| Biological rhythms are a universal phenomenon in living organisms and enable adaptation to the environment. Biological rhythms can be divided into 3 types on the basis of their cycle lengths: 1) circadian (or diurnal) rhythms 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 longer). Circadian rhythms, which are the rhythms associated with many cardiovascular parameters, are the most common and best studied of these rhythms. The electrical activity of the brain, which changes at the minute level, belongs to the ultradian class of rhythms, whereas the menstrual cycle is an infradian rhythm. In humans, almost every physiological system has some degree of circadian rhythm. The mechanism behind any of these rhythms can be viewed as endogenous, exogenous, or both. For example, the secretion of growth hormone closely depends on the sleep-wake cycle (ie, sleep is an external factor affecting the growth hormone rhythm), so growth hormone secretion can be viewed as an exogenous rhythm. In most circumstances, respiration is driven by internal mechanisms and can be considered an endogenous rhythm. However, most physiologic rhythms, including those of the cardiovascular system, have both endogenous and exogenous influences. It has been found that blood pressure follows a typical circadian rhythm—it maintains a higher level during the daytime, with peak values between 10 and 12 pm. During the night, blood pressure falls to lower values and reaches its trough value from 3 to 6 am, or 1 to 3 hours before awakening. However, the regulation of blood pressure is a complicated process, during which the RAAS, catecholamines, and endothelial vasoactive substances may play important roles. It is easily to postulate that the changes of circulation or tissue levels of these vasoactive substances would surely result the alternation of blood pressure. Accordingly, the critical perception of the chronobilogical features of vasoactive chemicals would be beneficial to a further understanding of circadian mechanisms of blood pressure. During the past decades, some preliminary results had been reported by scholars abroad in the aspects of diurnal manifestation of RAAS, catecholamines, and endothelial vasoactive substances, and circadian properties had been suggested, although most these studies were limited to serum level. As we know, biologic rhythm is endogenous and hereditability, and meanwhile, it is conformed and adjusted by environment signals. Light is the main zeitgeber to induce and control biologic rhythms. Circadian rhythms of mammals are timed by an endogenous clock with a period of about 24 hours located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Light synchronizes this clock to the external environment by daily adjustments in the phase of the circadian oscillation. Therefore in this study, we investigated the levels of renin, angiotensin-converting-enzyme (ACE), angiotensin-II, endothelin-1, and nitric oxide in plasma and myocardial tissue in rats raised under different light schedules. And meanwhile, we also examined the expression patterns of rennin mRNA, ACE mRNA, aldosterone synthase (AS) mRNA, and AT-1 mRNA in rat myocardial tissue. Also, the chronobiological features of plasma catecholamine, renin, and aldosterone and their relationship with the circadian rhythm of blood pressure were estimated based on a mild to moderate hypertensive cohort. Part 1 Effects of different light schedules on the circadian rhythm of RAAS Objective: To investigate the chronobiological properties of rat RAAS and the effects of different light schedules on it. Methods: Ninety-six male SPRD rats (with body weight 250-300g) were included in this study. After one week's free-running period in natural light-dark cycles, the rats were housed at 22±2°C and free access to food andwater. They were divided randomly into three groups according to their light conditions: rats that were kept under a standard 12/12 light–dark cycle (lights on at Zeitgeber time [ZT] 08.00 hours, and off at ZT20.00 hours) were designated as the "LD group"; rats that were kept in a constant darkness or a constant lightness were designated as the "DD group" or "LL group", respectively. Each group was maintained in its respective lighting condition for 8 weeks before the experiments. Animal experiments were conducted in accordance with guidelines of Hebei Geriatric Institute. For the determination of the diurnal pattern of renin, ACE, angiotensin-II in serum and myocardial tissue, as well as renin mRNA, ACE mRNA, AS mRNA, and AT-1 mRNA expressions in rat myocardial tissue, animals were sacrificed every 6 hours (at ZT02:00, 08:00, 14:00, and 20:00, respectively) by decapitation, and the indices above were measured. Cosinor fitting analysis and zero amplitude test were introduced to analyze the chronobiological features of RAAS in every group. 