Prolonged endothelin B receptor blockade causes pulmonary hypertension in the ovine fetus.

Abstract

Endothelin (ET)-1 contributes to regulation of pulmonary vascular tone and structure in the normal ovine fetus and in models of perinatal pulmonary hypertension. The hemodynamic effects of ET-1 are due to activation of its receptors. The ET(A) receptor mediates vasoconstriction and smooth muscle cell proliferation, whereas the ET(B) receptor mediates vasodilation. In a lamb model of chronic intrauterine pulmonary hypertension, ET(B) receptor activity and gene expression are decreased. To determine whether prolonged ET(B) receptor blockade causes pulmonary hypertension, we studied the hemodynamic effects of selective ET(B) receptor blockade with BQ-788. Animals were treated with an infusion of either BQ-788 or vehicle for 7 days. Prolonged BQ-788 treatment increased pulmonary arterial pressure and pulmonary vascular resistance (P < 0.05). The pulmonary vasodilator response to sarafotoxin 6c, a selective ET(B) receptor agonist, was attenuated after 7 days of BQ-788 treatment, demonstrating pharmacological blockade of the ET(B) receptor. Animals treated with BQ-788 had greater right ventricular hypertrophy and muscularization of small pulmonary arteries (P < 0. 05). Lung ET-1 levels were threefold higher in the animals treated with BQ-788 (P < 0.05). We conclude that prolonged selective ET(B) receptor blockade causes severe pulmonary hypertension and pulmonary vascular remodeling in the late-gestation ovine fetus.

• Authors: D D Ivy, T A Parker, S H Abman
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 279 Issue 4 Pg. L758-65 (Oct 2000) ISSN: 1040-0605 [Print] United States
• PMID: 11000137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antihypertensive Agents
• Endothelin Receptor Antagonists
• Endothelin-1
• Oligopeptides
• Piperidines
• Receptor, Endothelin A
• Receptor, Endothelin B
• Receptors, Endothelin
• Carbon Dioxide
• BQ 788
• Oxygen

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Blood Pressure (drug effects)
• Carbon Dioxide (blood)
• Endothelin Receptor Antagonists
• Endothelin-1 (physiology)
• Female
• Gestational Age
• Hemodynamics (drug effects, physiology)
• Hypertension, Pulmonary (chemically induced, embryology, physiopathology)
• Oligopeptides (pharmacology)
• Oxygen (blood)
• Piperidines (pharmacology)
• Pregnancy
• Pulmonary Circulation (drug effects, physiology)
• Receptor, Endothelin A
• Receptor, Endothelin B
• Receptors, Endothelin (physiology)
• Reference Values
• Sheep
• Vascular Resistance (drug effects)