DECREASED ENDOTHELIUM-DEPENDENT PULMONARY VASODILATOR EFFECT OF CALCITONIN-GENE-RELATED PEPTIDE IN HYPOXIC RATS CONTRASTS WITH INCREASED BINDING-SITES

Levels of calcitonin gene-related peptide (CGRP), a vasodilator peg ti de present in nerves and airway endocrine cells of the rat respiratory tract, are increased in hypoxic lung and decreased in plasma, suggest ing impaired CGRP release. We wanted to determine whether there was an adaptive functional response to reduced CGRP levels in hypoxia. Densi ty of binding sites for CGRP were compared with its vascular actions f ollowing hypoxia, and with binding following administration of the sen sory neurotoxin capsaicin to deplete neural CGRP. Autoradiography of l ung sections incubated with (125)l-labelled CGRP and other vasoactive peptides was used to quantify their binding sites, in male Wistar rats exposed to periods of hypoxia (inspiratory oxygen fraction (FI,O-2) = 0.1) ranging 0-10 days (n=5 each), in controls, and in rats treated n eonatally with capsaicin. Relaxation to CGRP was compared in pulmonary artery of control and hypoxic rats. CGRP binding was seen in the vasc ular endothelium and was significantly elevated after 5 days of hypoxi a (mean +/- SEM: control 4.6 +/- 0.4 versus hypoxic 16.6 +/- 2.4 amol . mm(-2)). CGRP-induced (5 x 10(-7) M) relaxation of pulmonary artery was reduced, compared with controls, following 8 and 21 days of hypoxi a (mean +/- SEM) percentage of relaxation to phenylephrine: 78 +/- 3, 36 +/- 5 and 32 +/- 3, respectively) and was abolished by removal of e ndothelium. Capsaicin treatment also significantly elevated vascular C GRP binding. Atrial natriuretic peptide (ANP) binding levels were decr eased in smooth muscle of all blood vessels after 7 days of hypoxia, b ut endothelin-1 (ET-1) and vasoactive intestinal peptide (VIP) binding was unchanged. We conclude that the vasodilator effects of CGRP are e ndothelium-dependent and, whilst they are reduced in hypoxic lung, thi s is not due to reduction in receptors, thereby implicating alteration s in the nitric oxide guanylyl cyclase system. Furthermore, adaptive r esponses in some peptide binding sites occur in hypoxia, which may be due to changes in endogenous peptide levels.