Captopril and platelet-activating factor (PAF) antagonist prevent cardiac allograft vasculopathy in rats: Role of endogenous PAF and PAF-Like compounds

Accelerated coronary artery disease (CAD) is the leading cause of late mort ality following cardiac transplantation. The vascular lesions are character ized by myointimal proliferation and perivascular mononuclear inflammatory infiltrates. Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero -3-phosphocholine) is a potent phospholipid mediator produced by inflammato ry cells and activated endothelial cells. Angiotensin II is known to activa te phospholipase A,, a critical enzyme in PAF synthesis. Using a rat hetero topic cardiac transplant model known to induce graft CAD, we previously rep orted that chronic administration of captopril, an angiotensin converting e nzyme inhibitor, reduces intimal proliferation and maintains luminal patenc y. The purpose of the current study was to determine if captopril regulates vascular remodeling by suppressing PAF synthesis and whether administratio n of a PAF antagonist ameliorates graft CAD. Captopril was found to decreas e levels of PAF and PAF-like compounds as well as reduce intimal lesions, d ecrease cellular rejection grade, and diminish allograft heart weights. Tre atment with a PAF antagonist significantly decreased proliferation of the i ntimal component of the vasculopathy and caused regression of the cardiac h ypertrophy, but had no significant effect on cellular rejection. In contras t, untreated animals had elevated plasma PAF levels, elevated heart weights , and severe myointimal proliferation with luminal stenosis 21 days post-tr ansplantation. These observations suggest that graft CAD is mediated, in pa rt, by PAF and PAF-like compounds, and suppression of endogenous PAF may pr event cardiac allograft vasculopathy.