Effect of misoprostol on myocardial contractility in rats treated with cyclosporin A.
The nephrotoxic side effects of the immunosuppressant cyclosporin A in animals and humans are well known. Misoprostol, a prostaglandin E analog, is used clinically in organ-transplant recipients taking cyclosporin A to protect against these side effects. We reported previously that long-term treatment of rats with cyclosporin A causes a diminution in myocardial peak contractile stress. There is an associated spontaneous sarcomere activity and rest depression of force in the absence of a change in myofilaments sensitivity to intracellular Ca2+. Here we investigated the potential protective effects of misoprostol on the myocardium of cyclosporin A-treated rats. Rats were treated with either cyclosporin A, misoprostol, or their combination. Force-[Ca2+]o and -[Sr2+]o, and force-interval relations as well as the sarcomere length were studied in trabeculae isolated from the right ventricles. At suboptimal [Ca2+]o, cyclosporin A shifted the force-[Ca2+]o relation to the left but reduced peak contractile stress by approximately 35% at the highest (optimal) [Ca2+]o. Co-treatment with misoprostol prevented the leftward shift, and treatment with misoprostol alone did not cause a leftward shift. The diminution of peak stress, however, did not recover with misoprostol treatment, and stress was further reduced. Treatment with only misoprostol also reduced stress generated by the muscles more than that by cyclosporin A alone. Intriguingly, activation of the myofilaments by Sr2+ failed to recover peak stress to control levels in any group treated with misoprostol. Unlike cyclosporin A, however, rest potentiation of force was more pronounced, and spontaneous sarcomere activity was absent with misoprostol. No histopathologic changes were observed with cyclosporin A or misoprostol treatment. Misoprostol modifies the cyclosporin A-induced changes in the Ca2+ handling, but further decreases the stress generated by the muscles.
Department of Medicine, University of Toronto, The Toronto Hospital, Ontario, Canada.
H S
HS
Banijamali
M H
MH
ter Keurs
H E
HE
ter Keurs
H
H
Benediktsson
L C
LC
Paul
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D066298:In Vitro Techniques; D016595:Misoprostol / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000473:pathology; D010865:Pilot Projects; D051381:Rats; D011917:Rats, Inbred Lew; D012518:Sarcomeres / Q000187:drug effects / Q000648:ultrastructure; D013324:Strontium / Q000494:pharmacology
D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D016595:Misoprostol; D016572:Cyclosporine; D013324:Strontium