No abstract

Abstract-We sought to define the contribution of each of the 2 kinin receptors (bradykinin 1 receptor [B 1 R] and bradykinin 2 receptor [B 2 R]) to the cardioprotection of angiotensin-converting enzyme (ACE) inhibition after acute myocardial infarct. Wild-type mice and gene knockout mice missing either B 1 R or B 2 R were submitted to coronary ligation with or without concurrent ACE inhibition and had evaluation of left ventricular systolic capacity by assessment of fractional shortening (FS). Baseline FS was similar in all of the animals and remained unchanged in sham-operated ones. At 3 weeks after myocardial infarct, in the wild-type group there was a 27% reduction of FS (PϽ0.5) without ACE inhibition and 8% with ACE inhibition; in the B 1 R Ϫ/Ϫ groups the FS was reduced by 24% and was no different (at 28%) with ACE inhibition; in the B 2 R Ϫ/Ϫ groups, however, the FS was decreased by 39% and with ACE inhibition was decreased further by 52%. Analysis of bradykinin receptor gene expression in hearts showed that when one receptor was missing, the other became significantly upregulated; but the B 1 R remained highly overexpressed in the B 2 R Ϫ/Ϫ mice throughout, whereas the overexpressed B 2 R became significantly suppressed in the B 1 R Ϫ/Ϫ mice in a manner quantitatively and directionally similar to that of wild-type mice. We conclude that both bradykinin receptors contribute to the cardioprotective bradykinin-mediated effect of ACE inhibition, not only the B 2 R as believed previously; but, whereas with potentiated bradykinin in the absence of B 1 R, the upregulation of B 2 R is simply insufficient to provide full cardioprotection, in the absence of B 2 R, the upregulated B 1 R actually seems to inflict further tissue damage. T he cardioprotective effect of angiotensin-converting enzyme (ACE) inhibition is now well established, 1 but the multiple mechanisms contributing to this effect are still being investigated, and new aspects and functions of the ACE are being reported. 2 The most important and clinically relevant results of ACE inhibition are diminished formation of angiotensin II and prolonged activity of bradykinin. However, whereas the former has been widely explored in studies ranging from basic research to large outcome clinical trials, the latter remains less well understood.Earlier studies explored the physiopharmacology of bradykinin and defined the bradykinin receptor (BR) 1 (B 1 R) and 2 (B 2 R), which mediate its multiple hemodynamic and metabolic effects 3 mainly via use of peptide analogs with agonistic and antagonistic properties. It has generally been accepted that all of the physiologically significant beneficial hemodynamic and metabolic actions of bradykinin are exerted via activation of the constitutive B 2 R. Indeed, acute or chronic infusion of B 2 R antagonists in animals 4 -6 or humans 7 was shown to partly reverse the antihypertensive effect of ACE inhibitors, to prevent the cardioprotective action of ACE inhibition in animals submitted to cardiac ischemia/reperfusion injury, 8,9...