Published online before print August 8, 2005, doi: 10.1161/01.HYP.0000172623.36098.4e
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(Hypertension. 2005;46:1060.)
© 2005 American Heart Association, Inc.
Part 2 Original Articles |
Differing Administration Time-Dependent Effects of Aspirin on Blood Pressure in Dipper and Non-Dipper Hypertensives
From the Bioengineering and Chronobiology Laboratories (R.C.H., D.E.A., A.M., J.R.F.), University of Vigo, Campus Universitario, Spain; and Hypertension and Vascular Risk Unit (C.C., J.E.L., M.R.), Hospital Clínico Universitario, Santiago de Compostela, Spain.
Correspondence to Prof Ramón C. Hermida, PhD, Director, Bioengineering and Chronobiology Laboratories, E.T.S.I. Telecomunicación, Campus Universitario, Vigo (Pontevedra) 36200, Spain. E-mail rhermida{at}tsc.uvigo.es
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Abstract |
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Aspirin is a potent antioxidative agent that reduces vascular production of superoxide, prevents angiotensin II–induced hypertension, and induces NO release. Low-dose aspirin administered at bedtime, but not on awakening, has also been shown to reduce blood pressure, possibly enhancing the nocturnal trough in NO production. Because endothelium-dependent vasodilation is blunted through a decrease in NO release in non-dipper compared with dipper patients, we compared the administration time-dependent influence of aspirin on ambulatory blood pressure in dipper and non-dipper hypertensive subjects. We studied 257 patients with mild hypertension (98 men and 159 women), 44.6±12.5 years of age, randomly assigned to receive 100 mg per day of aspirin either on awakening or at bedtime. Ambulatory blood pressure was measured for 48 hours at baseline and after 3 months of intervention. Blood pressure was slightly elevated after aspirin on awakening (increase of 1.5/1.0 mm Hg in the 24-hour mean of systolic/diastolic blood pressure; P<0.028). A highly significant blood pressure reduction was observed in patients who received aspirin at bedtime (decrease of 7.2/4.9 mm Hg in systolic/diastolic blood pressure; P<0.001). The reduction in nocturnal blood pressure mean was double in non-dippers (11.0/7.1 mm Hg) compared with dippers (5.5/3.3 mm Hg; P<0.001). This prospective trial corroborates the significant administration time-dependent effect of low-dose aspirin on blood pressure, mainly in non-dipper hypertensive patients. The timed administration of low-dose aspirin could thus provide a valuable approach, beyond prevention of cardiovascular disease, in the blood pressure control of patients with mild hypertension.
Key Words: blood pressure monitoring, ambulatory • hypertension, mild • nitric oxide • circadian rhythm
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Introduction |
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Acetylsalicylic acid (ASA; aspirin) is a nonsteroidal anti-inflammatory drug (NSAID) with demonstrated inhibitory effects on cyclooxygenases (COXs) responsible for arachidonic acid metabolism and prostaglandin production.1 Previous studies have demonstrated that ASA is a potent antioxidative agent that markedly reduces vascular production of superoxide in normotensive and hypertensive rats.2 In addition, ASA was found to prevent angiotensin II–induced hypertension and cardiovascular hypertrophy, mainly through its antioxidative properties in preventing the generation of superoxide.3 Moreover, recent results have demonstrated that ASA induces NO release from vascular endothelium.4,5 This effect appears to be attributable to a direct acetylation of the endothelial NO synthase protein.
No attention has been paid so far in these studies to potential administration time dependencies in the effects of ASA. However, a significant circadian variation has been demonstrated in several oxidative stress markers, including 8-hydroxydeoxyguanosine, malondialdehyde, and 8-isoprostane.6 The peak concentrations of the 3 markers occurred early in the evening, with trough values obtained during nocturnal sleep. These peak and trough times are highly correlated with those of serum NO.6,7 Moreover, among many other variables related to the regulation of blood pressure (BP), a predictable circadian variation has been demonstrated in plasma renin activity, angiotensin II, catecholamines, atrial natriuretic peptides, aldosterone, and angiotensin-converting enzyme.8
Previous laboratory animal and clinical trial research demonstrates administration time-dependent effects of ASA. Thus, the effects of ASA on lipoperoxides 
- and ß-adrenergic receptors and BP in clinically healthy subjects depend on the circadian timing of ASA administration.9 Moreover, ASA has also been shown to produce an administration time-dependent >30% inhibition of angiotensin II, associated to the documented effects of ASA on plasma renin activity.10 Most important, the administration time-dependent influence of ASA on BP was demonstrated previously in a randomized trial on healthy women9 and other independent double-blind, randomized, placebo-controlled clinical trials conducted: first on clinically healthy subjects,11 a second on normotensive and hypertensive subjects,12 a third on pregnant women at high risk for preeclampsia,13 and a fourth in untreated patients with mild hypertension.14 The findings of these BP studies, all of which used ambulatory BP monitoring (ABPM) to derive primary outcome variables, are consistent; BP-lowering effect of low-dose ASA is achieved when administered at bedtime but not on awakening.
