Role of Kinins in the Cardioprotective Effect of Preconditioning

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Abstract
Kinins acting on the B2 receptor appear to be involved in the cardioprotective effect of preconditioning on myocardial ischemia/reperfusion injury. We tested the hypothesis that in mice lacking the gene encoding for the B2 kinin receptor (B2 knockout mice; B2-KO) as well as in rats deficient in high-molecular-weight (HMW) kininogen (Brown Norway Katholiek rats; BNK), the cardioprotective effect of preconditioning is diminished or abolished. 129SvEvTac (SV129) mice and Brown Norway rats (BN) served as controls. We confirmed that plasma HMW kininogen in BNK rats was 100-fold lower than in BN and 140-fold lower than in Sprague-Dawley rats (33±4 versus 1814±253 and 2397±302 ng/mL, P<.01). Each strain of mice was divided into (1) controls (without preconditioning); (2) one cycle of preconditioning (3 minutes ligation and 5 minutes reperfusion); and (3) three cycles of preconditioning. Each strain of rats was divided into (1) controls; and (2) three cycles of preconditioning. All animals were subjected to 30 minutes of ischemia and 120 minutes of reperfusion. In SV129 controls, the ratio of infarct size to risk area (IS/AR) was 55.6±4.6%. One and three cycles of preconditioning reduced IS/AR to 38.6±3.2% and 31.1±2.3%, respectively (P<.05 and P<.01 versus control). This protective effect was absent in B2-KO mice: IS/AR was 54.8±2.9% in controls, 58.5±3.6% with one cycle of preconditioning, and 58.5±3.4% with three cycles. In BN rats without preconditioning, IS/AR was 84.7±3.9%; preconditioning reduced it to 61.6±3.4% (P<.01). In BNK rats, IS/AR was 87.1±4.8% in controls and 84.3±4.1% with preconditioning. Preconditioning also prevented reperfusion arrhythmias in BN but not BNK rats. Within species, risk area, mean blood pressure, and heart rate were similar between strains. We concluded that (1) preconditioning protects the heart against ischemia/reperfusion injury in mice and rats; (2) activation of prekallikrein, which in turn generates kinins from HMW kininogen, may contribute to the effect of preconditioning; and (3) an intact kallikrein-kinin system is necessary for the cardioprotective effect of preconditioning.