Adrenomedullin dilates rat pulmonary artery rings during hypoxia: role of nitric oxide and vasodilator prostaglandins.
Hypoxia decreases vasorelaxation and leads to pulmonary arterial hypertension. A newly identified 52 amino-acid peptide adrenomedullin (ADM) exerts vasodilator effect in intact animals under normoxic condition. We studied the effect of human ADM on rat pulmonary arterial and aortic rings under normoxic and hypoxic conditions. During normoxia, ADM caused a concentration-dependent relaxation of precontracted aortic and pulmonary arterial rings; the relaxation was much more pronounced in pulmonary arterial rings and was abolished by the nitric oxide (NO) synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and by deendothelialization. A fragment of ADM, ADM13-52, caused a degree of relaxation similar to that induced by ADM in pulmonary arterial rings, but not in the aortic rings, and the relaxation of pulmonary artery caused by ADM13-52 was not affected by the cyclooxygenase inhibitor indomethacin but was abolished by L-NAME and by deendothelialization. During hypoxia, ADM13-52 failed to relax pulmonary arterial rings, whereas ADM caused modest relaxation of pulmonary arterial rings (one third of the relaxation during normoxia), which was abolished by pretreatment with indomethacin. Our results indicate that the vasorelaxant effect of ADM is more pronounced in pulmonary artery than in the aorta; ADM has more potent vasodilator effect than ADM13-52 during hypoxia; ADM relaxes hypoxic pulmonary artery through an indomethacin-sensitive pathway; amino acids 1-12 in ADM must be present for relaxation of chronic hypoxic pulmonary arterial rings; and last, the presence of endothelium is necessary for the expression of ADM-mediated relaxation.
Yang
B C
BC
Department of Medicine, University of Florida College of Medicine, Gainesville, USA.
Lippton
H
H
Gumusel
B
B
Hyman
A
A
Mehta
J L
JL
D053607:Adrenomedullin; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010455:Peptides / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects; D051381:Rats; D014665:Vasodilator Agents / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D010455:Peptides; D014665:Vasodilator Agents; D053607:Adrenomedullin; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin