| Objective: Biological rhythm is a periodicity,regularity phenomenon, is one of the basic characters, and an important modulated style in living organisms. In both human and animals, endogenous biochronometer formed in brain can modulate important vital movements, for instance sleep cycle,body temperature,blood pressure and various kinds of endocrine glands'excrete rhythm and so on. Biological rhythms can be divided into 3 types on the basis of their cycle lengths: 1. Circadian rhythm (or Diurnal rhythm) with a period of approximately 24 hours; 2. Ultradian rhythms, with a period significantly shorter than 24 hours (hours, minutes, or even seconds); and 3. Infradian rhythms, with a period longer than 24 hours (days, months, or even longer). In human, circadian rhythm is the most common phenomenon and better investigated. The human blood pressure presents typical circadian rhythm. Thoroughly recognized the regulatory mechanism of blood pressure's biologic rhythm has very important significance in the prevention and treatment for hypertension. Blood pressure's regulation is a very complicated process. In this process, endothelial system and other vasoactive substances have considerable effects. Recent years, one of the most important research progress in cardiovascular field is the elucidation of the important roles of the endothelial vasoactive substances in heart regulation,circulate function and homeostatic equilibrium, for example, maintain angiotasis, inhibit blood platelet aggregation, sustain function balance of blood clotting and haematolysis, degrade blood vessel endothelium permeability, decrease adhesiopn molecule expression, restrain vascular smooth muscle hyperplasy, and so on. Studies have confirmed that the level of plasma endothelin (ET), nitric oxide (NO) and the activity of nitric oxide synthase (NOS)show circadian rhythms, their chronobiology character have closely correlation to the circadian rhythm of cardiovascular diseases. Therefore, thoroughly recognized these kinds of biological rhythm have important significance in deeply understand the relationship between endothelium function and physiological phenomena as well as pathological events in cardiovascular system. It also has important value to improve cardiovascular diseases'therapy and decrease malignant heart events. At present, a few authors have studied circadian rhythm of those substances'at molecular level. It requires deeply investigation to the relationship of the circadian rhythm between vasoactive substances and blood pressure. It also requires deeply study to the influence of vasoactive substances'circadian rhythm under the valsartan- administrating. We investigated the levels and rhythm of ET-1, NO, NOS in plasma and myocardial tissue and eNOS-mRNA in myocardial tissue in rats which were raised under different time of valsartan-dosing schedules. We also investigated the relationship between blood pressure and the levels and rhythm of those substances mentioned above. These studies play a very important role in explaning the rat even human blood pressure's circadian rhythm under different drug-dosing schedules in molecular level. They have important value to adjust drug-administrating time, to correct abnormal biological rhythm, and to recover physiological rhythm of blood pressure. They can provid a new train of thought for prevention and cure of hypertension and its complications.Methods: Ninety-six age-matched male SPRD rats (with body weight 250-300g) were included in this study. They were divided randomly into three groups according to the dosing time: rats that were administrated with valsartan at 07:00 in the morning were designated as the"M group"; rats that were treated with valsartan at 19:00 were designated as the"N group"; rats that were not treated with valsartan were designated as the"control group"or"C group". Valsartan-treated group was gorged 30mg/kg·d. Each group has 32 rats, every group divided randomly into 4 sub-groups (8 rats/group). After 4 weeks, we measured rat blood pressure with rat-tail manometer and ET-1,NO,eNOS,eNOS-mRNA in different time dot of the same day acrossing 24 hours. Cosinor fitting analysis and zero amplitude test were introduced to analyze the chronobiological features of the indices above. The compare of circadian values among 3 groups was managed based on Analysis of Variance (ANOVA), 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 M and N group than those in C group (P<0.01). But the differences between M group and N group were not significant (P=0.215). It showed that valsartan could impact the expression of ET-1: valsartan treated groups could significantly cut down the levels of ET-1 in plasma and myocardial tissue. There were not different between the two groups with different valsartan dosing schedules.2 The levels of NO,NOS in plasma and myocardial tissue in M and N group significantly were higher than those in C group, but the difference between N and C group of plasma NO was not significant statistically.3 The expression of eNOS-mRNA in myocardial tissue: M and N group higher than C group, but the difference was not significant.4 The average level of systolic blood pressure in M and N group was significantly higher than that in C group (P <0.05).5 Based on cosinor fitting analysis and zero amplitude test, all ET-1, NO, eNOS, eNOS-mRNA and blood pressure showed typical circadian rhythm. The peak value times of ET-1,NO and eNOS in plasma of C group occurred in turn were 22:33, 9:07, 10:54, of M group were 18:23, 4:49, 4:27, which were earlier than those in C group. Of N group were 21:14, 4:40, 2:45. The amplitudes of NO,NOS in Plasma and eNOS-mRNA in myocardial tissue of M and N group were higher than thaose of C group, but ET-1 in plasma was lower. These suggested that the total levels of NO and eNOS in plasma of valsartan-treated group were higher than those in control group. The peak values and amplitudes of ET-1, NO, eNOS, eNOS-mRNA in myocardial tissue were nearly the same of those in plasma. The peak of ET-1, NO, eNOS in myocardial tissue occurred in turn were 12:14, 8:23, 11:27 of C group, of M group were 10:11, 2:14, 3:21, earlier than those in C group, of N group were 16:29, 3:46, 3:29.6 Based on cosinor fitting analysis and zero amplitude test, eNOS-mRNA in myocardial tissue of the 3 groups showed typical circadian rhythm. The peak of eNOS-mRNA in myocardial tissue of C, M and N group were 15:37, 20:38 and 20:36, respectively. The amplitudes of M and N group were significantly higher than those in C group.7 Based on cosinor fitting analysis and zero amplitude test, Blood pressure of the 3 groups showed significantly circadian rhythm. The peak time of C, M and N group were 23:26, 10:27 and 17:00, respectively. The amplitudes of M group were higher than those in C group, but N group was lower than those in C group.Conclusion: 1 The expression of ET-1, NO, eNOS in plasma and myocardial tissue of C group showed significantly circadian rhythm, and eNOS-mRNA did, too.2 Administrating valsartan at different time schedule, the level of ET-1 was significantly decreased, while NO, eNOS, eNOS-mRNA were significantly raised.3 Treated with valsartan in morning, the levels of NO, eNOS, as well as eNOS-mRNA were much higher and ET-1 and blood pressure were much lower than those in night, moreover it could resume the circadian rhythm much better.The results mentioned above demonstrated that, ET-1, NO, eNOS and eNOS-mRNA all showed typical circadian rhythm, and the rhythm characters of each index were almost similarity. Treated with valsartan in morning could inhibit ET-1, increase NO and eNOS, resume circadian rhythm much effectively. |
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