Calcitonin gene-related peptide causes long-term inhibition of contraction in rat thoracic aorta through a nitric oxide-dependent pathway.

Calcitonin gene-related peptide (CGRP) is released into the circulation during pathogenesis of endotoxin and septic shock and appears to partly mediate vascular problems of shock. To explore the function of CGRP during shock, we investigated long-term action of CGRP, alone or in combination with interleukin-1beta (IL-1beta), another shock mediator, in isolated rings of rat thoracic aorta. CGRP or IL-1beta, by themselves, caused significant long-term (3 h) depression of contraction, while the combination of CGRP and IL-1beta had no synergistic effects. Dose-response curves to phenylephrine were significantly decreased and shifted to the right when aortic rings were incubated with 1 microM CGRP for 1 h followed by 2 h incubation without CGRP. Inducible nitric oxide synthase (iNOS) inhibitors, S-methylisothiourea sulfate (SMT) and N(G)-nitro-L-arginine (L-NNA), completely eliminated long-term depressant effect of CGRP. Our results suggest pathology of septic shock may involve long-term inhibition of vascular contraction mediated by CGRP via expression of iNOS.