This study was designed to characterize the calcitonin gene-related peptide (CGRP) receptors mediating vasodilation in the rat isolated perfused kidney and to address the question as to whether amylin, a 37 amino acid peptide having about 50% overall sequence homology with CGRP, interacts with common CGRP receptors or acts via distinct amylin receptors. Human alpha-CGRP (h alpha CGRP) and human beta-CGRP, rat alpha-CGRP and rat amylin amide produced dose-related vasodilation of the perfused renal vascular bed with pD2 estimates of rat alpha-CGRP (10.8 +/- 0.2), h alpha CGRP (10.5 +/- 0.2), human beta-CGRP (10.5 +/- 0.2) and rat amylin amide (9.4 +/- 0.3). In contrast, the CGRP2 receptor-selective agonist [acetamidomethyl-cysteine2.7]h alpha CGRP (0.1 mumol) was inactive. The CGRP1-receptor antagonist, h alpha CGRP8-37 reversibly antagonized the vasodilator response induced by h alpha CGRP with an apparent pK1 of 8.03 +/- 0.21. The analog h alpha CGRP8-37 (1 microM) also reversibly inhibited submaximal responses to rat amylin amide. In contrast, rat amylin8-37 (1 microM) had no significant inhibitory effect either on rat amylin amide- or on h alpha CGRP-induced vasodilation (P > .05), showing that rat amylin8-37 does not have affinity for the CGRP1 receptor in this preparation. These data suggest that the predominant CGRP receptors in the rat renal vascular bed are of the CGRP1 type, and that the vasodilation induced by rat amylin amide is due to CGRP1 receptor activation.