Metronidazole-induced myocardial depression: chemical and pharmacological studies on the role of calcium in-vitro

Abstract

The interaction of metronidazole with calcium to form a water-soluble complex has been studied by titration with ethylenediaminetetraacetate (EDTA), direct current and pulse polarographic reduction steps of the nitro-group at pH 5 and 7, and by ultraviolet absorption. Stoichiometric calculations, X-ray powder diffraction pattern of the synthesized metronidazole-calcium complex, and molecular ion peak at m/z 381 in the mass spectrum of this product, showed that a 2:1 complex is formed. The interaction of metronidazole with calcium on myocardial contractile performance of guinea-pig electrically-driven isolated left atria in physiological solution was also examined. Metronidazole induced a sustained, concentration-dependent depression of the tension that was reversed by changing the bathing fluid to physiological solution, and/or by adding excess calcium ion. The drug-induced negative inotropic response was antagonized competitively by increasing calcium ion in the bath, whereas noradrenaline antagonized metronidazole-induced negative inotropic responses non-competitively. Addition of the metronidazole-calcium complex to the bath did not affect normal myocardial contractile performance. The results show that metronidazole produces a direct negative inotropic effect on isolated atrial muscles by interfering with Ca2+, and by preventing Ca2+ function in the events leading to contractile activity of atrial muscles.