Preliminary Studies on Bemitradine-Induced Cardiotoxicity in Female Rats

Abstract

The mechanism of bemitradine (SC-33643) cardiotoxicity in female rats was investigated in the set of preliminary experiments reported here. Specifically, the involvement of bemitradine metabolites and the potential role of adrenal epinephrine release were examined. Desethylbemi-tradine (the primary metabolite of bemitradine) was shown to be cardiotoxic at oral dosages greater than 300 mg/kg for 7 days. In a separate experiment, a major metabolite (bemitradine glycol) unique to the rat was not cardiotoxic at dosages up to 600 mg/kg for 7 days. Treatment of rats with SKF 525-A enhanced the lethality and the cardiotoxicity of bemitradine. In contrast, prior treatments of rats with phenobarbital resulted in decreased cardiotoxicity of both bemitradine and desethylbemitradine (a bemitradine metabolite presumably further metabolized by the microsomal mixed function oxidases). In other independent experiments, bemitradine-induced cardiotoxicity was shown to be accompanied by adrenal damage and decreases in adrenal epinephrine. Propranolol (a β-antagonist) treatment protected rats against cardiotoxicity. Bemitradine also had a direct effect on the heart, as evidenced in an experiment in which bemitradine caused dose-related increases in the T-wave of the rat ECG complex. These data suggest that (1) both bemitradine and desethylbemitradine may be responsible for the cardiotoxicity, and the other downstream metabolites are not and (2) cardiotoxicity may be due to the combination of direct effects of bemitradine on the rat heart and the bemitradine-mediated release of adrenal epinephrine (a known cardiotoxin at high circulating levels).

References

1. Chengelis, C.P. , Levin, S. , and Burton, E. (1991). The chronic toxicity of bemitradine: A diuretic in rats. J. Am. Coll. Toxicol. 10, 443–460.

2. Walsh, G.M. , Suleymanov, O.D. , Feigen, L.P. , and Cafurny, E. (1987). Sustained increases in renal blood flow and glomerular filtration rate in conscious dogs treated with the novel diuretic SC-33643, in: Diuretics II: Chemistry, Pharmacology, and Clinical Applications, J. B. Puschett and A. Greenberg (eds). New York: Elsevier, pp. 95–98.

3. Gad, S.C. , and Weil, C.S. (1988). Statistics and Experimental Design for Toxicologists. Caldwell, NJ: Telford Press.

4. Van Vleet, J. , and Ferrans, V. (1986). Myocardial diseases of animals. Am. J. Pathol. 124, 99–178.

5. Waters Plasma Catecholamine Manual I, edition 02.06.86. Milford, MA: Millipore Corporation, Waters Chromatography Division. Manual Number 40530.

6. Coupland, R. , Tomlinson, A. , Crowe, J. , and Brindley, D. (1984). Effects of hypophysectomy and metyrapone on the catecholamine content and volumes of adrenaline and noradrenaline storing cells in the rat adrenal medulla. J. Endocrinol. 101, 345–352.

7. Holzworth, M. , and Brownfield, M. (1985). Serotonin coexists with epinephrine in rat adrenal medullary cells. Neuroendocrinology 41, 230–236.

8. Detweiler, D.K. (1980). The use of electrocardiography in toxicological studies with beagle dogs, in: Cardiac Toxicology. Boca Raton, FL: CRC Press.