Cardiac electrophysiological modulation by NS-7, a novel neuroprotective drug, of guinea pig ventricular muscles.
Effects of NS-7 (1 to 100 microM), a novel neuroprotective drug, on the action potentials in guinea pig ventricular muscles were investigated at different stimulation frequencies, different extracellular Ca(2+) concentrations ([Ca](o)) and in the presence of inhibitors for selective delayed rectifier K(+) channels. A conventional microelectrode technique was carried out. NS-7 caused inhibitory actions on the action potential configuration in a concentration-dependent manner. NS-7 at less concentrations than 30 microM did not affect, but at 100 microM decreased the action potential amplitude (APA) and the maximum rate of depolarization (V(max)) by 11.1 +/- 2.3% (n = 14, P < 0.05) and by 24.3 +/- 2.6% (n = 14, P < 0.01), respectively. NS-7 at 100 microM also prolonged the 75 and 90% repolarizations of action potential duration (APD(75) and APD(90)) by 14.5 +/- 2.2% (n = 14, P < 0.05) and 20.2 +/- 2.4% (n = 14, P < 0.01), respectively, but it at any concentrations failed to affect the 50% repolarization of action potential duration (APD(50)). The resting potential was unaffected. These responses were almost reversible after 10-to 20-min washout. The stronger inhibition was caused at higher frequencies of stimulation. NS-7 prolonged the APD at lower [Ca](o) than 3.6 mM. In the presence of 5 microM E-4031 or 30 microM 293B, NS-7 increased further the APD. These results indicate that NS-7 at relatively higher concentrations produced inhibitory actions on the cardiac muscles, and that the APD prolongation and the V(max) inhibition induced by NS-7 are dependent on stimulation frequencies, but are independent of [Ca](o) levels, resulting in exhibition of its cardioprotective action.
Satoh
Hiroyasu
H
Department of Pharmacology, Division of Molecular and Cellular Biology, Nara Medical University, Kashihara, Nara 634-8521, Japan. hysat@naramed-u.ac.jp
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004558:Electric Stimulation; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D016276:Ventricular Function
C106144:4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride; D000889:Anti-Arrhythmia Agents; D002839:Chromans; D004338:Drug Combinations; D018696:Neuroprotective Agents; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D002118:Calcium