科研之友
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摘要
We have found that niclosamide induced relaxation of constricted artery. However, niclosamide is insoluble, the low bioavailability and the resultant low plasma concentration limit its potential exertion in vivo. The aim of the present study is to synthesize a soluble poly (methacrylic acid-niclosamide) polymer (PMAN) and study the effects of PMAN on arterial function in vitro and the blood pressure and heart rate of rats in vivo. We synthesized the poly (methacrylic acid-niclosamide) polymer (PMAN), the chemical structure of which was identified by FTIR and H-1 NMR spectra. The average molecular weight and polydispersity index of PMAN were 5138 and 1.193 respectively. Compared with niclosamide, the water solubility of niclosamide in PMAN was significantly increased. PMAN showed dose-dependent vasorelaxation effect on rat mesenteric arteries with intact or denuded endothelium in phenylephrine (PE) and high K+ (KPSS)-induced vasoconstriction models in vitro. The efficacy of vasorelaxant effect and the cytotoxic effect of PMAN on vascular smooth muscle cells (A10) were lower than that of niclosamide. The LD50 of PMAN in mice (iv) was 80 mg/kg. Venous injection of PMAN (equivalent 5 mg niclosamide per kg) showed acute reduction of the rat blood pressure and heart rate in vivo. In conclusion, the solubility of niclosamide was increased in the way of poly (methacrylic acid-niclosamide) polymer, which relaxes the constricted arteries in vitro and reduces the rat blood pressure and heart rate in vivo, indicating that modifying niclosamide solubility through polymerization is a feasible approach to improve its pharmacokinetic profiles for potential clinic application.
