| Objective: Blood pressure (BP) is the pressure of the flowing blood against the walls of the arteries. The pressure is determined by many factors including the force and cardiac output, heart rate, and the resistance of the arteries. Blood pressure is continually changing depending on activity, temperature, diet, emotion, posture, physical state, and medication. In most cases, the fluctuation of blood pressure has a rhythm with a period of approximately 24 hours, which called circadian rhythm or diurnal rhythm. According to amplitude of the fluctuation, blood pressure rhythms can be divided into four types: 1 Dipper, which is defined as a 10-20% fall in nocturnal BP; 2 Extreme dipper, the nocturnal BP fall is greater than 20%; 3 Nondipper, the nocturnal BP fall is less than 10%; and 4 Reverse-dipper, the nocturnal BP level is higher than that of daytime. Compared with dippers, hypertensive individuals with a nondipping nocturnal blood pressure profile have more target organ damage and a worse cardiovascular prognosis. In order to protect target organ and reduce the incidence of cardiocerebral vascular events, it is important to maintain the blood pressure's distribution of dipper in the treatment of hypertension. Though effective non-drug treatment including adjustment of diet, weight reduction, and improve life style is corner-stone of antihypertensive treatment, antihypertensive drug is still the main means of the control of blood pressure. The different mechanisms and dosing-time of antihypertensives may influence their effects on the level and circadian rhythm of blood pressure. Full acquaintance of these influences will be benefit to correct the abnormal circadian rhythm of blood pressure and remain the normal ones. The mechanisms of the formulation of the circadian rhythm of blood pressure is not clear yet, but it has been already proved by some studies that concentration or activity of endothelial vasoactive substances such as endothelin-1 (ET-1), nitric oxide (NO), and endothelial nitric oxide synthase (eNOS) in plasma show typical circadian rhythm, which might regulate the circadian rhythm of blood pressure. Furthermore, the effects of diferent antihypertensive chemicals and dosing-time on the chronobiological features and circadian rhythm of endothelial vasoactive substances need to be investigated further. Therefore in this study, our aim is to investigate the chronobiological features of blood pressure, ET-1, NO, and eNOS in plasma and myocardial tissue, eNOS-mRNA in myocardial tissue, and the effects of hydrochlorothiazide and dosing-time on them in rats.Methods: One hundred and twenty-eight healthy age-matched (10 weeks) male Sprague Dawleys rats (with body weight 250-300g) housed at 22±2℃were included in this study. They were divided randomly into four groups: rats that were administrated with hydrochlorothiazide at 07:00 were designated as the"group MT"; rats administrated with hydrochlorothiazide at 19:00 as"group NT"; rats administrated with placebo at 07:00 as the"group MC"; rats administrated with placebo at 19:00 as"group NC". Rats of hydrochlorothiazide-treated groups was gorged with hydrochlorothiazide at the dose of 10mg/kg/d; rats of placebo-treated groups was gorged the same volume of water as the other two groups. Each group had 32 rats, and was divided into 4 sub-groups (8 rats/group). After 4 weeks, we measured the blood pressure of one sub-group rats in each group at different time of the same day with rat-tail manometer. On the other hand, we also detected their ET-1, NO, eNOS, and eNOS-mRNA of different time. Cosinor fitting analysis and zero amplitude test were introduced to analyze the chronobiological featrues of the indices above. The compare of mean values among 4 groups was manged based on analysis of variance (ANOVA), and P<0.05 was defined as statistically different borderline.Results: 1 While the levels of NO and eNOS in plasma and myocardial tissue, and the expression of eNOSmRNA in myocardial tissue were significantly higher in the treated groups (group MT and NT) than the other two groups (group MC and NC) by using ANOVA (P<0.05), that of ET-1 in the treated groups were lower. The difference of the vasoactive substances mentioned above between group MT and NT was not significant statistically, so did between group MC and NC. 2 Based on cosinor fitting analysis and zero amplitude test, the curves and characteristic values of ET-1, NO, eNOS and eNOSmRNA, each of which showed typical circadian rhythm, were obtained, respectively. The peaks of ET-1, in plasma and myocardial tissue of group MC, NC, MT and NT appeared respectively at 22:28, 22:27, 21:02, 21:33 and 01:49, 02:13, 00:34, 01:12, that of NO at 10:40, 10:26, 08:53, 09:27 and 14:33, 15:03, 13:10, 13:33, of eNOS at 07:51, 08:40, 05:56, 06:40 and 12:37, 12:26, 09:45, 10:23, of eNOSmRNA in myocardial tissue at 11:35, 11:54, 08:37, 08:58. While the amplitudes of NO, eNOS and eNOSmRNA in group MT and NT were higher than that of group MC and NC, the amplitudes of ET-1 was lower. But the amplitudes of ET-1, NO, eNOS and eNOSmRNA showed no difference between group MT and NT, so did between group MC and NC. On the other hand, while the peak-value-times of ET-1, NO, eNOS and eNOSmRNA in group MT and NT were earlier than that in the other two groups, the difference of that between group MT and NT was not significant statistically, neither did group MC and NC. 3 While the levels of blood pressure of group MT and NT were significantly lower than that of group MC and NC, there were no difference between group MT and NT, neither was between group MC and NC. 4 Based on cosinor fitting analysis and zero amplitude test, the blood pressure of group MC, NC, MT and NT showed typical circadian rhythm, with peak time at 20:40, 21:10, 19:28, 20:05, respectively. Compared to group MC and NC, the amplitudes of group MT and NT were smaller; the peak times of group MT and NT were earlier. Neither between group MC and NC nor group MT and NT showed significant difference.Conclusion: 1 The levels of ET-1, NO, eNOS in plasma and myocardial tissue of all rats show typical circadian rhythm, so do the expression of eNOSmRNA and the blood pressure of them. 2 Adminstrating hydrochlorothiazide either at morning or at evening, the levels of blood pressure and ET-1 are significantly decreased, while NO, eNOS and eNOSmRNA significantly increased, furthermore there are no difference between group MT and NT. 3 The administration of hydrochlorothiazide either at morning or at evening can make the peak times of blood pressure, ET-1, NO, eNOS and eNOSmRNA earlier, without resume the circadian rhythm of them. In addition the two different dosing-times bring on difference to them.
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