CARDIOPROTECTION BY CYCLOSPORINE-A IN EXPERIMENTAL-ISCHEMIA AND REPERFUSION - EVIDENCE FOR A NITRIC OXIDE-DEPENDENT MECHANISM MEDIATED BY ENDOTHELIN

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 experim entally infringed by imposing short-term global ischemia and reperfusi on (15 min each). External heart work (EHW), determined before and aft er ischemia, served as the criterion for quantitation of recovery. Con trol 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 medi ators directly, NO release in coronary effluent (continuously measured with an amperometric sensor) and release of 6-keto-prostaglandin F-1 alpha (6-keto-PGF(1 alpha)), a stable metabolite of prostacyclin (PGI( 2)), were determined in non-working Langendorff hearts, Oxidative stre ss during reperfusion was assessed by measuring glutathione release in coronary venous effluent, Cyclosporine A (0.8 mu) improved post-ische mic function significantly (59% recovery of EHW v 31% for controls), A t 0.08 mu M, CsA was without beneficial effect (30% recovery). The end othelin (ET)(A)- and ETB-receptor antagonist bosentan inhibited the pr otective action of 0.8 mu M CsA (32% recovery). Exogenous ET-1 (80pM) improved recovery to 53%, an effect which was blocked by the inhibitor of NO-synthase, N-G-nitro-L-arginine (NOLAG, 1 mu, 31% recovery). In the control group, post-ischemic NO release in coronary effluent recov ered 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 mu M CsA, NO release stayed at 100% of the pr e-ischemic value throughout: reperfusion, the difference between contr ols and CsA-treated hearts being significant after 20 min of reperfusi on. On the other hand, coronary venous release of 6-keto-PGF(1 alpha) was not different between the groups. Release of glutathione during ea rly reperfusion (first 5 min) was significantly lowered (P<0.05) to ab out 50% in CsA (0.8 mu M)- and ET-1-treated hearts as compared with co ntrols (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 stres s. (C) 1997 Academic Press Limited.