Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung

Abstract

Schindler MB, Hislop AA, Haworth SG. Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung. Am J Physiol Lung Cell Mol Physiol 292: L1273-L1279, 2007. First published January 26, 2007; doi:10.1152/ajplung.00173.2006.-The response of pulmonary arteries to endothelin-1 (ET-1) changes with age in normal pigs and is abnormal in pulmonary hypertension. The purpose of this study was to determine if the same is true of the pulmonary veins. We studied the wall structure and functional response to ET-1 in pulmonary veins from normal pigs from fetal life to adulthood and from pigs subjected to chronic hypobaric hypoxia either from birth for 3 days or from 3 to 6 days of age. In isolated normal veins, the contractile response decreased by 40% between late fetal life and 14 days of age with a concomitant twofold increase in endothelium-dependent relaxant response. The ET A antagonist BQ-123 reduced the contractile response significantly more in newborn than older animals, whereas the ET-B antagonist BQ-788 had no effect in fetal animals and maximally increased contraction at 14 days of age. Hypoxic exposure significantly increased pulmonary vein smooth muscle area and contractile response to ET-1. The relaxation response was impaired following hypoxic exposure from birth but not from 3 to 6 days of age. The ET A antagonist BQ-123 decreased contractile and increased dilator responses significantly more than in age-matched controls. Thus pulmonary veins show age-related changes similar to those seen in the pulmonary arteries with a decrease in ETA-mediated contractile and increase in ET-B-mediated relaxant response with age. Contractile response was also increased in hypoxia as in the arteries. This study suggests that pulmonary veins are involved in postnatal adaptation and the pathogenesis of pulmonary hypertension. postnatal adaptation; pulmonary hypertension A NUMBER OF ANIMAL AND HUMAN studies suggest a role for endothelin-1 (ET-1) in adaptation to extrauterine life (8,21) and in the pathogenesis of pulmonary hypertension (18). Endo et al. (8) found plasma ET-1 concentrations to be threefold higher at birth compared with 5 or 30 days in healthy human neonates, and similar changes have been described in piglets (21). ET-1 blood levels are elevated in patients with pulmonary hypertension and decrease following resolution in persistent pulmonary hypertension of the newborn (24), pulmonary hypertension due to congenital heart disease (18), and pulmonary hypertension due to acute lung injury (19).Experimental studies have shown that the contractile response to ET-1 decreases with increasing age in rabbit pulmonary arteries (7). The effect of age on the pharmacological responses of the porcine pulmonary veins to ET-1 has not been reported; however, as the threshold for ET-1-induced contraction is lower in pulmonary veins than in pulmonary arteries in the fetal lamb (29) and human (4), it is likely that the veins may also exhibit developmental changes in response to ET-1.In h...

Expression of store-operated Ca2+ entry and transient receptor potential canonical and vanilloid-related proteins in rat distal pulmonary venous smooth muscle

“…The functional significance of this reduction is unknown at this time; however, we think it may (or partially) reflect the molecular basis of the differential contractile and relaxant properties of proximal and distal PV, a fact that has been found in a previous report (4). In addition, it is also noteworthy that our results could be age related given that aging was thought to affect the contractile response of PV in various species including rat according to several lines of previous observations (31,32,45).…”

Regulation of the Pulmonary Circulation in the Fetus and Newborn

“…These studies suggest that endogenous ET-1 activity may not play a major role in the vasodilator response to ventilation with O 2 (620). In pulmonary vessels of rabbits and piglets, there is no change in ET Amediated contraction within 24 h after birth (155,511). In primary cultures of ovine pulmonary arterial endothelial cells of newborn lambs, ET-1 secretion is inhibited by an NO donor, activator of sGC, and cGMP analog.…”

“…Plasma ET-1 level in piglets within 2 h after birth is also high but decreases from 3 days of age to adulthood (363). In both rabbit pulmonary resistance arteries and porcine pulmonary veins, there is an age-related decrease in ET A -mediated contraction and increase in ET B -mediated EDNO-dependent relaxation (155,458,511).…”

Role of Endothelin in Uteroplacental Circulation and Fetal Vascular Function

“…ET-1 plays a key role in maintaining high basal pulmonary vascular resistance by acting mainly on ET A R in both pulmonary arteries and veins in the fetus [75–78]. Fetal pulmonary endothelial cells express ECE-1 that produces the majority of ET-1 in fetal lungs.…”