CGRP and somatostatin modulate chronic hypoxic pulmonary hypertension.
Chronic hypoxic pulmonary hypertension (PH), associated with increased pulmonary arterial pressure (PPA) and right ventricular hypertrophy (RVH), correlates significantly with calcitonin gene-related peptide (CGRP) and somatostatin (SOM) levels in lung and blood. CGRP's role in regulation of PPA in chronic hypoxia and its potential interactions with SOM were investigated. CGRP, its antibody (ab) and blocker, CGRP-(8-37), SOM-14, SOM-28, and SOM-ab, respectively, were infused into the pulmonary circulation of hypobaric hypoxia rats for 4, 8, and 16 days. Thereafter, under pentobarbital sodium anesthesia, PPA was measured in the right ventricle and main pulmonary artery. Chronic CGRP infusion prevented PH at all times, whereas immunoneutralization and receptor blocking exacerbated PH. SOM-28 also exacerbated while SOM-14 and SOM-ab decreased PH. RVH generally reflected the PPA. Radioimmunoassay confirmed successful infusion of the peptides with negligible peptide degradation in the pumps throughout 16 days and showed complete immunoneutralization of CGRP with its ab. Peptide levels in lung tissue suggest inhibition of CGRP release by SOM-28 and increased plasma SOM with CGRP infusion. In vitro pharmacological studies suggest that CGRP exerts a receptor-mediated nonadrenergic, nonmuscarinic vasodilatory effect in the lung which is independent of endothelium-derived relaxing factor and does not involve ATP-dependent potassium channels. We conclude that endogenous CGRP plays an important role in pulmonary pressure homeostasis during hypoxia, by directly dilating pulmonary vasculature, thus ameliorating the development of chronic hypoxic pulmonary hypertension in rats.
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Wisconsin 53706.
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S
Tjen-A-Looi
R
R
Ekman
H
H
Lippton
J
J
Cary
I
I
Keith
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001834:Body Water / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology*; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology; D002908:Chronic Disease; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000097:blood / Q000150:complications*; D008168:Lung / Q000378:metabolism; D008297:Male; D011651:Pulmonary Artery / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000378:metabolism / Q000494:pharmacology*
D013004:Somatostatin; D015740:Calcitonin Gene-Related Peptide