EFFECTS OF ACUTE REJECTION ON ENDOTHELIUM-DEPENDENT RELAXATION OF CORONARY-ARTERIES OF THE TRANSPLANTED HEART IN DOGS

Chronic rejection has been linked to premature coronary atherosclerosis in heart transplantation and may be related to altered vascular reactivity. However, the effect of acute rejection on coronary reactivity remains uncertain. To evaluate this aspect, coronary artery reactivity was studied during acute rejection in a canine model of heart transplantation. Two groups of mongrel dogs (n = 7) (20 to 30kg) underwent heterotopic heart transplantation (cervical position), and received either no treatment (noTx) or cyclosporine (CyA), 10 mg/kg/day. On day 7, recipient native (NH) and grafted hearts (GH) were harvested and 4-mm rings from the circumflex coronary artery were studied in organ chambers for endothelium and smooth muscle reactivity. At the harvesting, GHnoTx displayed a grade IV/IV histologic rejection while GHCyA (CyA dosage 250-350 nM) reached grade IIIa-IV. Intimal hyperplasia was found in coronary arteries of treated and non-treated GH [4/7 (noTx) vs 3/7 (CyA)]. Endothelium-dependent relaxation to thrombin was impaired in GH compared to NH and was not influenced by CyA treatment [EC(50) (-log M): GHnoTx: 1.12 +/- 0.18 vs NHnoTx: 1.67 +/- 0.16 (p = 0.06); GHCyA: 0.99 +/- 0.22 vs NHCyA: 1.64 +/- 0.09 (p = 0.02)]. Conversely, endothelium-dependent relaxation to 5-hydroxytryptamine (5-HT) was enhanced in both CyA-treated and noTx groups EE(50) (-log M); GHnoTx: 5.96 +/- 0.12 vs NHnoTx: 5.54 +/- 0.14 (p = 0.046); GHCyA: 6.65 +/- 0.19 vs NHCyA: 5.66 +/- 0.16 (p = 0.004)]. A facilitating effect of CyA on 5-HT was also seen in GH [GHnoTx vs GHCyA (p = 0.01)], suggesting a CyA intrinsic effect. Responses to acetylcholine and adenosine diphosphate were similar in all groups as well as endothelium-independent relaxation to sodium nitroprusside and contractile response to KCI and PGF(2 alpha). We conclude that, in our model, acute rejection does not specifically impair cGMP-mediated relaxation but affects in a receptor-specific manner the endothelinm-dependent relaxation. CyA did not prevent these effects but furthermore appeared to enhance the coronary endothelial sensitivity to 5-HT.