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.
Highlights
Rhythmicity is a fundamental property of all living organisms
The acrophase (Φ) was located in the first half of the dark span (Φ = 15.9 hours after light onset (HALO) ± 78 min) in young-grow-up mice (8 week old), while the Φ was detected nearly at the middle of light span (Φ = 5.2 HALO ± 90 min) in 4 week old young mice. These findings in rectal temperature confirmed the physiological synchronization of animals to the environmental LD cycle at the time of the Sodium nitroprusside (SNP) experiments
The administration of SNP to mice caused a short period of calmness followed by increased respiration and convulsions, which started 3-6 min following SNP injection
Summary
Biological rhythms are regular and periodic incident phenomena in living organisms. Circadian rhythms are an evolutionary adaptation to day/night alternations, that is, an adaptation to the environmental changes caused by the Earth’s rotation. Circadian rhythms in both the desired and nondesired (toxic) effects of chemical and physical agents are known [4,5,6,7] and the dosing of a medication at the proper biological time with reference to circadian rhythms can result in modulation of its toxicity [8,9,10]
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