Cilostazol enhances atorvastatin-induced vasodilation of female rat aorta during aging

Statins have cholesterol-independent effects including an increased vascular nitric oxide activity and are commonly used by patients with cardiovascular disease. Such patients frequently have cardiovascular diseases, which may be treated with cilostazol, a platelet aggregation inhibitor. This study was designed to investigate whether combined use of cilostazol would increase the inhibitory effect of statin on vascular smooth muscle and how maturation would affect these responses. Female Wistar rats, aged 3-4 months (young) and 14-15 months (adult), were sacrificed by cervical dislocation and the thoracic aorta was dissected and cut into 3- to 4-mm-long rings. The rings were mounted under a resting tension of 1 g in a 20-ml organ bath filled with Krebs-Henseleit solution. Rings were precontracted with phenylephrine (10^-6 M), and the presence of endothelium was confirmed with acetylcholine (10^-6 M). Then, the concentration-response curves were obtained for atorvastatin alone (10^-10 to 3 × 10^-4 M; control) and in the presence of cilostazol (10^-6 M) in young and adult rat aortas. This experimental protocol was also carried out in aorta rings, which had been pretreated with N^G-nitro-l-arginine methyl ester (l-NAME, 10^-4 M). Atorvastatin induced concentration-dependent relaxations in young and adult rat thoracic aorta rings precontracted with phenylephrine. The pIC₅₀ value of atorvastatin was significantly decreased in adult rat aortas. In addition, pretreatment of aortas with cilostazol enhanced the potency of atorvastatin in both young and adult aortas. Incubation with l-NAME did not completely eliminate the relaxations to atorvastatin in the presence of cilostazol. These results suggest that combined application of cilostazol with atorvastatin was significantly more potent than atorvastatin alone. Combined drug therapy may be efficacious in delaying the occurrence of cardiovascular events.