Dosing-Time Dependence of Lethal Toxicity Induced by Nitroprusside in Young Mice

Abstract

Sodium nitroprusside (SNP) is a potent vasodilator and is commonly used as an antihypertensive agent in postoperative cardiac surgical patients. In this study, we investigated whether the SNP-induced lethality is influenced by the dosing-time. Mortality was induced by administering SNP in different doses (4.9, 5.4, 6.0, 6.6 mg/kg, i.p.) to Swiss albino mice, 2 to 8 weeks old, synchronized for at least 2 weeks by 12 h light (rest)/12 h dark (activity) span. Each dose was administered to comparable groups of animals (n= 6) at six different circadian times: 1, 5, 9, 13, 17, and 21 hours after light onset (HALO). Both ?2 and cosinor methods were used to analyze the time series data. Statistically significant dosing time-dependent changes were validated in the daily scale with the males more sensitive than females. A ultradian (? = 12 h) rhythm was detected by cosinor (P < 0.002) for each of the three administered doses (4.9, 5.4, 6.0 mg/kg) in 2 week old mice of both genders. Moreover, in addition to the ultradian rhythm, a significant (P < 0.004) circadian (? = 24 h) component had been detected in 6 mg/kg SNP-treated male mice. However, there was only a circadian rhythm detected in 4 and 8 weeks old mice after acute SNP (6.0, 6.6 mg/kg) treatment, with peak time located at ? 21 and ? 17 HALO, respectively. In conclusion, tolerance to nitroprusside varies not only according to the circadian time but also according to the dose, age, and gender of animal.