title: Cardioprotection by cyclosporine A in experimental ischemia and reperfusion--evidence for a nitric oxide-dependent mechanism mediated by endothelin.
abstract: The acute effect of cyclosporine A (CSA) on myocardial function after ischemia and reperfusion and the mechanism of action was investigated in isolated working guinea-pig hearts. Myocardial function was experimentally infringed by imposing short-term global ischemia and reperfusion (15 min each). External heart work (EHW), determined before and after ischemia, served as the criterion for quantitation of recovery. Control hearts were perfused with modified Krebs-Henseleit buffer, other hearts received buffer supplemented with CsA +/- an endothelin receptor antagonist or exogenous endothelin +/- an inhibitor of nitric oxide (NO) synthesis. To assess the importance of endothelial production of mediators directly, NO release in coronary effluent (continuously measured with an amperometric sensor) and release of 6-keto-prostaglandin F1, (6-keto-PGFb), a stable metabolite of prostacyclin (PGI2), were determined in non-working. Langendorff hearts. Oxidative stress during reperfusion was assessed by measuring glutathione release in coronary venous effluent. Cyclosporine A (0.8 microM) improved post-ischemic function significantly (59% recovery of EHW nu 31% for controls). At 0.08 microM. CsA was without beneficial effect (30% recovery). The endothelin (ET)A- and ETB-receptor antagonist bosentan inhibited the protective action of 0.8 microM CsA (32% recovery). Exogenous ET-1 (80 pM) improved recovery to 53%, an effect which was blocked by the inhibitor of NO-synthase, NG-nitro-L-arginine (NOLAG. 1 microM. 31% recovery. In the control group, post-ischemic NO release in coronary effluent recovered from zero to about 100% of the pre-ischemic value by 10 min. but then decreased rapidly during the subsequent 15 min of reperfusion. In hearts treated with 0.8 microM CsA, NO release stayed at 100% of the pre-ischemic value throughout reperfusion, the difference between controls and CsA-treated hearts being significant after 20 min of reperfusion. On the other hand, coronary venous release of 6-keto-PGF1a was not different between the groups. Release of glutathione during early reperfusion first 5 min) was significantly lowered (P < 0.05) to about 50% in CsA (0.8 microMI- and ET-I-treated compared with controls (8.8 nmol/min). Cyclosporine A acts as a cardioprotective agent in our model of ischemia and reperfusion, presumably by elevating the level of endogenous nitric oxide and thereby reducing oxidative stress.
authors.affiliation: Department of Physiology, University of Munich, Federal Republic of Germany.
authors.forename: P
authors.initials: P
authors.lastname: Massoudy
authors.forename: S
authors.initials: S
authors.lastname: Zahler
authors.forename: C
authors.initials: C
authors.lastname: Kupatt
authors.forename: E
authors.initials: E
authors.lastname: Reder
authors.forename: B F
authors.initials: BF
authors.lastname: Becker
authors.forename: E
authors.initials: E
authors.lastname: Gerlach
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D000077300:Bosentan; D003326:Coronary Circulation; D016572:Cyclosporine / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D006439:Hemodynamics; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015425:Myocardial Reperfusion; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D018501:Antirheumatic Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D013449:Sulfonamides; D019335:Nitroarginine; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D016572:Cyclosporine; D005978:Glutathione; D000077300:Bosentan