The Specific Modulation Of BmK I, A Modulator For Voltage-gated Na+ Channels, On Rat Cardiac Activity And Potential Mechanisms

Abstract Objectives: In this study, the specific modulation of BmK I, a modulator forvoltage-gated Na+ channels and an α-like scorpion neurotoxin, on isolated rat cardiacmechanical and electrical activity and potential mechanisms have been investigatedusing Langendorff perfusion and electrophysiological technique. The researchincludes two parts:一 Cardiotonic and cardiotoxic effects of BmK I on the isolated rat hearts.The results obtained from Langendorff perfusion showed that BmK I evoked complexeffects characterized by a change of both cardiac mechanical and electrical activity.Langendorff perfusion shown that: a) LVDPmax and dp/dtmax were markedly increasedby BmK I (0.5-10 μM) in a dose-dependent manner (n=6, p<0.05), positivechronotropic effects were also induced by BmK I (n=6, p<0.05); b) negative inotropicaction and bradycardia could be elicited at the larger dose of BmK I (20 μM); c) thecoronary flow varied inversely with the positive inotropic effects, coronary flowreduced during positive inotropic effects from 14.5 to 8.6 ml/min after administrationof 500 nM BmK I (n=6, p<0.05); In addition, tachycardia and complex cardiacarrhythmias were induced by BmK I (0.5-20 μM). The modulating of BmK I on theheart mechanical, electrical activity and coronary flow could be partially recoveredafter washing. As propranolol was applied to block the release of catecholaminesbefore administration of BmK I, suggesting that the changes of cardiac mechanicaland electrical activity induced by BmK I might not due to catecholamine release from英文摘要the nerve terminal and subsequent stimulation of the β-adrenoceptor but attributableto the modulation of BmK I on cardiac voltage-gated sodium channels.二 Amechanism underlying rat heart mechanical activity increase modulated by BmK IThe results made by whole-cell patch-clamping and fluorescence digital imagingshown that: a) L-type Ca2+ current could not be modified by 500 nM BmK I (n=6); b)the inactivation process of Na+ currents was prolonged significantly without alteringthe peak amplitude of Na+ currents (n=6); c) the overall internal Na+ and Ca2+concentration could be augmented in the presence of BmK I (p<0.05 n=60~100); d)the increase of [Ca2+]i caused by 1 μM BmK I could be inhibited completely by 5 mMNiCl2, an antagonist of Na+-Ca2+ exchange, (p<0.05 n=60~100); e) The spontaneousCa2+ release induced by 10 mM caffeine from sarcoplasmic reticulum (SR) could notbe modulated by 500 nM BmK I in the absence of extracellular Ca2+. These resultsindicate that BmK I-induced [Ca2+]i increase was triggered by Ca2+ entering themyocytes via calcium entry mode Na+-Ca2+ exchange after accumulation of [Na+]iresulted from the delay of Na+ currents inactivation phase. Furthermore, BmK I failedto modulate Ca2+ release from SR in the absence of external Ca2+ suggesting that Ca2+release from SR induced by BmK I most likely involves a Ca2+-induced releasemechanism. Taken together, it may allow us to make a conclusion that cardiac VGSCsare also targets of BmK I, and Na+ accumulation through Na+ channels can trigger SRCa2+ release in rat cardiac myocytes by activating Ca2+ influx through calcium entrymode Na+-Ca2+ exchange. The BmK I-induced Ca2+release from SR may account forthe positive inotropic effects induced by BmK I.