An investigation of the cardiotoxic action of vancomycin in the isolated working rat heart.
The mechanism of cardiotoxic action of vancomycin was examined in preparations of isolated working rat hearts and spontaneously beating right atria. Vancomycin produced a concentration-dependent decrease in aortic flow, coronary flow and heart rate in the isolated working rat heart, with no significant effect on other haemodynamic parameters. At 5 mm, vancomycin produced a statistically significant decrease (compared with control values) in aortic flow (24.1 +/- 7.5%) and in the basal heart rate (34.3 +/- 3.5%) after 15 min incubation. Coronary flow was also reduced by 23.5 +/- 9.2%. Prolonged exposure of the preparation to 5 mm-vancomycin produced a marked time-dependent bradycardia accompanied by a time-dependent increase in the leakage of lactic dehydrogenase (LDH) into the perfusion medium. Moreover, a correlation (r = -0.94) was found between the time-dependent bradycardia and LDH leakage induced by Vancomycin. In the isolated spontaneously beating right atria pretreated with atropine, vancomycin (5 mm) also produced a time-dependent bradycardia similar to that found in the isolated working rat heart. Moreover, (45)Ca(2+)-flux studies indicated that vancomycin had no significant effect on the (45)Ca(2+) uptake into the right atrial muscle. These data suggest that: (1) vancomycin has a direct and acute cardiotoxic action at high concentrations (> 1 mm); (2) time-dependent bradycardia is a sensitive functional index for the cardiotoxicity induced by vancomycin; (3) the bradycardia elicited by vancomycin is due neither to the release of acetylcholine from the parasympathetic nerves innervating the heart nor to blockade of Ca(2+) entry.
Jim
K F
KF
Department of Investigative Toxicology, Smith Kline & French Laboratories, Research and Development Division, P.O. Box 1539, King of Prussia, PA 19406-0939, USA.
Matthews
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