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 renin, ACE, angiotensin-II in serum and myocardial tissue were significantly higher in DD than those in LD group by using ANOVA. Conversely, in comparison with LD group, the serum levels of renin, ACE, angiotensin-II in LL group were significantly reduced. 2. The expression levels of renin mRNA, ACE mRNA, AS mRNA, and AT-1 mRNA myocardial tissue were significantly higher in DD than those in LD group by using ANOVA. Conversely, in comparison with LD group, those levels in LL group were significantly reduced. 3. Based on cosinor fitting analysis and zero amplitude test, circadian rhythms were approved in all the three groups (i.e., LD group, LL group, and DD group), and the curves and characteristic values of serum level of renin, ACE, and angiotensin II were obtained respectively. Each of those RAAS component shows significant diurnal variation(P<0.05), with the peak timesat 07:26, 08:09, and 10:24, respectively in LD group. The results also showed that the serum levels of renin, ACE, and angiotensin II activity in both LL and DD groups present circadian variation, with the peaks occurring at 14:23, 13:08, 14:00 and 05:03, 05:31, 06:11, respectively, with somewhat later (LL group) or earlier (DD group) than those in LD group. Furthermore, the amplitudes of vibration in both LL group and DD group were decreased, which suggested that the oscillations of serum level of renin, ACE, and angiotensin II were attenuated in continually light or dark group. 4. Similar to the serum levels of renin, ACE, and angiotensin II, circadian variations of these three indices were also shown in myocardial tissue in all LD, LL, and DD groups following cosinor fitting analysis and zero amplitude test. And furthermore, the cosinor curves and characteristic values of renin, ACE, and angiotensin II in myocardial tissue were obtained respectively. Each of those RAAS component showed significantly diurnal variation(P<0.05), with the peak times at 05:58, 06:11, and 06:22, respectively in LD group. The results also showed that the tissue levels of renin, ACE, and angiotensin II activity in both LL and DD groups present circadian variation, with the peaks occurring at 14:33, 14:43, 15:25 and 04:51, 05:02, 05:21, respectively, with somewhat later (LL group) or earlier (DD group) than those in LD group. Furthermore, the amplitudes of vibration in both LL group and DD group were decreased, which suggested that the oscillations of renin, ACE, and angiotensin II in myocardial tissue were attenuated in continually light or dark group. 5. The expression of renin mRNA, ACE mRNA, AS mRNA, and AT-1 mRNA were found to oscillate following circadian rhythm in this study, and their chronobiology feature were similar to those of the RAAS components in serum and myocardial tissue, with the peak time of morning hours in LD group. Similarly, the peak values of these indices were somewhat later or early in LL or DD groups, respectively. The amplitudes of the cosinor curves were decreased in both LL and DD groups.6. MESOR of cosinor curves of renin, ACE, and angiotensin II in myocardial tissue were higher than those in serum, but the peak value times were almost the same, which suggested that the circulating RAAS and the tissue RAAS might possess the same chronobiological mechanism. The circadian characters of renin mRNA and ACE mRNA were similar to the other components of RAAS in serum as well as myocardial tissue, with a little bit earlier peak time when compared with the later. In conclusion, the results suggested circadian variations of renin, ACE, and angiotensin II in serum and myocardial tissue, and of renin mRNA, ACE mRNA, AS mRNA, and AT-1 mRNA in myocardial tissue with similar chronobiological characters. The diurnal nature might be endogenic, which cannot be canceled by changing the light schedules, although the chronobiological values could be altered at some extent. The diurnal oscillation of RAAS might begin with the molecular level. Part 2 Effects of different light schedules on the circadian rhythm of endothelin-1 and nitric oxide Objective: To investigate the chronobiological properties of rat ET-1 and NO and the effects of different light schedules on it. Methods: After one week's free-running period in natural light-dark cycles, ninety-six male SPRD rats ( body weight, 250-300g) were housed at 22±2°C and free access to food and water. They were divided randomly into three groups according to their light conditions: rats that were