On the other hand, some specific features of the 24-hour BP pattern are linked to the progressive injury of target tissues and the triggering of cardiac and cerebrovascular events.15 Many studies show the extent of the nocturnal BP decline is deterministic of cardiovascular injury and risk. Absence of the normal 10% to 20% sleep-time BP decline (dipper pattern) is associated with elevated risk of end-organ injury, particularly to the heart (left ventricular hypertrophy and myocardial infarct), brain (stoke), and kidney (albuminuria and progression to end-stage renal failure).16–18 Previous studies have found that non-dippers may be characterized by enhanced oxidative stress.19 Moreover, recent results have suggested that endothelium-dependent vasodilation is blunted through a decrease in NO release in non-dippers compared with patients who have dipper hypertension.20 The antioxidative properties of ASA and its documented beneficial effects on NO production could result in a further effect on BP in non-dippers compared with dippers.
In keeping with the chronopharmacological effects of ASA, this prospective randomized study investigated the comparative influence of ASA on BP in dipper and non-dipper subjects with mild hypertension who received low-dose ASA at different times of the day according to their rest–activity cycle and who were evaluated by 48-hour ABPM before and after 3 months of pharmacological intervention.
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Methods |
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Subjects
The study was conducted at the Hypertension and Vascular Risk Unit, Hospital Clínico Universitario, Santiago de Compostela, Spain, between June 2003 and February 2005. Shift workers, heavy drinkers (alcohol intake >80 g per day), smokers (>20 cigarettes per day), and heavy exercisers were excluded, as were individuals with contraindications to the use of ASA and those with either moderate or severe arterial hypertension (grade 2 or 3; ie, BP
160/100 mm Hg) or secondary arterial hypertension and cardiovascular disorders, including angina, heart failure, stroke, nephropathy, and retinopathy, or previous myocardial infarction or coronary revascularization, as revealed by thorough clinical evaluation according to the standardized protocol at the unit. Inclusion criteria required a diagnosis of previously untreated grade 1 (mild) essential hypertension based on conventional BP measurements (systolic BP [SBP] between 140 and 159 mm Hg or diastolic BP [DBP] between 90 and 99 mm Hg)21 and corroboration by ABPM at the time of recruitment. A positive diagnosis of hypertension based on ABPM required that either the diurnal mean be >135/85 mm Hg, or the nocturnal mean be >120/70 mm Hg.22,23 With these inclusion criteria, we identified and randomized 270 untreated volunteers. Among those, 257 volunteers (98 men and 159 women; 44.6±12.5 years of age) completed the study and provided all required information. The use of antihypertensive and any other medication, apart from the provided dose of ASA, was forbidden during the trial. The demographic characteristics of the participants are included in Table 1.
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After providing informed consent to participate in this prospective, randomized, open-label, blinded end point (PROBE), parallel-group trial, subjects were assigned randomly to receive ASA (100 mg per day) either on awakening or at bedtime. The dose of 100 mg used in this trial corresponds with the actual lower dose commercially available in Spain within the accepted range of low dose (75 to 150 mg24). Compliance was measured on the basis of tablet count and a personal interview with each volunteer. Benefits of the PROBE design and its validity compared with double-blind, placebo-controlled trials in assessing antihypertensive efficacy based on blinded ABPM measurements have been documented previously.25 The review board on human studies at our institution approved the protocol.
Blood samples were obtained in the clinic from the antecubital vein after nocturnal fasting between 8 AM and 9 AM on the same days when 48-hour ABPM was initiated, immediately before and after 3 months of timed treatment. Clinic BP measurements (6 per study visit after being seated for 5 minutes, on the same day just before starting ABPM) were always obtained by the same investigator with a validated automatic oscillometric device (HEM-737; Omron Health Care Inc.).26
The sample size for this trial was calculated as follows. Assuming an SD of 8 mm Hg for ABPM,14 with 41 subjects per arm, the study could have 80% power to show as significant at the 95% level changes of 5 mm Hg in ABPM between treatment groups. Assuming with the provided inclusion criteria a prevalence of non-dippers about one third of the total sample,14,27 a minimum of 123 patients per arm would be needed. The distribution of patients who completed the study was as follows (Table 1): 80 dipper and 46 non-dipper patients received ASA on awakening; 83 dipper and 48 non-dipper patients received ASA at bedtime.
