Altered cardiovascular responses to chronic angiotensin II infusion in aged rats

Regulatory Peptides 132 (2005) 67 – 73 www.elsevier.com/locate/regpep

Altered cardiovascular responses to chronic angiotensin II infusion in aged rats Marisa da Silva Lemos, Aline Nardoni Gonc¸alves Braga, Jose´ Roberto da Silva, Robson Augusto Souza dos Santos * Laborato´rio de Hipertensa˜o, Departamento de Fisiologia e Biofı´sica, Instituto de Cieˆncias Biolo´gicas ICB-UFMG, Av. Antoˆnio Carlos, 6627, Belo Horizonte, 31270-901, Belo Horizonte, MG, Brazil Received 25 February 2005; accepted 8 September 2005 Available online 24 October 2005

Abstract In this work we determined by telemetry the cardiovascular effects produced by Ang II infusion on blood pressure (BP) and heart rate (HR) in aged rats. Male Wistar aged (48 – 52 weeks) and young (12 weeks) rats were used. Ang II (6 Ag/h, young, n = 6; aged, n = 6) or vehicle (0.9% NaCl 1 Al/h, young, n = 4; aged, n = 5) were infused subcutaneously for 7 days, using osmotic mini-pump. The basal diurnal and nocturnal BP values were higher in aged rats (day: 98 T 0.3 mm Hg, night: 104 T 0.4 mm Hg) than in the young rats (day: 92 T 0.2 mm Hg, night: 99 T 0.2 mm Hg). In contrast, the basal diurnal and nocturnal HR values were significantly smaller in the aged rats. Ang II infusion produced a greater increase in the diurnal BP in the aged rats (D MAP= 37 T 1.8 mm Hg) compared to the young ones (D MAP= 30 T 3.5 mm Hg). In contrast, the nocturnal MAP increase was similar in both groups (young rats; D MAP= 22 T 3.0 mm Hg, aged rats; D MAP= 24 T 2.6 mm Hg). During Ang II infusion HR decreased transiently in the young rats. An opposite trend was observed in the aged rats. Ang II infusion also inverted the BP circadian rhythm, in both groups. No changes in HR circadian rhythm were observed. These differences suggest that the aging process alters in a different way Ang IIsensitive neural pathways involved in the control of autonomic activity. D 2005 Elsevier B.V. All rights reserved. Keywords: Renin-angiotensin system; Blood pressure; Telemetry; Aging; Rats; Circadian rhythm

1. Introduction Elderly people have a very high prevalence of hypertension, which markedly increases their risk for cardiovascular morbidity and mortality [1]. Hypertension in the elderly is caused at least in part by an intrinsic aging process in the vascular system not only in the large arterial but also in the peripheral resistance arteries [2]. In the setting of hypertension Ang II persistent elevation has been associated with increased cardiovascular morbidity and mortality [3]. Thus, one could suggest that part of the vascular alterations in aging could be due to the Ang II vasculotoxic effects. However the level of the activity of the RAS estimated by plasma renin activity is decreased with aging [4,5]. Although, there is evidence that older hypertensive patients are not predominantly low renin [6]. * Corresponding author. Tel./Fax: +55 31 34992926/34992956. E-mail address: [email protected] (R. Augusto Souza dos Santos). 0167-0115/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2005.09.004

Independently of the level of activity of the circulating RAS, Ang II could contribute for the cardiovascular changes observed with aging, due to an increased reactivity of the cardiovascular system of elderly patients to this hormone. Indeed, changes in the cardiovascular reactivity to Ang II have been demonstrated in the elderly. In humans, the venoconstriction response to Ang II was greater in the elderly [7]. In vitro studies performed in normal rabbits of different ages reveal in fact that Ang II augments isometric aortic vascular smooth muscle contraction in old rabbits [8]. In addition, with advancing age the old kidney becomes tonically vasoconstricted by endogenous Ang II [9]. It has also been suggested that the circadian pattern of BP depends on age and is influenced by the renin angiotensin system (RAS) [10]. Radio-telemetry recording showed an inverse circadian BP pattern in TG (mRen2)27 transgenic rats [11] which present overactivity of tissue RAS. In a previous study, we have shown that Ang II infusion in young rats also inverted the BP circadian rhythm without changing the HR

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animals underwent a 12-day acclimatization period in an isolated telemetry room. All experimental protocols were performed in accordance with the guidelines for the human use of laboratory animals of our institute and approved by local authorities.

circadian rhythm [12]. Recent studies have shown that aging is also associated with a variety of alterations of BP circadian rhythm in humans [13,14] as well as in animals [15,16]. Thus, the aim of the present study was to test the hypothesis that aging alters the cardiovascular responsivity to Ang II and its effects on BP and HR circadian rhythms. To test this hypothesis hemodynamic parameters changes produced by Ang II infusion in young and aged rats were compared using an implantable radio-telemetry system.

