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B-type natriuretic peptide (BNP) in myocardial ischaemia-reperfusion injury

D'Souza, Savio Pio Vitorino Baptista; (2003) B-type natriuretic peptide (BNP) in myocardial ischaemia-reperfusion injury. Doctoral thesis (M.D.), UCL (University College London). Green open access

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Abstract

Type-B natriuretic peptide (BNP) is an important hormone abundantly present as a pro-peptide in cardiomyocytes. Its release is triggered by exercise, hypoxia and myocardial ischaemia, in addition to chronic haemodynamic cardiac overloading states. BNP's main endocrine actions of vasodilation and natriuresis are mediated by a particulate receptor guanylyl cyclase, natriuretic peptide receptor-A (NPR-A), with subsequent elevation of intracellular cGMP. The role and mechanisms of action of BNP in cardiac ischaemia are not known. We hypothesised that BNP mediates cardioprotection during acute ischaemia-reperfusion, via guanylyl cyclase and cGMP elevation, and examined the role of KATP channel opening in the protective mechanism. The role of nitric oxide (NO) in BNP's signal transduction was also evaluated. Pharmacological studies were carried out in the Langendorff perfused rat heart. Endogenous BNP release was assessed by radio-immunoassay of coronary effluent samples following global normothermic ischemia. Peak concentrations in the first min of reperfusion were markedly elevated following 2 min, 5 min and 20 min of ischaemia. In rat hearts subjected to 35 min regional ischaemia, exogenous BNP limited infarct size in a concentration-dependent manner. The protective action of BNP was sensitive to inhibition by glibenclamide and 5-hydroxydecanoate, blockers of the mitochondrial KATP channel, but not by HMR1098, a blocker of the sarcolemmal KATP channel. Radio-immunoassayed cGMP in cardiac tissue showed a proportionate rise when hearts were subjected to graded durations of ischaemia and when perfused with BNP. Hearts perfused with varying concentrations of 8-bromo-cGMP, a cell-permeable cGMP analogue, were protected against infarction at the lower concentration. L-NAME a blocker of nitric oxide synthase (NOS), and ODQ a blocker of soluble guanylyl cyclase (sGC), both abolished cardioprotection when co-perfused with BNP, suggesting that NO and its activation of sGC play key roles in the protective effect of BNP. To evaluate the source of NOS, studies were undertaken using Western Blot techniques to probe the involvement of endothelial isoform of NOS (eNOS) known to be partially responsible for BNP's vasodilation. However, we found no evidence for acute phosphorylation of eNOS at serine 1177, following BNP or acute ischaemia. Finally, together, our findings indicate a previously-unrecognised cardioprotective action of exogenous BNP via opening of the putative mitochondrial KATP channel with the involvement of basal nitric oxide in the NO/sGC, and cGMP release in the signal transduction. The work contained in this thesis thus confirms a cytoprotective role for BNP in myocardial ischaemia-reperfusion injury and requires further studies in other species and in transgenic models.

Type: Thesis (Doctoral)
Qualification: M.D.
Title: B-type natriuretic peptide (BNP) in myocardial ischaemia-reperfusion injury
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10108336
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