title: ET-A receptor activity restrains coronary blood flow in the failing heart.
abstract: Circulating levels of the potent vasoconstrictor peptide endothelin-1 (ET-1) are increased in congestive heart failure (CHF). Coronary blood flow and myocardial oxygen consumption (MVO2) are decreased in some models of CHF. This study tested the hypothesis that ET-1 induced coronary vasoconstriction limits oxygen availability in the failing heart. The effects of selective ET-A receptor blockade with BQ610 (5 microg/min, intracoronary) and selective ET-B receptor blockade with BQ788 (5 microg/min, intracoronary) on coronary blood flow were examined at rest and during graded treadmill exercise in 8 dogs in which congestive heart failure (CHF) had been produced by rapid ventricular pacing for three to four weeks. In animals with CHF, ET-B receptor blockade caused no change in left ventricular (LV) pressure or coronary blood flow. In contrast, ET-A blockade with BQ610 resulted in modest significant increases of coronary blood flow at rest (from 22.4 +/- 2.1 to 27.9 +/- 3.0 mL/min) and during two exercise stages (from 26.9 +/- 2.0 to 30.7 +/- 1.9 during stage 1 exercise and from 28.5 +/- 2.0 to 31.7 +/- 1.3 mL/min during stage 2; all P < 0.05), with an upward shift in the relationship between coronary flow and rate-pressure product. The increase in coronary flow produced by ET-A blockade was not associated with an increase of either myocardial oxygen uptake or LV dP/dt. Thus, although ET-A receptor blockade caused a modest increase in coronary flow, this did not result in an increase of MVO2, implying that ET-A-mediated coronary vasoconstriction did not limit oxygen uptake by the failing heart.
authors.affiliation: Department of Medicine, University of Minnesota Health Sciences Center, Minneapolis, USA.
authors.forename: Mingxiao
authors.initials: M
authors.lastname: Hou
authors.forename: YingJie
authors.initials: Y
authors.lastname: Chen
authors.forename: Jay H
authors.initials: JH
authors.lastname: Traverse
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Li
authors.forename: Michel
authors.initials: M
authors.lastname: Barsoum
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D009842:Oligopeptides / Q000494:pharmacology; D044022:Receptor, Endothelin A / Q000819:agonists / Q000502:physiology*
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D044022:Receptor, Endothelin A; C087220:BQ 610