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

Abstract

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 M), and the presence of endothelium was confirmed with acetylcholine (10 M). Then, the concentration-response curves were obtained for atorvastatin alone (10 to 3 × 10 M; control) and in the presence of cilostazol (10 M) in young and adult rat aortas. This experimental protocol was also carried out in aorta rings, which had been pretreated with N-nitro-l-arginine methyl ester (l-NAME, 10 M). Atorvastatin induced concentration-dependent relaxations in young and adult rat thoracic aorta rings precontracted with phenylephrine. The pIC 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.

Statin‐mediated cholesterol depletion exerts coordinated effects on the alterations in rat vascular smooth muscle cell biomechanics and migration

“…2011; Nurullahoglu‐Atalik et al . 2017). With respect to the underlying mechanism, it has been demonstrated that statins increase nitric oxide (NO) and carbon monoxide (CO) production in the cardiovascular system; both these ‘gasotransmitters’ have significant vasodilatory and antiatherogenic activities (Wojcicka et al .…”

“…Furthermore, it was elucidated that some statins can inhibit the vasocontraction induced by extracellular Ca 2+ entry via the receptor‐operated Ca 2+ channel pathway, which is the primary mode of action that phenylephrine contracts VSMCs (Nurullahoglu‐Atalik et al . 2017). One possible interpretation for why the aortic tissue stiffness was unchanged could be due to the overwhelming aorta ECM protein composition that governs vessel stiffness rendering the impact of cellular stiffness on the overall tissue stiffness insignificant.…”

“…In addition, other statins have also been shown to inhibit conduit vessel constrictor responses (Ghaffari et al 2011). For example, atorvastatin induced concentration-dependent relaxation of young and adult phenylephrine-contracted rat aortas, acute pravastatin pretreatment inhibited vasoconstrictor responsiveness of isolated rat mesenteric small vessels, and simvastatin was able to produce vascular relaxation in rat small arteries (de Sotomayor et al 2000;Ghaffari et al 2011;Nurullahoglu-Atalik et al 2017). With respect to the underlying mechanism, it has been demonstrated that statins increase nitric oxide (NO) and carbon monoxide (CO) production in the cardiovascular system; both these 'gasotransmitters' have significant vasodilatory and antiatherogenic activities (Wojcicka et al 2011).…”

“…With respect to the underlying mechanism, it has been demonstrated that statins increase nitric oxide (NO) and carbon monoxide (CO) production in the cardiovascular system; both these 'gasotransmitters' have significant vasodilatory and antiatherogenic activities (Wojcicka et al 2011). Furthermore, it was elucidated that some statins can inhibit the vasocontraction induced by extracellular Ca 2+ entry via the receptor-operated Ca 2+ channel pathway, which is the primary mode of action that phenylephrine contracts VSMCs (Nurullahoglu-Atalik et al 2017). One possible interpretation for why the aortic tissue stiffness was unchanged could be due to the overwhelming aorta ECM protein composition that governs vessel stiffness rendering the impact of cellular stiffness on the overall tissue stiffness insignificant.…”

Vasoactive effects of fluoxetine in rat thoracic aorta smooth muscle

“…The endothelial damage controlled by applying Acetylcholine (Ach 10 -6 M). The vascular endothelium was considered as damaged when the aortic rings showed relaxation ≤10% 20 . After controlling the endothelial damage by applying Ach 10 -6 M, the damaged aortic rings were washed for 1 h to reduce the effect of anesthetic agents, and a second dose of phenylephrine (PE 10 -6 M) was administered.…”