abstract
1 We investigated the peripheral haemodynamic effects of human α-calcitonin gene-related peptide (CGRP) following administration of endothelin-1 or NG-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide production, in conscious, chronically-instrumented, Long Evans rats. 2 Infusion of endothelin-1 (3 nmol kg−1 h−1) caused hypertension, bradycardia and renal, mesenteric and hindquarters vasoconstrictions. Co-infusion of human α-CGRP (1.5 nmol kg−1 h−1) reduced the hypertension and abolished the hindquarters vasoconstriction caused by endothelin-1 but the renal and mesenteric vasoconstrictor actions of endothelin-1 were not affected. 3 Infusion of human α-CGRP (15 nmol kg−1 h−1) in the presence of endothelin-1 caused hypotension and hyperaemic vasodilatation in the hindquarters; the mesenteric vasoconstrictor effects of endothelin-1 were diminished, but there was only a transient reversal of the renal vasoconstrictor effects of endothelin-1. 4 Pretreatment with the non-peptide angiotensin II receptor antagonist, DuP 753 (10 mg kg−1), caused slight hypotension associated with renal, mesenteric and hindquarters vasodilatations, but DuP 753 did not affect responses to endothelin-1 infusion. However, under these conditions co-infusion of human α-CGRP (15 nmol kg−1 h−1) caused a sustained reversal of the renal vasoconstrictor effects of endothelin-1. 5 These results indicate that the failure of human α-CGRP to cause sustained reversal of the renal vasoconstrictor effects of endothelin-1 in the absence of DuP 753 was due to activation of the renin-angiotensin system (possibly as a consequence of the hypotension). 6 In the second experiment, l-NAME (10 mg kg−1) caused renal, mesenteric and hindquarters vasoconstrictions similar to those seen in the presence of endothelin-1. However, the renal vasoconstrictor effects of l-NAME were reversed completely by human α-CGRP (15 nmol kg−1 h−1), even though the latter caused hypotension comparable to that seen in the presence of endothelin-1. These results are consistent with a lack of functional activation of the renin-angiotensin system by human α-CGRP in the presence of l-NAME. 7 The vasoconstrictor effects of l-NAME on the hindquarters were completely reversed by infusion of human α-CGRP, but hindquarters flow and vascular conductance did not rise above baseline levels. Hence these results indicate the hindquarters hyperaemic vasodilator effects of human α-CGRP seen in the presence of endothelin-1 were contributed to by nitric oxide-mediated mechanisms.