ABPM Assessment
The SBP, DBP, and heart rate (HR) of each participant were automatically measured every 20 minutes from 7 AM to 11 PM and every 30 minutes during the night for 48 consecutive hours with a properly calibrated SpaceLabs 90207 device (SpaceLabs Inc.). Subjects were studied by ABPM under baseline conditions, when subjects were free of medication, and again after 3 months of timed intervention with ASA. They were assessed while adhering to their usual diurnal activity (8 AM to 11 PM for most) and nocturnal sleep routine. Participants were instructed to go about their usual activities with minimal restrictions but to follow a similar schedule during the 2 days of ABPM and to avoid daytime napping. No one was hospitalized during monitoring. ABPM always began between 10 AM and 12 PM. BP series were not considered valid for analysis if >30% of the measurements were lacking, if they had missing data for >2-hour spans, or if they were collected from subjects while they were experiencing an irregular rest–activity schedule or a nighttime sleep span of <6 hours or >12 hours during monitoring. Protocol-correct data series were collected from 257 subjects. Baseline BP profiles of 13 additional subjects (7 assigned to morning treatment with ASA and 6 to bedtime treatment) could not be used for analysis because the patients failed to return for the second ABPM at the end of intervention.
Actigraphy
During 48-hour ABPM, each participant wore a Mini-Motion-Logger actigraph (Ambulatory Monitoring Inc.) on the dominant wrist to monitor physical activity every minute. This compact (about half the size of a wrist watch) device functions as an accelerometer. The internal clocks of the actigraph and the ABPM devices were synchronized through their respective interfaces by the same computer. The actigraphy data were used to determine the onset and offset times of diurnal activity and nocturnal sleep to accurately determine the diurnal and nocturnal BP means of each subject. The mean activity for the 5 minutes before each BP reading was then calculated for further statistical analysis on circadian variability of activity, according to previous studies on this area.27,28
Statistical Methods
Each individual’s clock hour BP and HR values were first rereferenced from clock time to hours after awakening from nocturnal sleep according to the information obtained from wrist actigraphy. This transformation avoided the introduction of bias caused by differences among subjects in their sleep/activity routine.27 BP and HR time series were then edited according to conventional criteria to remove measurement errors and outliers.29 Thus, readings with SBP >250 or <70 mm Hg, DBP >150 or <40 mm Hg, and pulse pressure (difference between SBP and DBP) >150 or <20 mm Hg were automatically discarded. For descriptive purposes, the circadian rhythm of BP, HR, and wrist activity before and after 3 months of intervention was assessed objectively by population multiple-component analysis.30 The circadian rhythm parameters of midline estimating statistic of rhythm (average value of the rhythmic function fitted to the data), overall amplitude (one half the difference between the maximum and the minimum values of the best fitted curve), and orthophase (peak time, expressed as a lag from the time of awakening from nocturnal sleep) obtained for each group of patients before and after intervention were compared with a paired nonparametric test developed to assess differences in parameters derived from population multiple-components analysis.31 Hourly BP means obtained before and after intervention were compared by t test corrected for multiple testing with the Holm procedure.32 The daily (24-hour), diurnal, and nocturnal means of BP were further compared among groups by ANOVA. The demographic and clinical characteristics in Table 1 were compared among groups by ANOVA (quantitative variables) or nonparametric 
2 test.
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Results |
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Demographic and Analytic Characteristics
The baseline characteristics of the 2 groups of subjects (Table 1) were similar in age, height, weight, body mass index (BMI), waist and hip perimeters, and clinic SBP and DBP (average of the 6 morning measurements obtained just before ABPM). Moreover, there were no statistically significant changes in weight, BMI, and the waist and hip perimeters in either group after 3 months of intervention. Clinic BP measurements were reduced significantly from baseline ones (5.2 and 2.4 mm Hg in SBP and DBP; P<0.001) only in the group receiving ASA at bedtime. The serum values of glucose, creatinine, uric acid, cholesterol, triglycerides (Table 1), and other laboratory chemistry variables were comparable between the 2 treatment groups at baseline and after 3 months of intervention. Use of the low dose of 100 mg per day of ASA did not modify the baseline values of hemoglobin at any time of administration tested here (Table 1). Plasma lipids were reduced slightly after ASA at bedtime (Table 1), although the reduction would not be statistically significant if corrected for multiple testing.
