Effects of felodipine on vascular structure, function and monocyte-endothelial interaction in the hypercholesterolemic rabbit

Calcium entry antagonists have been shown to inhibit development of new lesions in hypercholesterolemic (HC) animals and humans. New lesion formation requires monocyte adhesion to endothelium. The purpose of this study was to determine if the calcium entry antagonist felodipine inhibited intimal lesion formation by inhibiting monocyte and/or endothelial determinants of adhesion. Male NZW rabbits (n=28) received the following treatment regimen for 10 weeks: Normal chow (NP, n=3); normal chow with felodipine infusion (NF, n=6); 0.5% cholesterol chow (CP, n=12); or 0.5% cholesterol chow and felodipine infusion (CF, n=7). After 10 weeks blood was collected for biochemical measurements and mononuclear cell binding assays, and thoracic aortae were harvested for vascular reactivity studies and histomorphometry. In the NF animals, felodipine did not significantly affect blood pressure, serum cholesterol levels, binding studies, vascular reactivity, or structure. Plasma cholesterol levels were significantly elevated in groups receiving the 0.5% cholesterol diet. Cholesterol feeding markedly augmented the endothelial adhesiveness for mononuclear cells (by 250%). After thoracic aortae (from CP, n=5) were incubated with felodipine (10^-7) for 1 hour, adhesiveness was markedly attenuated (74±9% vs 100%, p<0.05). Impaired endothelium-dependent relaxation (to acetylcholine) in the HC group was restored by felodipine treatment (40±7% vs 58±4% vs 67±5%; CP vs CF vs NF respectively). This effect was associated with a 2.2-fold reduction in lesion surface area of the thoracic aorta (8.2±6.3% vs 18.2±9.5%; CF vs CP; p=0.055). Moreover, the intimal-medial ratio reflecting lesion thickness was substantially reduced by felodipine treatment (0.05±0.02 vs 0.17±0.06; CF vs CP; p=0.025). In conclusion, low-dose felodipine attenuates monocyte-endothelial interaction and inhibits formation of lesions in HC animals. The salutary effect of felodipine is associated with an increase in vascular nitric oxide activity which may reduce endothelial adhesiveness.