Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat.

Abstract

IntroductionProstacyclin is a critical mediator of structure and function in the pulmonary circulation, causing both the inhibition of vascular smooth muscle growth and vasodilatation via the stimulation ofadenylate cyclase. To examine the potential role ofalterations in prostacyclin production or mechanism of action in chronic hypoxic pulmonary hypertension, we determined the effects of prolonged (7 d Hypoxic pulmonary hypertension is one of the critical mechanisms underlying persistent pulmonary hypertension ofthe neonate and the development of pulmonary hypertension in older children and adults with a variety of cardiac and respiratory illnesses (1, 2). This phenomenon has been well studied in the adult rat, yielding both physiologic and anatomic findings similar to those noted in the human (3-5). In the rat model, pulmonary hypertension is evident almost immediately after the onset of acute severe hypoxia, and it is also present with accompanying anatomic changes after more prolonged periods of hypoxia of milder degree. These events in the pulmonary circulation of the rat are contrasted by the maintenance of normal systemic blood pressure, mimicking the clinical experience with this problem (1, 4, 6, 7). Studies in the rat and other species indicate that locally-produced prostacyclin is important in the regulation ofvasomotor tone and vascular cell differentiation and growth in the pulmonary circulation (8, 9). These actions are mediated through the plasma membrane-bound enzyme adenylate cyclase, with prostacyclin stimulation of cyclic AMP (cAMP) production resulting in vasodilatation and the inhibition ofsmooth muscle cell growth (10, 1 1). In vivo experiments and in vitro studies with perfused isolated lung preparations have demonstrated that pulmonary production ofthis potent vasodilator increases with acute hypoxia, resulting in a degree of attenuation of the vasoconstrictor response (12,13). However, despite the initial increase in prostacyclin production, further hypoxia leads to the development of pulmonary hypertension with medial hypertrophy of muscular arteries and extension of vascular smooth muscle (VSM)' into peripheral, normally nonmuscular, arteries (3, 4). These alterations are prevented in the rat when angiotensin II is administered during the hypoxia period, most likely related to its ability to release prostaglandins (PG) (8). This suggests that changes in PG synthesis or PG-mediated mechanisms may be involved in the pathogenesis of chronic hypoxic pulmonary hypertension.To examine the potential role ofalterations in prostacyclin production or mechanism ofaction in chronic hypoxic pulmonary hypertension, we determined the effects ofprolonged (7 d) in vivo hypoxia on in vitro prostacyclin production and mediation of adenylate cyclase activity in rat main pulmonary arteries. PGE2 production and mediation ofadenylate cyclase activity were also investigated to determine if the results for prostacyclin are specific to that vasodilatory prostanoid. Based on the findings with acute hypox...

Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension

“…To ascertain whether PGISexpressing mice had a blunted response to hypoxic vasoconstriction, Tg + mice (n = 10) and Tg -littermates (n = 14) were exposed to acute hypoxia (FIO 2 PGIS-overexpressing mice are protected from the development of chronic hypoxic pulmonary hypertension. To determine the biologic efficacy of overexpression of PGIS, Tg + mice and Tglittermates were exposed to a simulated altitude of 17,000 ft for 5 weeks.…”

Rho Kinase Inhibitors Prevent Endothelium-Dependent Contractions in the Rat Aorta

“…Therefore, the production of prostacyclin metabolite was jpet.aspetjournals.org measured as an index of EDCF release in the presence of Rho kinase inhibition. The confirmed inhibitory effect of indomethacin (Shaul et al, 1991;Gluais et al, 2006) on the production of prostacyclin served as a positive control. Because the breakdown of prostacyclin into 6-keto prostaglandin F 1␣ is by nonenzymatic hydrolysis (Sun and Taylor, 1978;Rosenkranz et al, 1980), the present experiments indicate Rho kinase inhibitors expectedly do not affect it.…”

Thromboxane inhibition reduces an early stage of chronic hypoxia-induced pulmonary hypertension in piglets

“…PGI 2 production has been shown to be elevated in adult rats with chronic hypoxia-induced pulmonary hypertension (9,41). The elevation in PGI 2 may serve in a compensatory role to counteract pulmonary hypertension.…”