ABPM Characteristics
The circadian variation of SBP (top) and DBP (bottom) in untreated mild hypertensive patients (irrespective of their baseline dipping status) measured by 48-hour ABPM before and after 3 months of ASA on awakening is depicted in Figure 1 (left panels). There was no statistically significantly change in the diurnal means of BP after 3 months of 100 mg per day of ASA ingested on awakening. BP slightly increased during nocturnal resting hours (Table 2).
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The graphs on the right in Figure 1 show the significant reduction compared with baseline of 7.2 and 4.9 mm Hg in the 24-hour mean of SBP and DBP, respectively (P<0.001), after 3 months of 100 mg per day of ASA taken at bedtime. BP was reduced homogeneously during the hours of diurnal activity and nocturnal rest. Figure 1 further indicates that the mean reduction in BP at each hourly average during the 24-hour dosing interval was statistically significant (P always <0.05 after correcting for multiple testing). A reduction in BP was observed in 94% of the patients in this group. Only 2 patients experienced a significant BP elevation after treatment. Despite the significant effect on BP, HR remained unchanged after 3 months of treatment (decrease in the 24-hour mean of 1.3 bpm; P=0.218). The circadian pattern of wrist activity was also similar before and after 3 months of therapy (P=0.180 for comparison of 24-hour mean activity). Average duration of nocturnal rest determined by actigraphy was not statistically different (P=0.698) for the profiles obtained before and after intervention (Table 2).
The comparison of results provided in Figure 1 indicates the lack of statistically significant differences in BP at baseline among the 2 treatment groups. After intervention, results indicate a highly significant absolute and relative reduction in BP only after ASA ingested at bedtime but not on awakening (P<0.001 for SBP and DBP; Table 2).
ASA Effects According to Dipping Status
Figure 2 provides information on the comparison between the treatment groups of the changes in the diurnal, nocturnal, and 24-hour mean BP values after 3 months of therapy, with patients in each group divided according to their baseline dipping status. Results indicate the lack of significant effects of SBP (top) and DBP (bottom) of ASA administered on awakening in dipper (patients with >10% decline in the nocturnal relative to the diurnal BP mean using all data sampled for 48 hours) and non-dipper hypertensive patients. There was no difference in BP changes between dipper and non-dipper patients after morning dosing of ASA.
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Results from Figure 2 further indicate the statistically significant reduction in the 24-hour mean of SBP and DBP after ASA at bedtime. This reduction was comparable for dipper and non-dipper patients (P=0.361 and 0.857 for comparison of 24-hour mean reduction in SBP and DBP, respectively, between groups). The BP reduction during diurnal active hours was slightly although not significantly larger in dippers compared with non-dippers. However, the reduction in nocturnal BP mean was double in non-dippers (11.0 and 7.1 mm Hg in SBP and DBP, respectively) compared with dippers (5.5 and 3.3 mm Hg; P<0.001). Accordingly, there was a significant decrease in the nocturnal decline relative to the diurnal mean of BP (diurnal/nocturnal BP ratio) in non-dipper patients after bedtime dosing with ASA (4.0 and 4.4 for SBP and DBP; P<0.001). Among these patients, 58.3% reverted to a dipper BP pattern after treatment.
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Discussion |
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Corroborating previous findings,14 the major result from this study is that ASA selectively decreases BP as a function of the timing of its administration in relation to the rest–activity cycle of each individual subject. The administration time-dependent effects of ASA on BP demonstrated here are fully in agreement with conclusions found previously in clinically healthy normotensive subjects as well as in hypertensive patients using the same low dose of 100 mg per day ASA but for the much shorter time of just 1 week.11,12 However, a higher dose of ASA (500 mg per day) showed a pressor effect even when administered before bedtime.12 Indeed, it has been reported that NSAID may increase BP in normotensive and hypertensive subjects.33,34 In any event, the dose of ASA regularly used to show anti-inflammatory effects is markedly larger than the dose used as anticoagulant and recommended for prevention of cardiovascular events.35 Similar results regarding the time-dependent influence of low-dose ASA on BP were also shown in pregnant women who used 100 mg per day of ASA for most of their pregnancy,13 as well as in a previous independent trial in patients with mild hypertension.14 In the present study, low-dose ASA administered at bedtime not only significantly reduced the mean BP from ABPM but also conventional BP measurements.
