Effects of KT-362, a new antiarrhythmic agent with vasodilating action on intracellular calcium mobilization of atrial muscle.
Effects of KT-362 (5-[3[2-3, 4-dimethoxyphenyl) ethyl]amino]-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate; 3-100 microM) on the twitch contraction of isolated rabbit left atria were examined to elucidate the influence of this substance on the intracellular calcium mobilization of cardiac muscles. A 30-sec rest period interrupting the conditioning stimulation at rates greater than 0.5 Hz caused positive inotropy of the first postrest (B1) contraction (rest potentiation). The potentiated B1 contraction was much more resistant to the negative inotropic effect of nifedipine (1 and 3 microM) than the steady-state contraction. The nifedipine-resistant B1 contraction was abolished by ryanodine (30 nM) or caffeine (5 mM). Single treatment of the muscle with KT-362 much greater than or equal to 10 microM resulted in a concentration-dependent decrease in the steady state beat as well as in B1 contraction. In preparations pretreated with 1 microM nifedipine, KT-362 had greater inhibitory action against B1 contraction (IC50 = 7.8 microM). KT-362 (3 and 10 microM) reduced the late plateau amplitude of transmembrane action potential associated with the B1 contraction. Tetrodotoxin (1 and 3 microM) and quinidine (3 and 10 microM) caused a rightward shift of the force-frequency relationship for the B1 contraction but, unlike KT-362, they caused no or minimal reduction of the maximal B1 values. In the presence of 1 microM nifedipine, B1 contraction showed biphasic response to a prolongation of the preceding rest period, an initial rapid increase up to 30 sec was followed by a gradual decrease.(ABSTRACT TRUNCATED AT 250 WORDS)
Kodama
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Department of Pharmacology, University of Hawaii School of Medicine, Honolulu.
Shibata
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D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004558:Electric Stimulation; D006325:Heart Atria; D009130:Muscle, Smooth / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D011802:Quinidine / Q000494:pharmacology; D011817:Rabbits; D012433:Ryanodine / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D013841:Thiazepines; C051271:KT 362; D012433:Ryanodine; D011802:Quinidine; D002118:Calcium