B-type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart.

Natriuretic peptides are regulatory autacoids in the mammalian myocardium whose functions, mediated via particulate guanylyl cyclase/cGMP, may include cytoprotection against ischaemia-reperfusion injury. Previous work has identified that B-type natriuretic peptide (BNP) limits infarct size when administered prior to and during coronary occlusion through a K(ATP) channel-dependent mechanism. The present study examined the hypothesis that the protection afforded by BNP is mediated specifically at reperfusion in a postconditioning-like manner. Langendorff-perfused rat hearts were subjected to 35 min coronary artery occlusion and 120 min reperfusion, and infarct size was determined by tetrazolium staining. Postconditioning was effected by applying six 10-second periods of global ischaemia at the onset of reperfusion.Treatment with either BNP 10 nM or the NO donor S-nitroso-N-acetylpenicillamine (SNAP) 1-10 microM was commenced 5 min prior to reperfusion and continued until 10 min after reperfusion. Control infarct size (% of ischaemic risk zone) was 40.8 +/- 3.7%.BNP at reperfusion induced a significant limitation of infarct size (BNP 22.9 +/- 4.1% P<0.05 vs. control). Co-treatment at reperfusion with BNP and the K(ATP) channel blockers 5-hydroxydecanote (5HD, 100 microM), glibenclamide (Glib; 10 microM) or HMR1098 (10 microM) abolished the infarct-limiting effect of BNP (BNP + 5HD 41.0 +/- 3.9%, BNP + Glib 39.8 +/- 5.6%, BNP + HMR 1098 46.0 +/- 7.1%,P < 0.05 vs. BNP). BNP given together with L-NAME (100 microM) at reperfusion resulted in a marked loss of protection (BNP + L-NAME 53.1 +/- 3.8% P < 0.001 vs. BNP). In a second series of experiments, SNAP (1-10 microM) given at reperfusion was found not to be protective (SNAP 1 microM 30.2 +/- 4.9%, SNAP 2 microM 27.5 +/- 9.5%, SNAP 5 microM 39.2 +/- 5.7%, SNAP 10 microM 33.7 +/- 6.4%, not significant vs. control). In a third series of experiments, postconditioning significantly limited infarct size (14.9 +/- 3.6 % vs. control 34.5 +/- 4.9%, P < 0.01) and this effect of postconditioning was abolished in the presence of isatin (100 microM), a non-specific blocker of particulate guanylyl cyclases (35.1 +/- 6%, P < 0.05 vs. postconditioning). In conclusion, pharmacological activation of pGC by BNP can effectively induce protection against reperfusion injury, by mechanisms involving K(ATP) channel opening and endogenous NO synthase activation. Furthermore, endogenous activation of pGC could play a role in the mechanism of postconditioning.