Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites

Abstract

Pulmonary vascular tone is regulated by many vasoactive mediators produced either locally in endothelium, airway epithelium, vascular smooth muscle or nerves, or systemically via the blood. The main effect of alveolar hypoxia is pulmonary hypertension, which is modulated by many counteracting mediators. Amongst the possible candidates is calcitonin gene-related peptide (CGRP) [1], a potent vasodilator that is also present in the sensory innervation and endocrine cells of the rat respiratory tract [1][2][3], which is known to be involved in regulating pulmonary vascular tone [2,4].In previous studies, hypoxia has been shown to cause an increase in whole lung CGRP concentrations [5], particularly in the pulmonary endocrine cells [6,7], and decreased plasma levels of the peptide in rats [5]. Release We conclude that the vasodilator effects of CGRP are endothelium-dependent and, whilst they are reduced in hypoxic lung, this is not due to reduction in receptors, thereby implicating alterations in the nitric oxide guanylyl cyclase system. Furthermore, adaptive responses in some peptide binding sites occur in hypoxia, which may be due to changes in endogenous peptide levels.Eur Respir J., 1995Respir J., , 8, 2029Respir J., -2037 of endogenous CGRP may be of importance in maintaing pulmonary equilibrium, and impaired release may, thus, be relevant to the pulmonary hypertension that is a consequence of hypoxia.Peptides elicit their effect by interacting with specific receptors on the target cell, which in turn will activate various intracellular pathways that lead to a biological response. These receptors can be identified partly by ligand binding studies and localized quantitatively by using tissue sections for the binding. CGRP binding sites are of two types, termed CGRP1 and CGRP2 [8,9].We hypothesized that changes in the amount of CGRP released will be reflected by an adaptive response shown by changes in its binding sites and, thus, its physiological effects, and have directed our study to investigate the

Pharmacological characterization of CGRP receptors mediating relaxation of the rat pulmonary artery and inhibition of twitch responses of the rat vas deferens

“…CGRP acts in the rat pulmonary artery by an endothelium‐dependent mechanism via nitric oxide, as responses were abolished either by removal of the endothelium or with N G ‐nitro‐ L ‐arginine (which could be reversed with L‐arginine). This conclusion is consistent with previous binding and in vitro studies (Mannan et al ., 1995), and agrees well with the mechanism found in, for instance, the rat thoracic aorta (Gray & Marshall, 1992a,b).…”

Targeted blocking of gene expression for CGRP receptors elevates pulmonary artery pressure in hypoxic rats

“…The mRNA and protein levels of the most potent vasoconstrictor peptide, endothelin-1, were elevated in the lungs of patients and hypoxic rats with PH (6,10,12,35). However, absence of vasodilation rather than active vasoconstriction has been proposed as a cause of PH (4,24,38).…”

Engineering Ex Vivo–Expanded Marrow Stromal Cells to Secrete Calcitonin Gene–Related Peptide Using Adenoviral Vector

“…thelial cells and vascular smooth muscle cells via endothelium-dependent or endothelium-independent mechanisms, depending on vessel type and species [5][6][7]. CGRP deficiency has been suggested to be involved in cardiovascular diseases such as pulmonary hypertension [8][9][10], erectile dysfunction [11], and cerebral vasospasm after subarachnoid hemorrhage (SAH) [12,13]. Therefore, the enhancement of local CGRP delivery is a promising approach for the treatment of these cardiovascular disorders.…”