Endothelin-A Receptor Antagonist BQ123 Protects Against Myocardial and Endothelial Reperfusion Injury

Abstract

Background: This stu dy was designed to invest igate the ef· feet s of th e select ive endothelin-Areceptor antagonist BQ123 on myocardial and endothe lial funct ion after rever sible deep hypot hermic ischem ia and reperfusion . Methods: Isogenic intra-abdomina l het erotopic hea rt transplantati on was perfo rmed in l ew is rat s. Afte r one hour of cold ischemic preservation reperfusia n was sta rte d afte r a pplicatio n of either saline vehicle or BQ l23 (l !lmol/l).left-ventricular pressure-volum e relat ions and myocardial blood flow were asse sse d aft er one and 24 hour s of reperfu sion . Responses to endothelium-de pende nt vasodilator acetylcholine and endot helium-inde pende nt vaso dilato r sodium nitropru sside we re also det ermin ed. Results: BQ123 significant ly improved myocardial co ntract ility. as indicated by the leftward shift of the systolic pressure-volume relation and significantly increased myocardial blood flow during ea rly reperfu sion (p < 0.05). Although myocardial functi on and baseline myocardial blood flow were similar in both gro ups after 24 hour s of reperfuslon, endothelium-depende nt vasod ilatation was st ill sig nificantly higher in the BQ 123 group (p < 0.05). Conclusions: These results suggest that endot helin-A receptor antagonists may be useful in reducing ischemia/ reperfusion injury after heart transplanta tion by preservat ion of myocardial and endothelial function.

Differentiated and dose-related cardiovascular effects of a dual endothelin receptor antagonist in endotoxin shock

“…Thomas et al (27) found a positive inotropic effect from ET-1 in myocytes from normal porcine hearts, whereas the opposite effect was noted in failing hearts. Moreover, ETreceptor antagonism has been found to counteract reperfusion-induced cardiac contractile dysfunction (26,28). Hitherto, few studies have evaluated the cardiac effects of ET receptor antagonism in septic or endotoxin shock (29,30).…”

Pretreatment of Donors with Endothelin Receptor Antagonist TAK-044 Improves Cardiac Functional Recovery Following Preservation with University of Wisconsin Solution

“…Because it has been shown both experimentally and clinically that ischemia and reperfusion result in enhanced production and release of endothelin, it is thought that the development of myocardial injury is closely related to induction of ischemia and reperfusion induced endothelial damage (4). It has been reported that infusion of various endothelin receptor antagonists during reperfusion improves the recovery of myocardial function (3,4). Several studies have reported that endothelin receptor antagonists are useful in reducing ischemia/ reperfusion injury after heart transplantation (3).…”

Role of endothelin in cardiovascular disease

“…154 Other investigators have reported that BQ-123 abolished the postischaemic increase in coronary flow rate in isolated rat hearts after ischaemia and reperfusion, and that bosentan significantly impaired the recovery of systolic function during reperfusion, 155 although the majority of investigators report favourable actions of anti-endothelin agents in ischaemia/ reperfusion models.…”