2.2. Radio-telemetry monitoring of BP and HR A telemetry system (Data Sciences International, MN) was used for measuring systolic, diastolic and mean arterial pressure (MAP), HR and motor activity. This monitoring system consists of radio frequency transducers model TA11PAC40, receivers, a matrix, and an IBM-compatible personal computer with accompanying software (Dataquest A.R.T.-Gold 2.0) to store and analyze the data [17]. Under tribromoethanol anesthesia (2.5%, 1 ml/100 g BW), the catheters-transducer were implanted into the abdominal aorta just above the bifurcation of the iliac arteries, and the sensors were fixed to the abdominal wall. Before the experiments were started, the rats were housed in individual cages for 10– 12 days until the telemetry tracing indicated reestablishment of 24-h oscillations of BP and HR. Data were continuously sampled every 10 min for 10 s during all the study (21 days).

2. Methods 2.1. Animals Wistar aged (48 –52 weeks) and young male rats (12 weeks) were used. All rats were obtained from Cebio-Centro de Bioterismo do Instituto de Cieˆncias Biolo´gicas — Universidade Federal de Minas Gerais. Free access was allowed to standard diet (Nuvilab CR1-Nuvital Nutrientes) and tap water was supplied ad libitum. The rats were housed in separated cages, under controlled conditions of temperature (25 -C) and a 12:12-h light –dark cycle (light: 6:00 AM to 6:00 PM; dark: 6:00 PM to 6:00 AM). Before the experiments were started the Day

Night

A 450

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Fig. 1. Effect of chronic infusion of Ang II on the mean arterial pressure (MAP) and HR (HR) in young (A) and aged (B) rats. The bars represent the averaged values of MAP and HR during daytime and night time before, during, and after Ang II infusion (6 Ag/h). *Significantly different ( P < 0.05 ) compared with the average of the 3 last days of the period before infusion (ANOVA followed by the Dunnet’s test). See Methods for details. bpm, beats/min.

M. da Silva Lemos et al. / Regulatory Peptides 132 (2005) 67 – 73

2.4. Statistical analysis Linear data are presented as means T SE. Circular data (acrophases) are presented as the mean vector (in hours) and 95% confidence interval. The MAP and HR circadian variation were calculated from the night mean values (6:00 PM – 5:55 AM) compared with the day mean values (6:00 AM – 5:55 PM). For statistical analysis, 72 values for every 12 h (1 value at each 10 min) for each rat were computed. Comparisons between day and night values within the same group were made by unpaired Student’s t-test (Prism 4.0, Graphpad Software, 2003). Comparisons between the control period and the experimental and recovery periods were made by one-way ANOVA, followed by the Dunnet’s test. For this, the control values were obtained by averaging all values obtained in the last 3 days of the pre-infusion period. The MAP and HR acrophase, which is the time of the day or night of the peak of their circadian rhythm expressed in hours or in degrees (where 360corresponds to a 24-h full cycle), were obtained by rhythmic analysis (DQ-FIT software) [18,19] of all data points collected in the last 3 days of each experimental period (control, infusion, and recovery). Individual acrophases, derived from the DQ-FIT analysis, were averaged and compared using a circular statistics software (Software Oriana, version 1.06, Kovoch Computing Services, 1994). The comparisons between the circular mean of the acrophases were performed using the Watson f-test [20]. The MAP and HR data of the stress experiments were analyzed by paired Student’s t-test. Comparison between changes in MAP and HR produced by Ang II infusion in young rats and old rats were made using non-paired t-test. A value of P < 0.05 was considered statistically significant. 3. Results As expected, the basal MAP and HR values were significantly higher during the active phase (night period) compared to the resting phase (day period) of the animals in both groups. The basal MAP values (average of the 7-day preinfusion period) were higher in aged rats: day, 98 T 0.3 mm Hg and night, 104 T 0.4 mm Hg vs. day, 92 T 0.2 mm Hg, and night, 99 T 0.2 mm Hg in the young rats. Conversely, the basal HR values were lower in the aged rats: day, 267 T 1.1 beats/min and night, 311 T1.4 beats/min vs. day, 331 T 0.8 beats/min, and night, 380 T 1.3 beats/min in the young rats. The MAP day/ night difference (aged rats: 6 T 0.6 mm Hg, young rats: 7 T 1.1 mm Hg) and HR day/night difference (aged rats: 43 T 2.5 beats/

