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Natriuretic peptides modulate ATP-sensitive K(+) channels in rat ventricular cardiomyocytes.

ABSTRACT: B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and (Cys-18)-atrial natriuretic factor (4-23) amide (C-ANF), are cytoprotective under conditions of ischemia-reperfusion, limiting infarct size. ATP-sensitive K(+) channel (KATP) opening is also cardioprotective, and although the KATP activation is implicated in the regulation of cardiac natriuretic peptide release, no studies have directly examined the effects of natriuretic peptides on cardiac KATP activity. Normoxic cardiomyocytes were patch clamped in the cell-attached configuration to examine sarcolemmal KATP (sKATP) activity. The KATP opener pinacidil (200 μM) increased the open probability of the patch (NPo; values normalized to control) at least twofold above basal value, and this effect was abolished by HMR1098 10 μM, a selective KATP blocker (5.23 ± 1.20 versus 0.89 ± 0.18; P < 0.001). We then examined the effects of BNP, CNP, C-ANF and 8Br-cGMP on the sKATP current. Bath application of BNP (≥10 nM) or CNP (≥0.01 nM) suppressed basal NPo (BNP: 1.00 versus 0.56 ± 0.09 at 10 nM, P < 0.001; CNP: 1.0 versus 0.45 ± 0.16, at 0.01 nM, P < 0.05) and also abolished the pinacidil-activated current at concentrations ≥10 nM. C-ANF (≥10 nM) enhanced KATP activity (1.00 versus 3.85 ± 1.13, at 100 nM, P < 0.05). The cGMP analog 8Br-cGMP 10 nM dampened the pinacidil-activated current (2.92 ± 0.60 versus 1.53 ± 0.32; P < 0.05). Natriuretic peptides modulate sKATP current in ventricular cardiomyocytes. This may be at least partially associated with their ability to augment intracellular cGMP concentrations via NPR-A/B, or their ability to bind NPR-C with high affinity. Although the mechanism of modulation requires elucidation, these preliminary data give new insights into the relationship between natriuretic peptide signaling and sKATP in the myocardium.

SUBMITTER: Burley DS

PROVIDER: S-EPMC3951884 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Astrocytes form extensive intercellular networks through gap junctions to support both biochemical and electrical coupling between adjacent cells. ATP-sensitive K(+) (K(ATP)) channels couple cell metabolic state to membrane excitability and are enriched in glial cells. Activation of astrocytic mitochondrial K(ATP) (mitoK(ATP)) channel regulates certain astrocytic functions. However, less is known about its impact on electrical coupling between directly coupled astrocytes ex vivo. By using dual patch clamp recording, we found that activation of mitoK(ATP) channel increased the electrical coupling ratio in brain slices. The electrical coupling ratio started to increase 3 min after exposure to Diazoxide, a mitoK(ATP) channel activator, peaked at 5 min, and maintained its level with little adaptation until the end of the 10-min treatment. Blocking the mitoK(ATP) channel with 5-hydroxydecanoate, inhibited electrical coupling immediately, and by 10-min, the ratio dropped by 71% of the initial level. Activation of mitoK(ATP) channel also decreased the latency time of the transjunctional currents by 50%. The increase in the coupling ratio resulting from the activation of the mitoK(ATP) channel in a single astrocyte was further potentiated by the concurrent inhibiting of the channel on the recipient astrocyte. Furthermore, Meclofenamic acid, a gap-junction inhibitor which completely blocked the tracer coupling, hardly reversed the impact of mitoK(ATP) channel's activation on electrical coupling (by 7%). The level of mitochondrial Connexin43, a gap junctional subunit, significantly increased by 70% in astrocytes after 10-min Diazoxide treatment. Phospho-ERK signals were detected in Connexin43 immunoprecipitates in the Diazoxide-treated astrocytes, but not untreated control samples. Finally, inhibiting ERK could attenuate the effects of Diazoxide on electrical coupling by 61%. These findings demonstrate that activation of astrocytic mitoK(ATP) channel upregulates electrical coupling between hippocampal astrocytes ex vivo. In addition, this effect is mainly via up-regulation of the Connexin43-constituted gap junction coupling by an ERK-dependent mechanism in the mitochondria.

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Natriuretic peptides modulate ATP-sensitive K(+) channels in rat ventricular cardiomyocytes.

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