Receptor subtypes mediating renal actions of calcitonin gene-related peptide

Abstract

We previously reported that the renal arterial infusions of non-hypotensive doses of calcitonin gene-related peptide (CGRP) caused renal vasodilatation and increases in glomerular filtration rate at a low dose, but renal vasoconstriction, natriuresis and kaliuresis at a high dose. In the present study, we examined the effects of the specific CGRP 1 receptor antagonist CGRP-(8–37) (1 and 10 nmol/kg) and the putative CGRP receptor antagonist, [Tyr 0]CGRP-(28–37) (3 and 30 nmol/kg), on the renal vascular and tubular effects of CGRP in inactin-anaesthetized Sprague-Dawley rats. Renal arterial infusion of single doses of CGRP (0.3–300 pmol/kg per min) did not significantly alter mean arterial pressure or heart rate. However, during the continuous renal arterial infusion of either CGRP-(8–37) or [Tyr 0]CGRP-(28–37), a high dose of CGRP (300 pmol/kg per min) paradoxically reduced arterial pressure and increased heart rate. CGRP-(8–37) completely but [Tyr 0]CGRP-(28–37) incompletely inhibited the vasodilatation and increments in glomerular filtration rate elicited by low doses of CGRP. Both blockers abolished the renal vasoconstriction but did not inhibit diuresis, natriuresis and kaliuresis elicited by a high but non-hypotensive dose of CGRP. On the basis that CGRP-(8–37) is a competitive CGRP 1 receptor antagonist, our results suggest: (1) the renal vascular effect of CGRP is completely mediated via the activation of CGRP 1 receptors, (2) the renal tubular effects of CGRP are not mediated via CGRP 1 receptors, and (3) [Tyr 0]CGRP-(28–37) is a CGRP 1 receptor antagonist with potency and efficacy less than those of CGRP-(8–37).