Effects of cyclosporin and cremophor on working rat heart and incidence of myocardial lipid peroxidation.
Cyclosporin A (CsA) is widely used as the immunosuppressant of choice for preventing graft rejection. However, its clinical use is hampered by certain side effects, especially its nephrotoxicity and other cardiovascular side effects. CsA for intravenous infusion contains cremophor (Cre) and this vehicle has significant adverse effects on endothelial function and vascular muscle. The present study was aimed at investigating the direct effects of CsA and Cre on isolated and perfused rat hearts in the dosage that closely approximates the peak level achieved for the prevention of graft rejection in the rat. Transplantation is a clinical setting in which the myocardium may be exposed to transient ischemia. In this study, we have shown that the vehicle of CsA, namely Cre, has significant adverse effects on cardiac function. We observed a reduction in coronary flow and aortic output. Addition of CsA appeared to induce a further reduction of aortic flow. We have also shown that a significant increase of thiobarbituric acid reactive substances, considered as an index of lipid peroxidation, occurred in the reperfused heart in the presence of Cre+CsA. Our experimental study shows that Cre turned out to be toxic to myocardium by itself. In the heart, potential Cre-CsA interactions possibly potentiating CsA toxicity could not be excluded. The increase of lipid peroxidation in the heart perfused with CsA suggests that reactive oxygen species may be involved in the detrimental effects of this substance on the heart.
Tatou
E
E
CHU-Service de Chirurgie Cardiovasculaire, Dijon, France.
Mossiat
C
C
Maupoil
V
V
Gabrielle
F
F
David
M
M
Rochette
L
L
D015104:3,4-Methylenedioxyamphetamine / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D017202:Myocardial Ischemia / Q000139:chemically induced; D014677:Pharmaceutical Vehicles / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D013610:Tachycardia / Q000139:chemically induced; D014693:Ventricular Fibrillation / Q000139:chemically induced
D007166:Immunosuppressive Agents; D014677:Pharmaceutical Vehicles; D017382:Reactive Oxygen Species; C022131:cremophor; D011092:Polyethylene Glycols; D015104:3,4-Methylenedioxyamphetamine; D016572:Cyclosporine