Natriuretic peptides modulate ATP-sensitive K(+) channels in rat ventricular cardiomyocytes.
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.
Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK, burleyds@cardiff.ac.uk.
Dwaine S
DS
Burley
Charles D
CD
Cox
Jin
J
Zhang
Kenneth T
KT
Wann
Gary F
GF
Baxter
D000818:Animals; D006352:Heart Ventricles / Q000166:cytology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism* / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism* / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D054086:KATP Channels; C495963:natriuretic peptide precursor type B, rat; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D011189:Potassium Chloride