Summary
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 μg/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 vasodilator 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.
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References
Pool PE, Massle BM, Venkataraman K, et al. Diltiazem as monotherapy for systemic hypertension: A multicenter, randomized, placebo-controlled trial. Am J Cardiol 1986;57:212–217.
Petru MA, Crawford MH, Sorensen SG, et al. Short and long term efficacy of high-dose oral diltiazem for angina due to coronary artery disease: A placebo-controlled, randomized, double-blind crossover study. Circulation 1983;68: 139–147.
Rosanski JJ, Zaman L, Castellanos A. Electrophysiologic effects of diltiazem hydrochloride in supraventricular tachycardia. Am J Cardiol 1982;49:621–628.
Kiyomoto A, Sasaki Y, Odawara A, et al. Inhibition of platelet aggregation by diltiazem: A comparison with verapamil and nifedipine and inhibitory potencies of diltiazem metabolites. Circ Res 1983;52:115–119.
Mehta JL. Influence of calcium channel blockers on platelet function and arachidonic acid metabolism. Am J Cardiol 1985;55:158B-164B.
Birx DL, Berger M, Fleischer TA. The interference of T-cell activation by calcium channel blocking agents. J Immunol 1984;133:2904–2909.
Ernst E, Matrai A. Diltiazem alters blood rheology. Pharmatherapeutica 1988;5:213–216.
Sugano M, Nakashima Y, Matsushima T, et al. Suppression of atherosclerosis in cholesterol-fed rabbits by diltiazem injection. Arteriosclerosis 1986;6:237–241.
Ginsburg R, Davis K, Bristow MR, et al. Calcium antagonists suppress atherogenesis in aorta but not in the intramural coronary arteries of cholesterol-fed rabbits. Lab Invest 1983;49:154–158.
Narita H, Ginsburg R. In vitro study of the effect of clentiazem on rabbit aorta and on myocardium. Cardiovasc Drugs Ther 1990;4:723–730.
Kikkawa K, Murata S, Nagao T. Calcium antagonistic and spasmolytic activities of a new 1,5 benzothiazepine derivative in isolated canine and monkey arteries. Drug Res 1988;38:526–531.
Murata S, Kikkawa K, Yabana H, et al. Cardiovascular effects of a new 1,5 benzothiazepine calcium antagonist in anesthetized dogs. Drug Res 1988;38:521–525.
Narita H, Murata S, Yabano K, et al. Long lasting hypotensive and antihypertensive effects of a new 1,5-benzothiazepine calcium antagonist in hypertensive rats and renal hypertensive dogs. Drug Res 1988;38:515–520.
Smith MS, Verghese CP, Shand DG, et al. Pharmacokinetic and pharmacodynamic effects of diltiazem. Am J Cardiol 1983;51:1369–1374.
Dagher E, Dumont L, Chartrand C. Positive hemodynamic interaction between amrinone and diltiazem in anesthetized dogs. Can J Physiol Pharmacol 1989;67:1092–1097.
Lefebvre M, Garceau D, Spénard J, et al. High performance liquid chromatographic method for the assay of TA-3090 and its pharmacokinetic parameters in healthy volunteers. J Pharm Biomed Anal 1989;7:1919–1924.
Sokal RR, Rohlf RJ, eds. Biometry. San Francisco: W.H. Freeman, 1969.
Isshiki T, Pegram BL, Frochlich ED. Hemodynamic comparison of diltiazem and TA-3090 in spontaneously hypertensive and normal Wistar-Kyoto rats. Am J Cardiol 1988;62(Suppl):796–866.
Dumont L, Derouin M, Chartrand C, et al. Peripheral vasodilator and cardiac properties of the 1,5 benzothiazepine calcium antagonist analog, TA-3090, in dogs. Can J Physiol Pharmacol 1991;69:512–517.
Clozel JP, Billette J, Caillé G, et al. Effects of diltiazem on atrioventricular conduction and arterial blood pressure: Correlation with plasma drug concentrations. Can J Physiol Pharmacol 1984;62:1479–1486.
Skarvan K, Priebe HJ. Cardiovascular effects of diltiazem in the dog. Br J Anaesth 1988;60:660–670.
Hemann P, Morselli PL. Pharmacokinetics of diltiazem and other calcium entry blockers. Acta Pharmacol Toxicol 1985;57(Suppl II):10–20.
Browne RK, Dimmitt DC, Miller LD, et al. Relationship between plasma diltiazem and cardiovascular responses in conscious dogs. J Cardiovasc Pharmacol 1983;5:483–490.
Nayebpour M, Talajic M, Jing W, et al. Autonomic modulation of the frequency-dependent actions of diltiazem on the atrioventricular node in anesthetized dogs. J Pharmacol Exp Ther 1990;253:353–361.
Nakamura S, Ohashi M, Suzuki T, et al. Metabolic fate of the new Ca2+-channel blocking agent (+)-(2S,3S)-3-acetoxy-8-chloro-(2-(dimethylamino)ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-2,5-benzo-thiazepin-4-(5H)-one maleate: Distribution, excretion and protein binding in rats and dogs. Drug Res 1989;39:1100–1108.
Dumont L, Archambeault P, Giasson S, et al. Inotropic and chronotropic properties of benzothiazepine-like calcium antagonists. FASEB J 1991;5(4):A874.
Oesterle SN, Alderman EL, Beir-Scott L, et al. Diltiazem and propranolol in combination: Hemodynamic effects following acute intravenous administration. Am Heart J 1986;111:489–496.
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Valérie, V., Louis, D., Marc, L. et al. Relationship between the cardiovascular effects and both plasma and myocardial levels of clentiazem, a new benzothiazepine calcium antagonist, in anesthetized dogs. Cardiovasc Drug Ther 5, 997–1003 (1991). https://doi.org/10.1007/BF00143527
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DOI: https://doi.org/10.1007/BF00143527