Mechanisms of calcitonin gene-related peptide-induced increases of pulmonary blood flow in fetal sheep

Fetal pulmonary blood flow is regulated by various vasoactive substances. One, calcitonin gene-related peptide (CGRP), increases pulmonary blood flow. We examined four key physiological mechanisms underlying this response using the blocker drugs CGRP receptor blocker (CGRP(8-37)), nitric oxide synthase inhibitor [N-omega-nitro- L-arginine (L-NNA)], adenosine triphosphate-dependent potassium (K-ATP) channel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin) in 17 near-term fetal sheep. Catheters were placed in the left (LPA) and main pulmonary arteries, and an ultrasonic flow transducer was placed around the LPA to measure flow continuously. CGRP was injected directly into the LPA (mean 1.02 mu g/kg) before and after blockade, and responses to CGRP were statistically compared. Before blockade, CGRP increased LPA blood flow from 23 +/- 25 to 145 +/- 77 ml/min (means +/- SD), and these increases were significantly attenuated by CGRP(8-37) (n = 6; 91% inhibition), L-NNA (n = 6; 86% inhibition), and glibenclamide (n = 6; 69% inhibition). No significant changes were found with indomethacin (n = 6; 4% inhibition). Thus, in the fetal pulmonary circulation, CGRP increases pulmonary blood flow not only through its specific receptor but also, in part, through nitric oxide release and K-ATP channel activation.