60

∆ MAP (mmHg)

A 7-day infusion of Ang II (6 Ag/h, n = 6, for each group) or vehicle (NaCl 0.9% 1 Al/h, n = 5, aged; n = 4, young) was carried out using osmotic mini-pumps (ALZET, model 2001) implanted subcutaneously in the dorsal region, under tribromoethanol anesthesia (2.5%, 1 ml/100 g BW). Ang II was purchased from Bachem (Torrance, CA).

min, young rats: 49 T 1.5 beats/min) were not different between aged and young animals. As shown in Fig. 1, the Ang II infusion produced a significantly MAP increase in aged and young rats. As shown in Fig. 2, the MAP increase was higher in the diurnal period in the aged rats (D MAP= 37 T 1.8 mm Hg) compared to the young rats (D MAP= 30 T 3.5 mm Hg, P < 0.05, unpaired t test). In contrast, the nocturnal MAP increase was similar in both groups (young rats; D MAP= 22 T 3.0 mm Hg, aged rats; D MAP= 24 T 2.6 mm Hg). As shown in Fig. 1, in the young rats, there was a significant decrease in HR that was more pronounced in the first three days (day 3: day, 290 T 2.0 beats/min; night, 349 T 2.3 beats/min). Thereafter, HR values progressively increased reaching values similar to those of the control period at the end of the infusion. In contrast in the aged rats, in parallel to the increase in MAP there was no significant alteration in diurnal HR and a nocturnal tachycardia was observed at the end of the Ang II infusion (day 6: day, 272 T 2.3 beats/min; night, 323 T 2.5 beats/min). As shown in Fig. 2, the bradycardia observed in the young rats during the Ang II infusion (average of the infusion period;

*

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69

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-50 ANG II Infusion (Day) Young

ANG II Infusion (Night) Aged

Fig. 2. Changes in diurnal and nocturnal mean values of MAP and HR during the Ang II infusion in the young rats and aged rats. *P < .05, compared to the young.

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day, D = 24 T 8.9 beats/min; night, D = 12 T 7.6 beats/min) contrasted with the opposite trend in the diurnal and nocturnal period in the aged rats (average of the infusion period; day, D = 2.5 T 3.9 beats/min; night, D = 4.2 T 4.0 beats/min). In addition, a diurnal and nocturnal tachycardia was observed in the recovery period, in the aged rats, seven days after the end of the Ang II infusion the HR (day 12): day, 309 T 2.2 beats/min; night, 361 T 2.4 beats/min). Ang II infusion also inverted the MAP circadian rhythm and this inversion persisted until the forth day after Ang II infusion end in both groups. The MAP values became higher during the animal resting phase compared to the MAP values during the animal active phase in the aged rats and in the young rats (Fig. 1). Accordingly, there was also an inversion in the MAP acrophase in both groups. In the aged rats, the MAP acrophase was 11:56 PM (95% confidence interval 08:56 PM –12:56

AM) in the control period and changed to 11:49 AM (95% confidence interval 10:35 PM– 01:03 PM) in the infusion period. In the young rats, the MAP acrophase changed from 12:53 AM (95% confidence interval 09:57 PM – 03:48 AM) in the control period to 02:28 PM (95% confidence interval 11:32 AM –05:25 PM) in the infusion period, reaching values similar to those of the control period seven days after the Ang II infusion ending. However, contrasting with the young rats this shifted acrophase was maintained seven days after the end of the Ang II infusion in the aged rats (12:40 PM; 95% confidence interval 09:32 PM– 11:41 AM). These changes had no apparent relationship with alterations in locomotor activity (data not shown). Contrasting with the MAP changes, the circadian variation of HR was not significantly affected by the Ang II infusion in both groups (aged rats: acrophase; 11:47 PM; 95% confidence

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Fig. 3. Representative recordings of the effects of the infusion of Ang II (6 Ag/h) on HR (A, beats/min), blood pressure (B: mm Hg) and activity (C: counts/min) in aged and young rats. Bpm, beats/min. The arrows indicate the beginning and the end of infusion.

