DILTIAZEM PRESERVES DIRECT VASODILATOR RESPONSE BUT FAILS TO SUPPRESSINTIMAL PROLIFERATION IN RAT ALLOGRAFT CORONARY-ARTERY DISEASE

Background: We investigated the effect of diltiazem on transplant coro nary artery disease in rat cardiac allografts both with standard histo logic techniques and by measuring coronary vascular resistance and vas odilator response of the coronary arteries. Methods: Hearts from Lewis rats were transplanted into Fischer 344 rats in an abdominal position without immunosuppression as a chronic rejection model. The rats were randomly divided into two groups: (1) no drug intervention (control; n = 36) and (2) diltiazem in drinking water (n = 33). Syngeneic transp lants, Lewis donor to Lewis recipient, were used for isograft comparis on (n = 17). Rat allografts were observed for length of survival, and at 4 months the surviving allografts were transferred to Langendorff p erfusion, where coronary vascular resistance and its response to acety lcholine and nitroglycerin were examined. Allografts were also examine d histologically and assigned transplant coronary artery disease and c ellular rejection grades. Results: Graft survival at 4 months was 43%, 38%, and 100% in control, diltiazem, and isograft groups, respectivel y. In the control group baseline coronary vascular resistance was much higher than in isografts (243 +/- 52 versus 35.3 +/- 6.2 cm H2O . gm . min/ml, p < 0.05) and the response to acetylcholine and nitroglyceri n was significantly lower than that in the isografts (acetylcholine 6. 2% +/- 4.8% versus 16.4% +/- 3.3%, p < 0.05; nitroglycerin 5.6% +/- 4. 7% versus 12.6% +/- 5.7%, p < 0.05). In the diltiazem group baseline c oronary vascular resistance (191 +/- 72 cm H2O . gm . min/ml) and the response to acetylcholine (7.3% +/- 2.9%) were similar to those in the control group (p = not significant); however, the response to nitrogl ycerin was better than that in the control group and in fact similar t o that in the isograft group (13.6% +/- 7.0%; p < 0.05 versus control group, p = not significant versus isograft group). Histologic examinat ion showed no coronary artery disease in isografts but equivalent mark ed transplant coronary artery disease and inflammation in both the con trol (transplant coronary artery disease grade 2.9 +/- 0.6, cellular r ejection grade 3.6 +/- 0.7) and diltiazem (transplant coronary artery disease grade 3.0 +/- 0.8, cellular rejection grade 4.3 +/- 0.9) group s. Conclusion: In this transplant coronary artery disease model, dilti azem did not suppress the development of coronary intimal proliferatio n, but it did help preserve the vasodilative properties of the allogra ft coronary arteries in response to nitroglycerin, a direct vasodilato r.