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 atherosclerosi s in heart transplantation and may be related to altered vascular reac tivity. 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 transpl antation. Two groups of mongrel dogs (n = 7) (20 to 30kg) underwent he terotopic heart transplantation (cervical position), and received eith er 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 chambe rs for endothelium and smooth muscle reactivity. At the harvesting, GH noTx displayed a grade IV/IV histologic rejection while GHCyA (CyA dos age 250-350 nM) reached grade IIIa-IV. Intimal hyperplasia was found i n 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, endothe lium-dependent relaxation to 5-hydroxytryptamine (5-HT) was enhanced i n 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 NHCy A: 5.66 +/- 0.16 (p = 0.004)]. A facilitating effect of CyA on 5-HT wa s also seen in GH [GHnoTx vs GHCyA (p = 0.01)], suggesting a CyA intri nsic effect. Responses to acetylcholine and adenosine diphosphate were similar in all groups as well as endothelium-independent relaxation t o sodium nitroprusside and contractile response to KCI and PGF(2 alpha ). We conclude that, in our model, acute rejection does not specifical ly 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.