res-701-1 and Hypertension--Pulmonary

Although plasma levels of endothelin-1 (ET-1) increase in patients with pulmonary hypertension (PH), its role in PH is unknown. We investigated the contribution of endogenous ET-1 to cardiopulmonary changes in beagles with dehydromonocrotaline (DMCT)-induced PH.. Eight 3-month-old beagles were given a single injection of 3 mg/kg DMCT via the right atrium. During the 8 weeks after injection, the mean pulmonary arterial pressure (PAP) and plasma ET-1 level increased significantly from 11.6 +/- 2.3 to 35.9 +/- 7.1 mm Hg and from 1.24 +/- 0.25 to 3.25 +/- 0.94 pg/mL, respectively. In controls, ET-1 infusion elevated the systemic arterial pressure (SAP) but did not alter PAP. In PH beagles, ET-1 infusion increased SAP, which was attenuated by FR139317 (an endothelin type [ET] A receptor antagonist), and produced a dose-dependent decrease in PAP, which was attenuated by RES-701-1 (an ETB receptor antagonist). In PH beagles, FR139317 infusion decreased PAP, and RES-701-1 infusion increased PAP. Sarafotoxin S6c (an ETB agonist) infusion decreased PAP in PH beagles.. These results suggest that endogenous ET-1 is elevated in PH disease and may mitigate PH by acting on ETB receptors.

Topics: Animals; Azepines; Dogs; Endothelins; Hemodynamics; Hypertension, Pulmonary; Indoles; Monocrotaline; Peptides, Cyclic; Viper Venoms

This study investigated the pharmacologic effect of endothelin receptor antagonists on cardiopulmonary hemodynamic variables in a beagle model of pulmonary hypertension.. We recently developed a beagle model of pulmonary hypertension that allows accurate determination of cardiopulmonary hemodynamic variables and is associated with elevated plasma endothelin-1 concentrations similar to those in pulmonary hypertension in humans.. Twelve beagles (pulmonary hypertension, n = 6; control group, n = 6) were studied during baseline conditions and during right atrial infusion of FR139317 (an ETA receptor antagonist), RES-701-1 (an ETB receptor antagonist), nitroglycerin and prostaglandin E1. Pulmonary hypertension was induced in experimental beagles 8 weeks after injection with 3 mg/kg body weight of dehydromonocrotaline.. FR139317 lowered pulmonary artery and systemic arterial pressures in both pulmonary hypertensive and control beagles, with a significantly greater effect on pulmonary artery pressure in pulmonary hypertensive dogs. RES-701-1 tended to increase pulmonary artery pressure only in pulmonary hypertensive beagles. Nitroglycerin depressed pulmonary artery and systemic arterial tone equally well in control and pulmonary hypertensive animals. Prostaglandin E1 produced a greater decrease in systemic arterial pressure in pulmonary hypertensive than in normal beagles despite having the same effect on pulmonary artery pressure in both.. ETA receptor antagonists decrease pulmonary artery pressure in a beagle model and may therefore be clinically useful for treatment of pulmonary hypertension.

Topics: Alprostadil; Animals; Azepines; Dogs; Endothelin Receptor Antagonists; Hemodynamics; Hypertension, Pulmonary; Indoles; Monocrotaline; Nitroglycerin; Peptides, Cyclic; Pulmonary Circulation