Bradykinin-dependent cardioprotective effects of losartan against ischemia and reperfusion in rat hearts.
It is unclear whether losartan, an angiotensin II type 1 (AT1) receptor antagonist, protects the heart against acute ischemia-reperfusion injury. Therefore we evaluated cardiac protection conferred by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, we sought to determine both the extent of this protection and its dependence on bradykinin in comparison with quinaprilat, a cardioprotective angiotensin-converting enzyme inhibitor. Cardiac protection was assessed as recovery of coronary flow, left ventricular developed pressure, phosphocreatine, and adenosine triphosphate (ATP) in isolated perfused rat hearts after 15 min of global ischemia and 30 min of postischemic reperfusion. We found that, in hearts pre- and postischemically treated with losartan (1 microM) or quinaprilat (0.1 microM), these variables all recovered significantly better than those in untreated control hearts. In hearts that were only postischemically treated with losartan, these variables also recovered significantly better than those in control hearts. In contrast, in hearts treated with the combination of the bradykinin B2 receptor antagonist Hoe 140 with quinaprilat or losartan, the recovery of the variables no longer differed from that in control hearts. In conclusion, losartan protects the heart against acute ischemia-reperfusion injury. This protection can be achieved by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, the extent of this protection is equivalent to that conferred by quinaprilat and, unexpectedly, dependent on bradykinin.
Zhu
P
P
Cardiovascular Research Group, University Hospital Basel, Switzerland.
Zaugg
C E
CE
Hornstein
P S
PS
Allegrini
P R
PR
Buser
P T
PT
D000255:Adenosine Triphosphate / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000502:physiology*; D003326:Coronary Circulation / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D044005:Tetrahydroisoquinolines; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D044005:Tetrahydroisoquinolines; D010725:Phosphocreatine; D000804:Angiotensin II; C054501:quinaprilat; D000255:Adenosine Triphosphate; D019808:Losartan; D001920:Bradykinin