Diltiazem preserves direct vasodilator response but fails to suppress intimal proliferation in rat allograft coronary artery disease

Background: We investigated the effect of diltiazem on transplant coronary artery disease in rat cardiac allografts both with standard histologic techniques and by measuring coronary vascular resistance and vasodilator 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 transplants, Lewis donor to Lewis recipient, were used for isograft comparison (n = 17). Rat allografts were observed for length of survival, and at 4 months the surviving allografts were transferred to Langendorff perfusion, where coronary vascular resistance and its response to acetylcholine and nitroglycerin were examined. Allografts were also examined histologically and assigned transplant coronary artery disease and cellular rejection grades. Results: Graft survival at 4 months was 43%, 38%, and 100% in control, diltiazem, and isograft groups, respectively. 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 nitroglycerin 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 coronary 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 nitroglycerin was better than that in the control group and in fact similar to that in the isograft group (13.6% ± 7.0%; p < 0.05 versus control group, p = not significant versus isograft group). Histologic examination showed no coronary artery disease in isografts but equivalent marked transplant coronary artery disease and inflammation in both the control (transplant coronary artery disease grade 2.9 ± 0.6, cellular rejection grade 3.6 ± 0.7) and diltiazem (transplant coronary artery disease grade 3.0 ± 0.8, cellular rejection grade 4.3 ± 0.9) groups. Conclusion: In this transplant coronary artery disease model, diltiazem did not suppress the development of coronary intimal proliferation, but it did help preserve the vasodilative properties of the allograft coronary arteries in response to nitroglycerin, a direct vasodilator.