| Objective: The fluctuation of blood pressure (BP) has a rhythm with a period of approximately 24 hours, which called circadian rhythm or diurnal rhythm. According to amplitude of the fluctuation, BP rhythms can be divided into four types: 1 Dipper, which is defined as a 10-20% fall in nocturnal BP; 2 Nondipper, the nocturnal BP fall is less than 10%; 3 Extreme dipper, the nocturnal BP fall is greater than 20%; and 4 Reverse-dipper, the nocturnal BP level is higher than that of daytime. Lots of researches indicates that abnormal BP rhythm is an independent preditor of cardiovascular events. Compared with dippers, hypertensive individuals with a nondipping nocturnal BP profile have more target organ damage and a worse cardiovascular prognosis.As a dihydropyridine calcium channel blocker, nifedipine used to be one of the most important antihypertensive drugs, but it is not recommended by guideline for its short half life period and unstablily of lowing BP. In virtue of undeveloped social economy, nifedipine still should be recommend to common hypertensive individuals, especial nondipper and morning BP surge group, because of its obvious effect and cheap cost. Combination of nifedipine and long acting antihypertensive drug may be a new train of thought for treatment of abnormal BP rhythm, and it can prevent the occurrence of cardiovascular events and pretect target organ.Studies have confirmed that the level of plasma endothelin (ET), nitric oxide (NO) and the activity of nitric oxide synthase (NOS) show circadian rhythms, and their chronobiology characters have closely correlation to the BP rhythm. Therefore, thoroughly recognized these kinds of biological rhythm have important significance in deeply understand the relationship between endothelium function and BP rhythm. It also has important value to improve hypertension therapy and decrease malignant heart events. At present, a few authors have studied circadian rhythm of those substances at molecular level. It requires further study to the influence of vasoactive substances circadian rhythm under the nifedipine-administrating.Therefore in this study, we investigated the levels and rhythm of ET-1, NO, eNOS in plasma and myocardial tissue and eNOS-mRNA in myocardial tissue in rats under the nifedipine-administrating. The study can conduct us to recover normal BP rhythm, and has important significance in cure of hypertension and its complications.Methods: Sixty-four age-matched (10 weeks) healthy male Sprague Dawleys rats (with body weight 250-300g) housed at 22±2°C were included in this study. They were divided randomly into two groups: rats that were administrated with nifedipine were designated as the"group T", and those treated with water were designated as the"group N". The rats those in group T were gorged 6mg·kg-1·d-1 nifedipine; rats of group N were gorged the same volume of water as the as group T. Each group includes 32 rats, every group divided randomly into 4 sub-groups (with 8 rats/group). After 4 weeks, we detected the levels of ET-1, NO, eNOS and eNOS-mRNA at different time at the interval of 6 hours (with one sub-group at 02:00, 08:00, 14:00 and 20:00, respectively). Cosinor fitting analysis and zero amplitude test were introduced to analyze the chronobiological features of the indices above. The compare of circadian values among two groups was managed based on T test, and p<0.05 was defined as statistically different borderline.Results: 1 The levels of ET-1 in plasma and myocardial tissue were significantly lower in group T than those in group N (p<0.05). It showed that nifedipine could impact the expression of ET-1: nifedipine treated groups could significantly cut down the levels of ET-1 in plasma and myocardial tissue.2 The levels of NO, eNOS in plasma and myocardial tissue in group T were significantly higher than those in group N (p<0.05). It showed that nifedipine could impact the expression of NO, eNOS: groups T could significantly rise up the levels of NO, eNOS in plasma and myocardial tissue. 3 The expression of eNOS-mRNA in myocardial tissue of group T were significantly higher than those in group N.4 Based on cosinor fitting analysis and zero amplitude test, all ET-1, NO, eNOS and eNOS-mRNA showed typical circadianrhythm. The peak value times of ET-1, NO and eNOS in plasma of group N occurred in turn were 22:43, 10:25, 07:35, of group T were 21:56, 08:24, 05:29, which were earlier than those in group N. The amplitudes of ET-1, NO, eNOS in plasma were similar in the two groups. The peak value times of ET-1,NO and eNOS in myocardial tissue of group N occurred in turn were 02:07, 14:04, 12:39, of group T were 01:14, 12:57, 11:40, which were earlier than those in group N. The amplitudes of ET-1, NO, eNOS in myocardial tissue were similar in the two groups.5 Based on cosinor fitting analysis and zero amplitude test, eNOS-mRNA in myocardial tissue of the two groups showed typical circadian rhythm. The peak of eNOS-mRNA in myocardial tissue of group N, T were 11:45, 09:05 respectively. The amplitudes of eNOS-mRNA in myocardial tissue of the two groups were similar.Conclusion:1 The expression of ET-1, NO and eNOS in plasma and myocardial tissue of group N showed significantly circadian rhythm, and so did eNOS-mRNA.2 Administrating nifedipine can make the peak times of ET-1, NO, eNOS and eNOS-mRNA earlier, without resume the circadian rhythm of them. Administrating nifedipine resulted the significantly decreased in the level of ET-1, while the levels of NO, eNOS as well as eNOS-mRNA were significantly raised.
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