OBJECTIVES: Thienopyridines are prodrugs currently used as anti-aggregating agents. The aim of this study was to determine if these compounds might have vascular activity independent of hepatic bioactivation. METHODS: The direct activity of thienopyridines was studied in rat caudal arterial rings and aortic smooth muscle cells in culture. KEY FINDINGS: Both compounds (0.01 µm-100 µm) showed a concentration-dependent vasorelaxation in arterial tissues precontracted with phenylephrine, 5-hydroxytryptamine and KCl. The relaxation induced by 100 µm ticlopidine and clopidogrel was greater than 80%. The relaxation by ticlopidine was compared with the activity of acetylcholine. These two agents showed similar potency, although ticlopidine was slightly more active. Pretreatment with the nitric oxide synthase inhibitor L-NAME inhibited the relaxation by acetylcholine but not that by ticlopidine. To further study vasorelaxation by ticlopidine, other pharmacological inhibitors including propranolol, nifedipine and suramin were used. These compounds lacked inhibitory effects on the vasorelaxation by ticlopidine. In vascular smooth muscle cells, 1 µm ticlopidine induced a decrease in cell proliferation, while incubation with both ticlopidine and ADP or 2-methioADP led to an additive effect. CONCLUSIONS: The data suggest that ticlopidine and clopidogrel cause relaxation of arterial tissues and influence vascular smooth muscle cell proliferation directly without hepatic biotransformation. Furthermore, the arterial relaxation induced in vitro by thienopyridines is endothelium independent, and β-adrenergic and P2 receptors are not involved.
OBJECTIVES:Thienopyridines are prodrugs currently used as anti-aggregating agents. The aim of this study was to determine if these compounds might have vascular activity independent of hepatic bioactivation. METHODS: The direct activity of thienopyridines was studied in rat caudal arterial rings and aortic smooth muscle cells in culture. KEY FINDINGS: Both compounds (0.01 µm-100 µm) showed a concentration-dependent vasorelaxation in arterial tissues precontracted with phenylephrine, 5-hydroxytryptamine and KCl. The relaxation induced by 100 µm ticlopidine and clopidogrel was greater than 80%. The relaxation by ticlopidine was compared with the activity of acetylcholine. These two agents showed similar potency, although ticlopidine was slightly more active. Pretreatment with the nitric oxide synthase inhibitor L-NAME inhibited the relaxation by acetylcholine but not that by ticlopidine. To further study vasorelaxation by ticlopidine, other pharmacological inhibitors including propranolol, nifedipine and suramin were used. These compounds lacked inhibitory effects on the vasorelaxation by ticlopidine. In vascular smooth muscle cells, 1 µm ticlopidine induced a decrease in cell proliferation, while incubation with both ticlopidine and ADP or 2-methioADP led to an additive effect. CONCLUSIONS: The data suggest that ticlopidine and clopidogrel cause relaxation of arterial tissues and influence vascular smooth muscle cell proliferation directly without hepatic biotransformation. Furthermore, the arterial relaxation induced in vitro by thienopyridines is endothelium independent, and β-adrenergic and P2 receptors are not involved.
Authors: Jesse C Ikeme; Pablo E Pergola; Rebecca Scherzer; Michael G Shlipak; Oscar R Benavente; Carmen A Peralta Journal: Clin J Am Soc Nephrol Date: 2017-04-26 Impact factor: 8.237