Synergistic Inhibitory Effect of Angiotensin-Converting Enzyme Inhibitor and Heparin on Intimal Hyperplasia After Rat Aorta Injury

The respective efficacies of angiotensin-converting enzyme (ACE) inhibitor and standard heparin were investigated with respect to their inhibitory effects on intimal hyperplasia after balloon denudation of rat aorta. Local angiotensin II effects in the artery wall may participate in regulation of the vascular response to arterial injury, apparently independent of the plasma renin and angiotensin system. ACE inhibitors have been shown to block intimal hyperplasia after arterial injury in rats. Increasing evidence points toward an inhibitory effect of heparin on intimal hyperplasia independent of anticoagulation. Balloon catheter aortic denudation was performed in 25 rats pharmacologically treated from six days or one day before to fourteen days after surgery and split into four groups: group A (control group), normal feeding; group B (ramipril group), ramipril 10 mg/kg/day orally; group C (heparin group), heparin 1200 IU/kg/day subcutaneously; group D (combined group), both ramipril and heparin. Animals were killed and aortas were perfused and fixed at physiologic pressure fourteen days after denudation. Cross-sectional intima-to-media area ratios (I-M ratio) were calculated by an image analyzer system. (continued on next page) Morphometric analysis of cross sections showed marked intimal thickening in the control group with a mean I-M ratio of 95.1 ±2.76%. In contrast, the I-M ratios in the ramipril group were significantly reduced by 37.3 ±2.06% (P = 0.0001) and in the heparin group by 29.7 ± 1.58%. The I-M ratio of animals treated with both ramipril and heparin was 16.6 ±1.3% (P=0.0001) (Figs. 1-7). Blood pressure in the ramipril group decreased from 111.7 ±5.16 mmHg and 91.7 ±2.58 mmHg (P = 0.0001) and in the combined group from 111.7 ± 6.06 mmHg to 92.5 ± 5.24 mmHg and 85.0 ±3.16 mmHg (P=0.0001) after seven days and fourteen days, respectively, whereas heparin had no effect on blood pressure (114.2 ±8.61 mmHg to 111.7 ±6.06 mmHg and 111.7 ±4.08 mmHg) (Fig. 8). Both the ACE inhibitor ramipril and heparin significantly reduced intimal hyperplasia. More significant reduction of intimal hyperplasia was obtained when these two drugs were given together. These data have led the authors to conclude that ACE inhibitors and heparin together inhibit intimal thickening after injury, and an apparently synergistic effect of these two drugs may be obtained. These results may be useful for clinical application to prevent the proliferation that occur after endarterectomy or bypass surgery.