ET(A) receptor blockade improves post-ischaemic functional recovery in 'hibernating' rat myocardium.
Endothelin-1 (ET-1) is a potent vasoconstrictor, and ET(A) receptors mainly mediate this effect. Elevated plasma levels of ET-1 are observed in patients with coronary heart disease. The release of this peptide from the damaged endothelium may play a role in the initiation and maintenance of myocardial ischaemia. This study examines the ET(A) receptor-mediated role of endogenous ET-1 in post-ischaemic myocardial function after prolonged hypoperfusion in normal non-failing hearts. In an isolated rat heart model for short-term myocardial hibernation, left ventricular functional recovery after 3 h of hypoperfusion (15% of pre-ischaemic flow) followed by 2 h of reperfusion was determined. Under steady-state conditions, coronary flow, left ventricular pressure (LVP) and dP/dt(max) were measured in the isovolumically beating heart. Additionally, the maximal inotropic response (LVP and dP/dt(max)) to calcium stimulation was determined. To study the role of ET(A) receptors under these pathophysiological conditions, one group was treated with the ET(A) antagonist BQ 610 (0.8 micromol/l) during hypoperfusion, and compared with a control group which received a saline infusion during hypoperfusion. Reperfusion for 2 h after 3 h of hypoperfusion resulted in partial functional recovery in both groups. Post-ischaemic recovery was significantly better in the hearts that were treated with the ET(A) antagonist BQ 610 during hypoperfusion (LVP, +19.5% compared with control; dP/dt(max), +13.7% compared with control). The inotropic response to calcium was nearly normalized after ET(A) blockade. Thus the normal non-failing myocardium profits from ET(A) receptor blockade during a prolonged period of hypoperfusion, resulting in significantly better post-ischaemic recovery of myocardial function.
Medizinische Klinik, Abt. III, Eberhard-Karls-Universität, Otfried-Müller-Str. 10, 72076 Tübingen, Germany. martin.beyer@med.uni-tuebingen.de
Martin E
ME
Beyer
Marcus
M
Fischer
Tobias
T
Hövelborn
Hans Martin
HM
Hoffmeister
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D017682:Myocardial Stunning / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009842:Oligopeptides / Q000627:therapeutic use*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D012965:Sodium Chloride / Q000494:pharmacology; D013268:Stimulation, Chemical; D013997:Time Factors
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D044022:Receptor, Endothelin A; C087220:BQ 610; D012965:Sodium Chloride; D002118:Calcium