Relationship between the cardiovascular effects and both plasma and myocardial levels of clentiazem, a new benzothiazepine calcium antagonist, in anesthetized dogs.
We evaluated the relationship between the cardiovascular effects of clentiazem (TA-3090), a new 1,5-benzothiazepine calcium antagonist with high lipophilicity, and both its plasma and myocardial concentrations. Anesthetized, open-chest dogs, instrumented for hemodynamic data recording and blood sampling, were divided into three groups treated with 15, 50, or 200 micrograms/kg of clentiazem, respectively, as an intravenous bolus. At the end of the protocol (240 minutes), myocardial samples were tested for clentiazem. The results indicated that the peripheral and coronary vasodilatory effects of clentiazem were dose dependent and closely related to its plasma concentrations. It was also observed that the minimal effective plasma concentration was in the range of 15-20 ng/ml. Sustained negative chronotropic effects were recorded at the highest dose only and were best related to the amount of clentiazem detectable in the myocardium, suggesting that myocardial clentiazem retention is a major factor governing its depressant cardiac impact.
Valérie
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Département de Pharmacologie, Faculté de Médecine, Université de Montréal, Québec, Canada.
Louis
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D
Marc
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L
Denis
G
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Claude
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Gilles
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C
D000818:Animals; D002121:Calcium Channel Blockers / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D002319:Cardiovascular System / Q000187:drug effects*; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D009206:Myocardium / Q000378:metabolism*
D002121:Calcium Channel Blockers; C056595:clentiazem; D004110:Diltiazem