Comparison of in vitro cardiovascular function with in vivo echocardiographic assessment after long-term administration of cyclosporine to rats.
Clinical reports indicate that cyclosporine is able to induce heart failure without rejection after heart transplantation. This supposition is supported by ex vivo animal studies, yet ex vivo studies do not account for the potential of counter-regulatory mechanisms, and the clinical observations seem rare in comparison with the number of patients treated with cyclosporine. We hypothesized that cyclosporine administration to rats would fail to exhibit any effect on myocardial contractility in vivo notwithstanding a negative influence ex vivo. Transthoracic echocardiographic examinations (two-dimensional targeted M-mode tracings) were done in a blinded fashion before and after 1-week treatment of rats (10 or 20 mg/kg/day cyclosporine i.p. vs. vehicle). After excision of the hearts, contractility and changes in coronary tone were determined ex vivo during flow-constant perfusion. Neither cyclosporine nor vehicle treatment resulted in changes of echocardiographic parameters (left ventricular diameter, fractional shortening). The heart rate was significantly increased in the high-dose cyclosporine group. This group showed a significant 38% reduction of contractility during the subsequent perfusion ex vivo, whereas low-dose cyclosporine or vehicle had no effect on myocardial performance. Vasoconstriction did not account for this impairment, because coronary tone was unaltered. Cyclosporine, given in doses used in animal studies, impairs myocardial contractility ex vivo but fails to exhibit any effect on myocardial performance in vivo, possibly because of an increase in sympathetic tone. Considering that the denervated transplanted heart in humans is even sensitized to adrenergic stimuli, our finding makes unlikely a clinical contribution of cyclosporine to failure after orthotopic heart transplantation.
Braun-Dullaeus
R C
RC
Department of Medicine, Giessen University, Germany.
Feussner
M
M
Walker
G
G
Tillmanns
H
H
Haberbosch
W
W
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D004452:Echocardiography; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D016572:Cyclosporine