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71

Table 1 Mean arterial pressure and HR before, during and after subcutaneous vehicle infusion in aged and young rats

Vehicle aged rats (1 Al/h, n = 5)

MAP (mm Hg) HR (bmp)

Vehicle young rats 1 Al/h, n = 4)

MAP (mm Hg) HR (bmp)

Day Night Day Night Day Night Day Night

Before infusion

During infusion

After infusion

CT

Day 2

Day 3

Day 4

Day 5

Day 6

Day 11

Day 12

Day 13

102 T 0.4 105 T 0.4 285 T 1.4 318 T 1.3 90 T 0.5 94 T 0.4 336 T 1.4 370 T 1.4

99 T 0.5* 105 T 0.5 304 T 1.8* 336 T 1.9* 90 T 0.6 94 T 0.6 340 T 1.8 374 T 1.9*

100 T 0.5* 106 T 0.9 300 T 1.8 338 T 2.1* 90 T 0.7 93 T 0.7 343 T 1.9* 372 T 2.0

102 T 6.7 103 T 6.7 313 T 3.7* 338 T 2.0* 92 T 0.7 94 T 0.6 344 T 2.1* 372 T 1.9

98 T 0.7* 105 T 0.6 311 T 2.1* 338 T 2.1* 91 T 0.7 94 T 0.6 343 T 1.9* 367 T 1.8

100 T 0.7 106 T 0.6 307 T 2.0* 336 T 2.2* 91 T 0.8 94 T 0.6 339 T 2.3 371 T 2.1

101 T 0.7 107 T 0.5* 295 T 2.0* 334 T 2.2* 91 T 0.7* 94 T 0.6 330 T 2.0* 363 T 2.1

99 T 0.8* 104 T 0.6* 296 T 2.7* 327 T 2.4* 89 T 0.7 93 T 0.7 332 T 1.9* 363 T 1.9*

99 T 0.7* 106 T 1.1* 292 T 2.0 329 T 2.4* 88 T 0.7 93 T 0.6 331 T1.8* 356 T 1.9

The before infusion values (CT) are the average of the last three days of the pre-infusion period (see Methods for details) compared to each day of the infusion period *P < 0.05, ANOVA followed by Dunnet’s test. (n = 5 and 4 in aged and young rats, respectively).

interval 11:23 PM– 12:12 AM before infusion vs. 10:59 PM; 95% confidence interval 09:49 PM – 12:09 AM, during infusion; young rats: Acrophase; 11:46 PM; 95% confidence interval 10:34 PM – 12:57 AM before infusion, vs. 12:22 AM; 95% confidence interval 11:36 PM – 01:09 AM, during infusion). Fig. 3 shows a representative recording of BP, HR and locomotor activity before, during and after Ang II infusion in an aged rats and a young rats. In the groups that received vehicle infusion, there were no significant changes in MAP or HR values in the young rats and only minor and transient changes in the aged rats (Table 1). 4. Discussion The major finding of this work was that aged rats presented an altered cardiovascular response to Ang II infusion compared to the young ones. Ang II produced a greater increase in the diurnal MAP of aged rats as compared to the young. In addition, during Ang II infusion HR decreased transiently in the young rats while an opposite trend was observed in the aged rats. The basal diurnal and nocturnal BP values were higher in the aged rats than in the young rats. In contrast, the basal diurnal and nocturnal HR values were significantly smaller in the aged rats. Controversial results have been reported concerning differences in the basal cardiovascular parameters between young and aged rats [21,22]. In our study an important contribution to detect this discrete alteration could have been the accuracy of the telemetry BP acquisition method. As demonstrated before this method is useful to unmask differences that could not be observed in studies which used more conventional methods for measuring BP and HR [23]. The nocturnal BP and HR were higher than the diurnal BP and HR values that correspond to the animal active phase in both groups. These results are in agreement with many studies in rats that show the BP and HR are higher in the animal active phase [24,25]. It is interesting to note that the aged rats also presented a 1-h shift in the MAP acrophase (11:00 PM) compared to the young rats (12:01 AM) which was not associated to changes in the activity acrophase (data not shown). A similar observation was previously made by Zhang and Sannajust [15].

