Role of Endothelins and Nitric Oxide in the Pulmonary Circulation of Perinatal Lambs During Hyperoxia and Hypoxia

Abstract

Endothelins (ET) have opposite vascular effects mediated through different receptors: ET A receptors mediating vasoconstriction and ET B receptors mediating vasoconstriction as well as vasodilation. The role of ET in acute hypoxic pulmonary vasoconstriction (HPV) was studied after dual ET receptor blockade with bosentan and nitric oxide (NO) synthase inhibition with nitro-Larginine (L-NA). We started from the hypothesis that ET antagonism may inhibit HPV but, if not, would do so after NO synthase inhibition. HPV was evaluated in anesthetized lambs, with an intact pulmonary circulation, by the increase in the mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao) gradient in response to hypoxia (inspiratory oxygen fraction of 0.1) at different levels of pulmonary flow (multipoint pressure/flow relationships). ET receptor antagonism decreased pulmonary and systemic vascular tone both in hyperoxia and hypoxia. ET antagonism had no effect on HPV. NO synthase inhibition increased pulmonary vascular tone more in hypoxia than in hyperoxia so that HPV was enhanced. After L-NA, bosentan still decreased pulmonary vascular tone in hypoxia but did not affect the magnitude of HPV. The present results suggest that ET and NO are involved in the regulation of basal pulmonary vascular tone. Furthermore, the vasodilator effect of bosentan persisted in the presence of NO synthase inhibition, suggesting a non NO-dependent vasodilator mechanism. The results from these experiments are in agreement with the idea that ET do not play a major role in HPV in the perinatal lamb, even when it is enhanced by NO synthase inhibition. (Pediatr Res 59: 131-136, 2006) E T are powerful vasoactive mediators synthesized and released by the vascular endothelium (1). Plasma levels of circulating ET-1, the predominant isoform of ET, vary with age: in the fetus and newborn infants they are higher than in neonates and infants up to 3 months of age; they then become nearly constant and similar to adult levels (2-4). ET-1 plasma levels are also elevated in newborns and children suffering from diseases associated with pulmonary hypertension (PHT) and are correlated with the severity of the disease (5-7).ET have opposite vascular effects mediated through different receptors. ET A receptors, located on vascular smooth muscle cells, mediate ET-1 vasoconstriction. ET B receptors are found on vascular smooth muscle cells, where they mediate vasoconstriction, and also on endothelial cells, where their stimulation produces vasodilation, presumably through the endothelial synthesis of NO and prostacyclin (8,9). Activation of the ET B receptor mediates pulmonary clearance of circulating ET-1 and reuptake of ET-1 by endothelial cells (8). In addition, although it is generally proposed that endothelial NO synthesis is related to ET-B receptor stimulation (8 -11), another study shows that activation of ET-A receptors also can enhance NO production in the vasculature (12). In experimental studies on the regulation of the pulmonary vascular tone in peri...

Dual endothelin receptor blockade with tezosentan markedly attenuates hypoxia‐induced pulmonary vasoconstriction in a porcine model

“…Similarly, bosentan did not attenuate HPV in dogs (Hubloue et al. 2003) and perinatal lambs (Biarent et al. 2006).…”

sGC stimulation totally reverses hypoxia‐induced pulmonary vasoconstriction alone and combined with dual endothelin‐receptor blockade in a porcine model

“…Although it is widely recognized that ET-1 plays an important role in the effects of chronic hypoxia, its role in acute HPV has been controversial. Studies on ET-receptor blockade, both in vivo and in vitro, in different species, have shown both attenuation (Bonvallet et al 1994, Holm et al 1996, Sato et al 2000, Goirand et al 2003, Modesti et al 2006, Petersen et al 2008 and no attenuation (Douglas et al 1993, Takeoka et al 1995, Lazor et al 1996, Hubloue et al 2003, Biarent et al 2006 of the HPV response.…”

“…Hypoxia per se has been found to increase the amount of ET-1 mRNA in the lung and right atrium (Kourembanas et al 1991, Elton et al 1992, the ET-1 immunoreactivity in plasma, as well as stimulate preproendothelin-1 promotor activity (Aversa et al 1997) and up-regulate the amount of ET-receptors (Soma et al 1999). Studies on ET-receptor blockade, both in vivo and in vitro, in different species, have shown both attenuation (Bonvallet et al 1994, Holm et al 1996, Sato et al 2000, Goirand et al 2003, Modesti et al 2006, Petersen et al 2008 and no attenuation (Douglas et al 1993, Takeoka et al 1995, Lazor et al 1996, Hubloue et al 2003, Biarent et al 2006 of the HPV response. Studies on ET-receptor blockade, both in vivo and in vitro, in different species, have shown both attenuation (Bonvallet et al 1994, Holm et al 1996, Sato et al 2000, Goirand et al 2003, Modesti et al 2006, Petersen et al 2008 and no attenuation (Douglas et al 1993, Takeoka et al 1995, Lazor et al 1996, Hubloue et al 2003, Biarent et al 2006 of the HPV response.…”