In order to examine whether the truncated fragments of hCGRP, hCGRP(8-37) or hCGRP(12-37), behave as competitive CGRP receptor antagonists in the vascular system of the rat, systemic blood pressure was continually monitored in pentobarbital-anesthetized Sprague-Dawley rats. The IV administration of 7.9-527 pmol hCGRP/rat caused dose-related reductions in mean arterial blood pressure that lasted, depending on the dose, about 3-10 min. In contrast, hCGRP fragments 8-37 or 12-37 proved inactive up to 60,000 pmol/rat. Pretreatment with either 10 or 30 nmol hCGRP(8-37) or 20 or 90 nmol hCGRP(12-37)/rat reduced the magnitude of the CGRP-induced hypotensive responses caused by 79 pmol hCGRP/rat; pretreatment with 10 nmol of the hCGRP fragments displaced about 3-fold the hCGRP as well as the [Cys(ACM)2.7]hCGRP dose-response curve to the right in a parallel fashion. The specificity of hCGRP(8-37) as a CGRP receptor antagonist was documented by the finding that it did not antagonize the hypotensive responses induced with bradykinin, histamine or substance P.