kept under a standard 12/12 light–dark cycle (lights on at Zeitgeber time (ZT) 08.00 hours, off at ZT20.00 hours) were designated as the "LD group"; rats that were kept in a constant darkness or a constant lightness were designated as the "DD group" or "LL group", respectively. Each group was maintained in its respective lighting condition for 8 weeks before the experiments. Animal experiments were conducted in accordance with guidelines of Hebei Geriatric Institute. For the determination of the diurnal pattern of ET-1 and NO, animals were sacrificed every 6 hours (at ZT02:00, 08:00, 14:00, and 20:00,respectively) by decapitation. Serum NO was measured by nitrate reductase, and serum ET-1 was measured by radioimmunoassay. The chronobiological features of endothelial vasoactive substance in every group were then analyzed. Cosinor fitting analysis and zero amplitude test were introduced to analyze the chronobiological features of RAAS in every group. 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. Result: 1.The levels of ET-1 in plasma and myocardial tissue were significantly higher in DD than those in LD group by using ANOVA (P<0.01). Conversely, in comparison with LD group, the serum levels of ET-1 in LL group were significantly reduced (P< 0.05). The levels of NO in serum and myocardial tissue significantly increased in DD group and decreased in LL group when compared with LD group(both P<0.01). The results confirmed that different light schedules issue effects on the levels of ET-1 and NO. 2. Based on cosinor fitting by least squares technic, curves and characteristic values of serum levels of ET-1, NO were obtained respectively. Each of those endothelial vasoactive substance showed significantly circadian variation(P<0.05), with the peak times at 02:08 and 06:13, respectively. The results also showed that the serum levels of ET-1 and NO in both LL and DD groups presented circadian variation, with the peaks occurring at 05:18, 07:04 and 22:48, 04:49, respectively. Furthermore, the amplitude of vibration in DD group was higher. 3. It was found that all of the levels of ET-1 and NO in myocardial tissue in the 3 groups showed significant circadian rhythms(P<0.05). The highest values were seen at 04:58,07:22 (LD group), 07:41,15:03 (LL group) and 19:56,08:16 (DD group), respectively. Conclusions: 1.Results of this study confirmed that both the levels of ET-1 and NO in serum and myocardial tissue following significantly circadian variation. 2. Constant light or dark exposure may lead to the changes of chronobiological features of the levels of ET-1 and NO in serum andmyocardial tissue. These findings suggested that the circadian rhythms of ET-1 and NO were sustained under light-dark alternation. However, which is not absolutely, the mechanism behind any of these rhythms can be viewed as endogenous, exogenous, or both. Our study suggested that the circadian rhythms of ET-1 and NO were driven by internal mechanisms and can be considered as an endogenous rhythm. 3.Light signal might change the chronobiological features of vasoactive substances in both serum and myocardial tissue. Part 3 Chronobiological feature of plasma epinephrine, norepinephrine, renin, and aldosterone and their relationship with the circadian rhythm of blood pressure Objective: To investigate the chronobiological feature of plasma epinephrine, norepinephrine, renin, and aldosterone and their relationship with the circadian rhythm of blood pressure. Methods: One-hundred and four untreated hypertensive patients (76 males and 28 females, age 35-70 [average 40±13] years old) were included in this study. The criterias for inclusion were: systolic clinic blood pressure≥140mmHg and/or diastolic clinic blood pressure≥90mmHg at 3 continues day. According to the circadian characters of blood pressure from ambulatory blood pressure monitoring, the patients were allocated into 3 groups: Group I, or non-dippers group, 36 patients with the nocturnal decrease in blood pressure is <10%; Group II, or dippers group, 41 cases whose blood pressure decreases by 10% to 20% during nighttime compared with daytime values; and GIII, or extreme-dippers group, 27 patients whose nighttime blood pressure falls ≥20% compared with daytime. While blood pressure was monitoring, plasma epinephrine, norepinephrine, renin, and aldosterone were measured at the interval of 4 hours within the 24-hours day. Cosinor fitting analysis and zero amplitude test were introduced to analyze the chronobiological features of the related indices, and the character values of their cosinor curves among the three groups were compared by using ANOVA.
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