Electrophysiological and antiarrhythmic studies of new-type calcium channel blockers, labedipinedilols, on cardiac myocytes and tissues

• Main Authors: An-Hsiang Huang, 黃安祥
• Other Authors: Ing-Jun Chen
• Format: Others
• Language: zh-TW
• Published: 2003
• Online Access: http://ndltd.ncl.edu.tw/handle/91288360312702163441

碩士 === 高雄醫學大學 === 醫學研究所 === 91 === Labedipinedilol-A, -B and -C are synthetic 1,4-dihydropyride derivatives with /-adrenoceptor and calcium channel blockading activities. As demonstrated previously, labedipinedilol-A, -B and -C have been described with triple blocking activities on /-adrenergic receptor and L-type calcium channel, functioning in a molecule displaying monotherapy properties on rats. However, a direct electrophysiological characterization of these drugs has not yet been documented at single cell level. The aim of present study is to elucidate the ionic mechanisms underlying the labedipinedilol-A, -B and -C actions on cardiac myocytes and to assess the antiarrhythmic activities. Under the whole-cell configuration, we investigate the effects of labedipinedilol-A on action potential, sodium current (INa), L-type calcium current (ICaL), transient outward potassium current (Ito), and inward rectifier potassium current (IK1) in single isolated ventricular myocytes from rats by using patch-clamp techniques. In single isolated ventricular myocytes form rats, labedipinedilol-A abbreviate markedly action potential duration (APD) and reduce in action potential amplitude (APA) in a concentration-dependent manner, but having no effect on the resting membrane potential (RMP). Whole-cell voltage clamp study reveals that labedipinedilol-A produces a concentration-dependent reduction in sodium current (INa) amplitude, recorded in low [Na+]o solution. Extracellular application of labedipinedilol-A significantly reduces the peak amplitude of L-type calcium current (ICaL) with concentration-dependent inhibition. On the contrary, both the transient outward potassium current (Ito) and inward rectifier potassium currents (IK1) are enhanced by the addition of labedipinedilol-A. These results indicate that labedipinedilol-A acts as a inhibitor of the sodium and L-type calcium channel, but a activator of the transient outward and inward rectifier potassium channel. In the experiment of antagonizing -adrenergic receptors, labedipinedilol-A can competitively antagonize the effect of β-adrenoceptor agonist, (-)isoproterenol, on L-type calcium current. We investigate the protective effect of labedipinedilol-A on ouabain-induced arrhythmia in isolated whole atria from guinea-pigs. The results indicate that labedipinedilol-A significantly prolongs the onset time of extra-systole (arrhythmia) induced by ouabain in isolated atria. We also investigate the effects of labedipinedilol-B and -C on action potential, sodium current and L-type calcium current in single isolated ventricular myocytes form rats. Similar to labedipinedilol-A, labedipinedilol-B and -C inhibit the action potential duration and action potential amplitude. According to the extent of shortening of action potential duration, the sequences are labedipinedilol-A > labedipinedilol-C > labedipinedilol-B in turn. Similar to the actions of labedipinedilol-A, labedipinedilol-B and -C also inhibit the peak amplitude of sodium and L-type calcium current in ventricular myocytes isolated from rats. The degrees of inhibition of sodium current are labedipinedilol-A > labedipinedilol-B > labedipinedilol-C, respectively. The sequences of inhibitory effects for L-type calcium current are labedipinedilol-C > labedipinedilol-A > labedipinedilol-B, respectively. All of them are stronger than nifedipine for L-type calcium current in isolated rat ventricular myocytes. The different inhibitory capacity for sodium and L-type calcium current of labedipinedilol-A, -B, and -C are originated from the functional group in the structure. Such as the structure of labedipinedilol-B lacks a methoxy moiety on phenyl ring, differ from labedipinedilol-A and -C. The electron-donating substituent, i.e. methoxy, plays an important role in affecting biological activities. The methoxy moiety on phenyl ring is beneficial for receptor or channel binding. These findings may provide some explanations of ionic mechanism for the effects of new-type calcium channel blockers, labedipinedilol-A, -B and -C, in the cardiac myocytes and a new aspect of their possible clinical therapeutic actions.