The Ang II infusion produced a higher MAP increase in the old rats during the resting phase compared to the increase occurred in the same period in the young rats. However, no differences were observed in the increase observed during the active phase between the groups. This finding may be related to the non-dipper phenomenon that is more frequent in aged hypertensive individuals than in young hypertensive [14]. As consequence of its preferential pressor effect during the resting phase Ang II infusion produced an inversion of the MAP circadian rhythm in both groups. This observation is in accordance with previous findings in TGR (mRen2)27 rats, which present an overactive tissue RAS [11]. Further, BP reductions in TGR (mRen2)27 rats by angiotensin converting enzyme (ACE) inhibitors [26] and angiotensin AT1-receptor antagonists [27] are greater during the resting phase, reinforcing the hypothesis that the RAS is involved in determining circadian BP pattern by mainly influencing the resting period MAP. This is an unexpected relationship considering that Ang II is importantly involved in the modulation of the sympathetic activity [28] which in turn is high during the active phase [29]. The related observation that Ang II infusion inverts day – night rhythm of BP in Sprague Dawley but not in TGR(ASrAOGEN) rats [30], which present inhibition of the angiotensinogen synthesis exclusively in the brain [31], indicates that a functional brain RAS is an important factor in determining the 24-h BP rhythm changes induced by Ang II. It is important to note that the BP circadian inversion produced by the Ang II infusion persisted until the fourth day after Ang II infusion end in both groups suggesting a role for indirect non-hemodynamic mechanisms in the Ang II effect. Taken together these findings suggest that Ang II infusion may change central and/or peripheral expression of circadian rhythm related genes. Indeed, it has been demonstrated that mice aorta and vascular smooth muscle cells (VSMCs) possess a circadian oscillation system which is comparable to the suprachiasmatic nucleus control system and that the circadian genes expression (Per homologous clock genes identified in Drosophila melanogaster — mPer2, dbp and Bmall) in VSMCs is induced by Ang II through AT1 receptors [32]. The related observation that the mPer mRNA expression is decreased in the old mice SCN [33] may explain some of the differences found in the BP circadian rhythm between young rats and aged rats in our study.

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One could suggest that the BP circadian variation inversion produced by the Ang II infusion in young rats was due to the BP increase, but young male SHR do not present this inversion [24]. On the other hand the animal age seems to influence the BP circadian rhythm control as suggested by the inversion of the BP circadian rhythm also observed in aged SHR [34]. A different pattern was also observed in the HR changes during the Ang II infusion in aged and young rats. In the young rats, the increase in MAP produced by Ang II infusion was associated with a significant bradycardia that peaked at the day 3 of infusion. Thereafter, HR progressively increased reaching values similar to those of the control period, at the end of the infusion. The mechanism of these changes in HR was not investigated in our study. However, a decrease in baroreflex sensitivity induced by Ang II acting at blood brain barrier deficient areas such as subfornical area may have contributed to these observations [35]. Indeed, we have previously shown that chronic infusion of Ang II in rats, selectively depress the bradycardic component of the baroreflex [36]. In the aged rats, the MAP increase during the Ang II infusion, was not accompanied by HR changes in the beginning of the infusion. Actually, the HR increased during the nocturnal period at the end of the infusion. Among other possibility this pattern probably was due to the well known decreased baroreflex sensitivity in aged animals [37]. Interestingly, in the recovery period the old rats presented an important nocturnal and diurnal tachycardia contrasting with the absence of changes in young rats. Alterations in the cardiac autonomic reactivity to Ang II infusion associated to the baroreflex dysfunction combined with genetic expression changes in aged rats could have contributed to these results. Further studies are obviously necessary to clarify these possibilities. Contrasting with the results found in the BP circadian variation, no changes in HR circadian variation was observed during Ang II infusion in both groups. Similar results were obtained in young SD rats infused with Ang II [30]. TGR (mRen2)27 also presented no alteration in the HR circadian variation [38]. Whether the predominant effect of Ang II on BP as compared to HR is related to difference in central or peripheral mechanisms remain to be established [39]. In summary, using radio-telemetry recording of cardiovascular parameters, several important cardiovascular differences between aged and young rats have been uncovered in this study. In addition to a lower HR and slightly increased BP, aged rats showed an increased responsiveness to Ang II infusion, especially in the resting period in which a higher increase in MAP was observed. The absence of reflex bradycardia and nocturnal taquicardia during Ang II infusion in aged rats further strengthens the differences between young and aged rats. This is particularly interesting if one takes into account that 12 months is only a mild aging (the rat life span is 2.4 years in average). Our findings also stressed the need to use more appropriated methods for cardiovascular parameters acquisition when seeking for small but physiologically relevant differences. Further studies are need to clarify whether the increased response to Ang II infusion in aged rats were due to changes in AT1 receptors expression [40,41] or signaling

