Tissue Kallikrein Is Involved in the Cardioprotective Effect of AT1-Receptor Blockade in Acute Myocardial Ischemia

Abstract

Angiotensin-converting enzyme inhibitors limit infarct size in animal models of myocardial ischemia reperfusion injury. This effect has been shown to be due to inhibition of bradykinin degradation rather than inhibition of angiotensin II formation. The purpose of this study was to determine whether angiotensin AT1 receptor blockade by losartan or its active metabolite EXP3174 protects against myocardial ischemia-reperfusion injury in mice and whether this protection is mediated by the kallikrein kinin system. We subjected anesthetized mice to 30 min of coronary artery occlusion followed by 3 h of reperfusion and evaluated infarct size immediately after reperfusion. Losartan (Los) or EXP3174 [2-n-butyl-4-chloro-1-[(2Ј-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] were administered 5 min before starting reperfusion at dosages determined by preliminary studies of blood pressure effect and inhibition of angiotensin pressor response. Compared with saline, both drugs significantly reduced myocardial infarct size by roughly 40% (P Ͻ 0.001). Pretreatment of mice with the selective AT2 receptor antagonist PD123,319 [S-(ϩ)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid] did not affect infarct size in the absence of losartan but abolished the reduction in infarct size provided by losartan. In tissue kallikrein gene-deficient mice (TK Ϫ/Ϫ ), losartan no longer reduced infarct size. Pretreatment of wild-type mice with the B 2 receptor antagonist icatibant reproduced the effect of TK deficiency. We conclude that AT1 receptor blockade provides cardioprotection against myocardial ischemia-reperfusion injury through stimulation of AT2 receptors. Kallikrein and B 2 receptor are major determinants of this cardioprotective effect of losartan. Our results support the hypothesis of a coupling between AT2 receptors and kallikrein during AT1 receptor blockade, which plays a major role in cardioprotection.

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B 2 Receptor– and Angiotensin AT 2 Receptor–Mediated Mechanism

“…12 Our finding that icatibant prevented the cardioprotective effect of aliskiren is consistent with the involvement of B 2 receptors, although unlike other studies we did not detect an effect of icatibant on valsartan-induced cardioprotection. 25,[27][28][29] Many previous studies have shown interaction between the B 2 and AT 2 receptors.…”

“…12 Our finding that icatibant prevented the cardioprotective effect of aliskiren is consistent with the involvement of B 2 receptors, although unlike other studies we did not detect an effect of icatibant on valsartan-induced cardioprotection. 25,[27][28][29] Many previous studies have shown interaction between the B 2 and AT 2 receptors. [33][34][35][36][37][38] Siragy et al 35 showed that PD123319 suppressed basal bradykinin levels and prevented valsartan-induced increase in bradykinin levels in renal interstitial fluid.…”

“…In contrast to the findings for the kidney by Siragy et al, 35 we found that PD123319 did not modify basal cardiac bradykinin levels nor prevent the aliskiren-induced increase in bradykinin levels. Our study demonstrates that B 2 receptor-mediated cardioprotection is dependent on a functional AT 2 receptor, although the exact nature of the interaction between the B 2 and AT 2 receptors remains to be determined (Figure 4).In contrast to the reduction in infarct size produced by short-term ACE inhibitor and ARB administration, [23][24][25][26][27][28][29] we and others 39 showed that short-term aliskiren administration did not produce cardioprotection, despite reduction in angiotensin peptide levels. Rather, a longer period of aliskiren administration, sufficient to increase tissue kallikrein protein and mRNA and bradykinin levels, 12 was required to produce cardioprotection.…”

“…The bradykinin receptor type 2 (B 2 ) receptor antagonist icatibant prevents the reduction in I/R injury produced by ACE inhibitors, [23][24][25][26] whereas both icatibant and the angiotensin II receptor type 2 (AT 2 ) receptor antagonist PD123319 attenuate cardioprotection by ARBs. 25,[27][28][29] Our finding that aliskiren increases cardiac bradykinin levels 12 raised the possibility of cardioprotection, independent of any effect of aliskiren on renin.…”

Recombinant adeno-associated virus-mediated human kallikrein gene therapy protects against hypertensive target organ injuries through inhibiting cell apoptosis

“…They also found that chronic AT1 blockade is associated with reduced myocardial apoptosis in essential hypertension [15] . The beneficial effects of angiotensin-converting enzyme inhibition in hypertension, cardiovascular and renal disease can be partially attributed to kinin accumulation resulting from the activation of the B2 receptor [16,17] . Previous animal studies suggested that kallikrein/kinin protects against myocardial apoptosis after ischemia/reperfusion injury [18,19] .…”