Decrease of Endothelin Receptor Subtype ETB and Release of COX-Derived Products Contribute to Endothelial Dysfunction of Porcine Epicardial Coronary Arteries in Left Ventricular Hypertrophy

Desjardins, Fanny*†; Aubin, Marie-Claude*†; Carrier, Michel*‡; Perrault, Louis P*†‡

Journal of Cardiovascular Pharmacology:
Original Article
Abstract

Alterations in the regulation of coronary circulation play a major role in the enhanced susceptibility to ischemic injury of the myocardium in left ventricular hypertrophy (LVH). The present study was designed to assess the role of endothelium-dependent contracting factors and endothelin receptors in the coronary endothelial dysfunction in LVH, occurring 2 months after aortic banding in a swine model. Hemodynamic and morphologic analyses were performed in LVH and control groups. Vascular reactivity studies were performed in rings from control and aortic banding groups to assess the contribution of endothelin (ET-1) receptor subtypes to the contraction induced by ET-1 and IRL-1620 (an ETB receptor agonist), with and without endothelium. The effects of cyclooxygenase (COX)-derived products induced by ET-1, serotonin (5-HT), and bradykinin (BK) were evaluated, with or without indomethacin (a COX antagonist). ET-1 receptor density was assessed by confocal microscopy and Western blot experiments. The wall-to-lumen ratio, determined in digital planimetry, was increased in the LVH group with no significant changes in coronary perfusion pressures. There was a significant increase in contractions to ET-1 in the LVH group, which were reduced by exposure to indomethacin and daltroban (thromboxane A2 [TXA2] receptor antagonist). Relaxations to 5-HT and BK were improved by indomethacin in the LVH group. There was no significant change in ETA receptor density (3.113 ± 0.389 vs 3.594 ± 0.314) but a decrease in ETB receptor density (6.435 ± 0.265 vs 4.588 ± 0.089; P < 0.001) in the LVH group. The coronary endothelial dysfunction of swine epicardial coronary arteries in LVH secondary to 2 months of aortic banding involves both relaxing and contracting factors. ETA receptors and COX-derived products are preferentially implicated in the increased contractions to ET-1. Strategies aimed at decreasing ET-1 effects with ET-1 antagonists selective for ETA receptors could improve the coronary endothelial dysfunction in LVH.

Author Information

From the *Research Center, †Department of Pharmacology, and ‡Department of Surgery, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.

Received for publication October 6, 2004; accepted February 1, 2005.

This work was supported by the “Fonds de la recherche de l'Institut de Cardiologie de Montréal (FRICM),” the Department of Surgery, University of Montreal. Dr. Louis P. Perrault is a Research Scholar from the “Fonds de la Recherche en Santé du Québec (FRSQ).”

Reprints: Dr. Louis P. Perrault, Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec H1T 1C8, Canada (e-mail: louis.perrault@icm-mhi.org).

© 2005 Lippincott Williams & Wilkins, Inc.