Effects of birth-related stimuli on L-arginine-dependent pulmonary vasodilation in ovine fetus

Abstract

To determine the effects of birth-related stimuli on L-arginine-dependent vasodilation or nitric oxide (NO) activity in the perinatal lung, we studied the fetal pulmonary vascular effects of nitro-L-arginine (L-NA), a specific inhibitor of NO formation, during 1) mechanical ventilation without altering fetal blood gas tensions; 2) administration of high oxygen concentrations; and 3) increased flow or shear stress. In the first protocol, 13 late-gestation fetal lambs were ventilated with low fraction of inspired oxygen concentration (FIO2 less than or equal to 0.10) for 60 min after infusion of L-NA or saline into the left pulmonary artery (LPA). In control animals, LPA flow steadily increased during 60 min of ventilation. With L-NA treatment, the rise in flow and decrease in total pulmonary resistance (TPR) were reduced 67% (P less than 0.001 vs. control) and 28% (P less than 0.01 vs. control), respectively. Subsequent ventilation with high FIO2 (1.00) decreased mean pulmonary arterial pressure (PAP) in control but not in L-NA-treated animals. TPR remained fourfold greater in L-NA-treated animals than in control animals (P less than 0.001). In the second protocol, with partial compression of the ductus arteriosus, LPA flow increased 300% and TPR decreased 61% over 30 min. After L-NA treatment the rise in blood flow and decrease in TPR was markedly attenuated (P less than 0.001). We conclude that the perinatal pulmonary vasodilator response to ventilation without changing arterial oxygen tension and ventilation with increased oxygen tension are modulated by NO.(ABSTRACT TRUNCATED AT 250 WORDS)

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

“…Low fetal PaO 2 (21,22), lack of a gas-liquid interface (1), and production of vasoconstrictor mediators such as leukotrienes (23,24) and endothelin-1 (25) contribute to maintain high PVR in the fetus. However, endogenous release of NO modulates the vasoconstrictor tone in the late-gestation fetus (4,5) and mediates pulmonary vasodilation to several physiologic and pharmacologic stimuli such as acetylcholine, shear stress, and oxygen (4,5,26,27). NO production also contributes to the decrease in PVR at the time of birth (4, 28 -30).…”

“…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).…”

Ventilation and oxygenation induce endothelial nitric oxide synthase gene expression in the lungs of fetal lambs.

“…First, in fetal lambs, acetylcholine decreases pulmonary vascular resistance and increases pulmonary blood flow (41); these hemodynamic effects are blocked by N -nitro-l-arginine or other l-arginine analogs which inhibit NO synthesis (41). Second, inhibition of NO synthesis increases pulmonary vascular resistance in fetal lambs and attenuates the increase in pulmonary blood flow induced by maternal hyperbaric oxygen exposure, ventilation with air or oxygen (8)(9)(10)16), or compression of the ductus arteriosus. Third, l-arginine, the precursor of NO, increases pulmonary blood flow in fetal and newborn lambs and augments endothelium-dependent pulmonary vasodilation (8, Figure 2.…”

“…When endothelial cells are subjected to shear stress, a diverse set of responses is initiated, some of which occur within minutes, others which occur within hours or days (39). In vivo, the acute compression of the ductus arteriosus increases fetal pulmonary blood flow; this increase is blocked by inhibition of NO synthesis, suggesting that the increase in pulmonary blood flow has increased shear stress, increasing NOS activity and NO production (9). This increase in NO activity induced by shear stress is associated with rapid changes in endothelial cell calcium concentration, ionic conductance, adenylate cyclase activity, and inositol triphosphate generation (20)(21)(22)(23)39).…”

“…The increase in alveolar or pulmonary and systemic arterial blood oxygen tensions decreases pulmonary vascular resistance either directly by dilating the small pulmonary arteries, or indirectly by stimulating the production of vasodilator substances such as nitric oxide (NO) 1 (8)(9)(10). Endothelial cells synthesize NO and l -citrulline from l -arginine by the action of the enzyme endothelial nitric oxide synthase (eNOS) (11,12).…”