Mechanisms of adrenomedullin-induced increase of pulmonary blood flow in fetal sheep

Mechanisms of adrenomedullin-induced increases in fetal pulmonary blood flo w were examined in 19 near-term fetal sheep using four key blocker drugs: n itric oxide synthase inhibitor (N-omega-nitro-L-arginine), calcitonin gene- related peptide (CGRP) receptor blocker, ATP-dependent potassium (K-ATP) ch annel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin). Catheters were inserted into the left pulmonary artery and superior vena c ava to administer drugs and into the main pulmonary and carotid arteries to measure pressures and heart rate. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow continuously. Adrenomedul lin (mean 1.06 mu g/kg) was injected into the left pulmonary artery before and after infusion of N-omega-nitro-L-arginine (mean 96.5 mg/kg, n = 6), gl ibenclamide (mean 11.8 mg/kg, n = 6), CGRP receptor blocker (mean 312.0 mu g/kg, n = 6), and indomethacin (mean 1.7 mg/kg, n = 8). Blockade was confir med by appropriate agonist injection. The adrenomedullin-induced response i n left pulmonary artery blood flow was inhibited by N-omega-nitro-L-arginin e (inhibition rate 99%) and significantly attenuated by glibenclamide (inhi bition rate 44%); however, no significant changes were found with CGRP rece ptor blocker or indomethacin (inhibition rate 0 and 17%, respectively). The responses of the main pulmonary and carotid arterial pressures were simila rly affected by those blockers. Our data suggest that in the fetal pulmonar y circulation, the adrenomedullin-induced increase in pulmonary blood flow depends largely on nitric oxide release and partly on K-ATP channel activat ion, and does not involve the CGRP receptor or a cyclooxygenase-mediated me chanism.