Role of the Alpha2-Adrenoceptors on the Pulmonary Circulation in the Ovine Fetus

Abstract

Recent in vitro studies reported that nitric oxide release and pulmonary vasorelaxation can be mediated by endothelial ␣ 2 -adrenoceptor activation. As norepinephrine (␣ 1 -,␣ 2 -, and ␤ 1 -adrenoceptor agonist) was found to induce pulmonary vasodilation in the ovine fetus, we hypothesized that ␣ 2 -adrenoceptors may modulate basal pulmonary vascular tone and mediate the vascular effect of norepinephrine during fetal life. To determine the role of ␣ 2 -adrenoceptors and the mechanisms of norepinephrine-mediated vasodilation in the fetal pulmonary circulation, we tested, in chronically prepared late-gestation fetal lambs, the hemodynamic response to 1) yohimbine (␣ 2 antagonist); 2) UK 14,304 (␣ 2 agonist) with and without L-nitro-arginine (nitric oxide synthase inhibitor); and 3) norepinephrine infusion with and without yohimbine. We found that yohimbine increased mean pulmonary artery pressure by 15% (p Ͻ 0.05), decreased pulmonary flow by 22% (p Ͻ 0.01), and increased pulmonary vascular resistance by 51% (p Ͻ 0.01). UK 14,304 increased pulmonary flow by 145% (p Ͻ 0.01) and decreased pulmonary vascular resistance by 58% (p Ͻ 0.01). L-Nitro-arginine abolished the UK 14,304-mediated pulmonary vasodilation. Norepinephrine (0.5 g·kg Ϫ1 ·min Ϫ1 ) increased both pulmonary flow by 61% (p Ͻ 0.01) and pulmonary arterial pressure by 13% (p Ͻ 0.01) and decreased pulmonary vascular resistance by 33% (p Ͻ 0.01). Yohimbine abolished the norepinephrine-induced pulmonary vasodilation. This study suggests that 1) a basal ␣ 2 -adrenoceptor activation-induced pulmonary vasodilation exists during fetal life; 2) the pulmonary vascular effects of ␣ 2 -adrenoceptor activation are related at least in part to nitric oxide production; and 3) the norepinephrine-mediated pulmonary vasodilation involves ␣ 2 -adrenoceptor activation. As a surge of norepinephrine exists at birth, we speculate that norepinephrine and endothelial ␣ 2 -adrenoceptor activation may play a significant role in pulmonary vasodilation at birth. High resistance and low blood flow characterize the fetal pulmonary circulation. PVR decreases dramatically during the normal transition from the fetal to neonatal circulation at birth. Three main factors contribute to the increase of Q p during this transition: ventilation of the lung (1), increased O 2 (2), and hemodynamic forces, such as increased shear stress (3). Vasoactive mediators released from the endothelium, such as NO, play a major role in the regulation of acute changes in vascular tone in the perinatal lung, and in many cases, modulate the pulmonary vascular response to these birth-related stimuli (4). Inhibition of NO synthesis can attenuate the postnatal adaptation of the pulmonary circulation (5). The vasodilator action of several substances, such as acetylcholine, bradykinin, or ADP, and shear stress are dependent, at least in part, on NO release (6). More recently, in vitro studies reported that NO release and pulmonary vasorelaxation can also be mediated by endothelial ␣ 2 -adrenoceptor activation (7-9). Ho...

Sex differences in the pulmonary circulation: implications for pulmonary hypertension

“…␣ 2 -Adrenoreceptor activation has also been shown to mediate pulmonary vasodilation in fetal life. This effect is partly related to NO production (80). In this regard, estrogens themselves play a role in the perinatal cardiopulmonary transition (18,68).…”

Higher risk of persistent pulmonary hypertension of the newborn after cesarean

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A high incidence of persistent pulmonary hypertension (PPHN) among neonates delivered by elective cesarean has been reported. This norepinephrine-mediated pulmonary vasodilation involves α 2 -adrenoceptor activation and is related to NO production [4]. A likely hypothesis for PPHN after cesarean is that there might be an advantage to labor and vaginal delivery for the pulmonary vascular bed of the neonate [3].

Mechanisms explaining the increase in PPHN after cesarean remain unclear.

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Prise en charge médicale per- et postnatale de la hernie congénitale diaphragmatique

“…Cette chute rapide des RVP est la conséquence d'une vasodilatation [7]. De multiples mécanismes contribuent à cette adaptation circulatoire à la vie extra-utérine, comme la ventilation alvéolaire, l'augmentation des pressions partielles en O 2 , les contraintes vasculaires de cisaillement (shear stress) et la libération de médiateurs vasodilatateurs [8][9][10].…”

“…Chez le foetus de brebis, la noradrénaline augmente le débit pulmonaire et réduit les RVP [44]. L'effet vasodilatateur pulmonaire de la noradrénaline en période périnatale est lié à la libération de NO, par activation des récepteurs 2 -adrénergiques endothéliaux [9,44]. Par ailleurs, la noradrénaline améliore l'adaptation cardiocirculatoire à la naissance chez des agneaux porteurs d'une HTAPP [53].…”