B-type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart |
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Authors: | D S Burley Gary F Baxter |
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Institution: | (1) The Royal Veterinary College, University of London, London, UK;(2) Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3XF, UK |
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Abstract: | 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 KATP 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 μM 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 KATP channel blockers 5-hydroxydecanote (5HD, 100 μM), glibenclamide (Glib; 10 μM) or HMR1098 (10 μM) 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 μM) 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 μM) given at reperfusion was found not to be protective (SNAP 1 μM 30.2 ± 4.9%,
SNAP 2 μM 27.5 ± 9.5%, SNAP 5 μM 39.2 ± 5.7%, SNAP 10 μM 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 μM), 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 KATP channel opening and endogenous NO synthase activation. Furthermore, endogenous activation of pGC could play a role in the
mechanism of postconditioning. |
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Keywords: | ATP-sensitive potassium channel B-type natriuretic peptide guanylyl cyclase infarct ischaemia-reperfusion nitric oxide postconditioning reperfusion injury |
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