specially in blood vessels and blood brain barrier deficient areas. Changes in the coupling of angiotensinergic inputs with central and peripheral mechanisms involved in blood pressure control also are attractive possibilities for future studies. Independent of the possible mechanisms involved, our data suggest that besides cardiovascular structure and metabolic changes, an increased reactivity to Ang II may contribute to the higher prevalence of hypertension in the old. Acknowledgements This work was supported by Fundac¸a˜o de Amparo a` Pesquisa do Estado de Minas Gerais (FAPEMIG), Coordenadoria de Amparo a` Pesquisa do Ensino Superior (CAPES), Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPq) and Programa de Grupos de Exceleˆncia (PRONEX). References [1] Kochanek KD, Smith BL. Deaths: preliminary data for 2002. Natl Vital Stat Rep 2004;11:52(13):1 – 47. [2] Ettaouil K, Safar M, Plante GE. Mechanisms and consequences of large artery rigidity. Can J Physiol Pharmacol 2003;8:205 – 11. [3] Alderman MH, Madhavans, Ooil WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 1991; 324:1098 – 104. [4] Noth RH, Lassman MN, Tan SY, Fernandez-Cruz Jr A, Mulrow PJ. Age and the renin-aldosterone system. Arch Intern Med 1997;137(10): 1414 – 7. [5] CraneCrane MG, Harris JJ. Effect of aging on renin activity and aldosterone excretion. J Lab Clin Med 1976;87(6):947 – 59. [6] Alderman MH, Cohen H, Sealey JE, Laragh JH. Plasma renin activity levels in hypertensive persons: their wide range and lack of supression in diabetic and in most elderly patients. Am J Hypertens 2004;17:1 – 7. [7] Harada K, Ohmori M, Fujimura A. Vasoconstricting effect of angiotensin II in human hand veins: influence of ageing, diabetes mellitus and hypertension. Hypertens Res 2002;25(5):683 – 8. [8] Plante GE, Lamontagne F, Sirois P. Contribution of the vascular interstitial matrix to induced contraction by angiotensin II. In vitro studies on the rabbit aorta, mesenteric artery and vein. Arch Mal Coeur Vaiss 1996 (Aug);89(8):997 – 1001. [9] Baylis C. Renal responses to acute angiotensin II inhibition and administered angiotensin II in the ageing, cinscious, catheterized rat. Am J Dis 1993;22(6):842 – 50. [10] Stoynev AG, Ikonomov OC, Minkova NK, Zacharieva SZ, Stoyanovsky VG. Circadian rhythms of arterial pressure: basic regulatory mechanisms and clinical value. Acta Physiol Pharmacol Bulg 1999;24(3):43. [11] Lemmer B, Mattes A, Bohm M, Ganten D. Circadian blood pressure variation in transgenic hypertensive rats. Hypertension 1993;22:97 – 101. [12] Braga ANG, Lemos MS, Fontes WRP, Silva JR, Santos RAS. Effects of angiotensins on day – night fluctuations and stress-induced changes in blood pressure. Am J Physiol Regul Integr Comp Physiol 2002;282: R1663 – 71. [13] Spieker C, Wienecke M, Grotemeyer KH, Suss M, Barenbrock M, Zierden E, Rahn KH, Zidek WJ. Circadian blood pressure rhythms in elderly hypertensive patients. Int Med Res 1991;19(4):342 – 7. [14] Watanabe Y, Tyoshima T, Otsuka K, Watanabe H, Suzuki Y, Kuwajima I, Halberg F. Circadian profiles of blood pressure with respect to age. Nippon Ronen Igakkai Zasshi 1994;31(3):219 – 25 [Abstract]. [15] Zhang B, Sannajust F. Diurnal rhythms of blood pressure, HR, and locomotor activity in adult and old male Wistar rats. Physiol Behav 2000;70:375 – 80.

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[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39] [40]

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