Antiischemic effects of CP-060S, an inhibitor of pathologically modified sodium channels, assessed in the canine experimental model of angina pectoris.
CP-060S is a novel compound that can inhibit the slow inward calcium current as well as the veratridine-induced, noninactivating sodium current. Antiischemic and cardiovascular effects of CP-060S were assessed by using halothane-anesthetized beagle dogs and compared with the effects of semotiadil, a benzothiazine calcium antagonist. The first or second diagonal branch was narrowed. ECG, unipolar electrograms from both ischemic and nonischemic regions, and systemic and left ventricular pressure were monitored. The left ventricle was electrically driven at 190-240 beats/min for 3 min to induce reversible myocardial ischemia. The severity of ischemia was judged by the magnitude of ST-segment depression. CP-060S (0.1 mg/kg, i.v.) significantly attenuated the pacing-induced ST-segment depression in the ischemic region >2 h, whereas during the sinus rhythm, it showed reversible negative chronotropic, inotropic, and dromotropic effects and induced transient depressor response, which would not necessarily be considered favorable (n = 8). A smaller dose of CP-060S (0.03 mg/kg, i.v.) showed a similar antiischemic and cardiovascular profile, but each effect was less potent than that of the higher dose (n = 7). Semotiadil (0.1 and 0.3 mg/kg, i.v.) also showed cardiovascular suppression similar to that of CP-060S; however, the antiischemic effect was not detected during the whole experimental period (n = 6). Thus the inhibition of the noninactivating sodium current may be the primary reason for the antiischemic effect of CP-060S and could become a new cytoprotective principle in the treatment of patients with ischemic heart disease.
Sugiyama
A
A
Department of Pharmacology, Yamanashi Medical University, Nakakoma, Japan.
Hashimoto
K
K
D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000627:therapeutic use; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D008297:Male; D017202:Myocardial Ischemia / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D013844:Thiazoles / Q000097:blood / Q000627:therapeutic use*; D053778:Thiazolidines; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; C104781:CP 060S; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013844:Thiazoles; D053778:Thiazolidines