Cardioprotective effect of an endothelin receptor antagonist during ischaemia/reperfusion in the severely atherosclerotic mouse heart.
1. Endothelin (ET) receptor antagonists are cardioprotective during myocardial ischaemia and reperfusion through a nitric oxide (NO)-dependent mechanism. The aim of the present study was to investigate whether the ET receptor antagonist, bosentan, is cardioprotective in atherosclerotic mice. 2. Buffer-perfused hearts from apolipoprotein E/LDL receptor double knockout (KO) and wild-type (WT) mice were subjected to global ischaemia and reperfusion. 3. Following reperfusion, the recovery of rate-pressure product (RPP; left ventricular developed pressure (LVDP) x heart rate) was equally impaired in WT and KO mice given vehicle (34+/-8 and 29+/-9%, respectively). The ET(A)/ET(B) receptor antagonist bosentan (10 micromol l(-1)) improved recoveries to 57+/-10% in WT and to 68+/-10% in KO mice (P<0.01). Similar effects were observed for the recovery of left ventricular end-diastolic pressure (LVEDP), developed pressure and dP/dt. 4. Bosentan improved the recovery of coronary flow in both KO and WT mice. Recovery of coronary flow was significantly higher in the KO mice given bosentan (135+/-15%) than in the WT group (111+/-12%; P<0.01). ET-1 (1 nmol l(-1)) impaired recovery of coronary flow in both WT and KO mice though this effect was more pronounced in the KO mice (P<0.01). 5. Coronary outflow of NO during reperfusion was enhanced in both KO and WT mice following bosentan administration. 6. The ET(A)/ET(B) receptor antagonist bosentan protects the atherosclerotic mouse heart from ischaemia/reperfusion injury. The observation that ET receptor blockade and stimulation have a greater effect on coronary flow in atherosclerotic hearts indicates an increased activation of the ET system in atherosclerotic coronary arteries.
Gonon
Adrian T
AT
Department of Cardiology, Karolinska University Hospital, S-17176 Stockholm, Sweden.
Bulhak
Alexander
A
Bröijersén
Anders
A
Pernow
John
J
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000077300:Bosentan; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D005355:Fibrosis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D015424:Reperfusion; D013449:Sulfonamides
D002316:Cardiotonic Agents; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D019001:Nitric Oxide Synthase; D000077300:Bosentan