With respect to the potential mechanism(s) involved in the responsiveness of BP to ASA administered at different times according to the rest–activity cycle, the effects of ASA on - and ß-adrenergic receptors depend markedly on the circadian timing of ASA administration.9 -Adrenoceptor blockade more effectively reduces peripheral resistance in the early morning hours than at other times of the day.36 Moreover, a recent study exploring the administration time-dependent effects of the new gastrointestinal therapeutic system formulation of the -blocker doxazosin37 concluded that daily ingestion of the medication at bedtime resulted in a statistically significant doubling of the amount of 24-hour mean BP reduction compared with morning dosing. Most important, ASA has been shown to provide a significant inhibition of angiotensin II dependent on the dose and circadian time of ASA administration.10 Moreover, ASA is known to acetylate a variety of proteins, including COX-2. COX-2 inhibition has also been shown to decrease renin content and to lower BP in a model of renovascular hypertension.38 These results may be relevant inasmuch as ASA given at the end of the activity cycle could thus target the nocturnal peak of plasma renin activity while enhancing the nocturnal trough in the production of NO.7 This hypothesis gains relevancy given the significantly enhanced effect of ASA in reducing the nocturnal mean of BP in non-dipper hypertensive patients (Figure 2), who are characterized by a decrease in NO release compared with dipper patients.20 The potential added impact on NO or plasma renin activity attributable to the timed administration of low-dose ASA deserves further investigation.
The mechanisms underlying the loss of the nocturnal decline in BP are still unclear. Nonetheless, the extent of the nocturnal decline in BP in hypertension seems to be of clinical importance. Verdecchia et al16 showed that after an average follow-up period of 3.2 years, non-dipper hypertensive patients experienced nearly 3x as many adverse cardiovascular events as dippers. More recently, Staessen et al,17 summarizing results from the Syst-Eur trial, in which nitrendipine was dosed at bedtime, reported that non-dippers experienced a greater incidence of stroke and myocardial infarction than the group of persons who had a normal dipping pattern after treatment. Results of this trial also suggested that nighttime BP was the best predictor of risk. A recent evaluation of the data from the Ohasama Study indicated that after an average follow-up of 9.2 years, a 5% decrease in the decline of nocturnal SBP in hypertensive patients was associated with a 31% increased risk of cardiovascular mortality.18
The potential reduction in cardiovascular risk associated with the normalization of the circadian variability of BP (converting a non-dipper to dipper pattern) has not yet been clearly established. Apart from the Syst-Eur trial mentioned above, results from the Heart Outcomes Prevention Evaluation (HOPE) substudy, in which patients were evaluated by ABPM, indicated a significant BP reduction, mainly during hours of nighttime sleep.39 The authors suggested that the beneficial effects on cardiovascular morbidity and mortality in the HOPE study may be related to the 8% increase in the diurnal/nocturnal ratio of BP seen after ramipril was administered at bedtime. The potential advantages in terms of cardiovascular risk reduction from bedtime administration of ASA, mainly in non-dipper patients, deserve further prospective investigation.
Results from this prospective trial refer exclusively to untreated patients with newly diagnosed mild hypertension. Other studies have shown no influence of low-dose ASA on BP in hypertensive patients under pharmacological therapy,40,41 yet the time of ingestion of ASA (presumably morning27) has not been reported. Whether or not ASA enhances the effects of antihypertensive medication or if such a possible influence is circadian time dependent are further issues of clinical interest that should be addressed in future research.
Regarding other relevant issues related to ASA administered at different times of the day, compliance was not different in this trial between awakening and bedtime dose. The number of patients who concluded the study was similar at both treatment times, and no patients abandoned the trial because of secondary effects. With respect to tolerability and potential side effects, a previous endoscopic trial on volunteers who took high-dose ASA (1300 mg) at different times on separate study days has shown that the evening dose compared with the morning dose produced 37% fewer gastric hemorrhagic lesions.42 Although low-dose ASA would be associated generally with lower potential risks compared with higher doses, previous studies have concluded that nighttime administration of ASA is better tolerated than morning administration.42
Perspectives
The results from this prospective trial in untreated patients with mild hypertension corroborate previous findings on the administration time-dependent influence of low-dose ASA on BP. These beneficial effects are significantly larger in non-dipper compared with dipper patients, mainly in the control of nocturnal BP, a result that may be related to the documented increase in NO release from vascular endothelium attributable to ASA. Apart from the documented benefits of ASA in the secondary prevention of cardiovascular disease, results indicate that the timed administration of low-dose ASA with respect to the rest–activity cycle of each individual patient could provide a valuable approach for BP control of patients with mild essential hypertension. Apart from the BP-lowering effect, low-dose ASA administered at bedtime, but not on awakening, has also been shown to be protective against preeclampsia, gestational hypertension, intrauterine growth retardation, and preterm delivery in high-risk pregnant women.13 Whether or not low-dose ASA administered at the end of the activity cycle is able to provide further cardiovascular protection in hypertensive patients beyond documented findings deserves prospective investigation.
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Acknowledgments |
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This research was supported in part by grants from Xunta de Galicia (PGIDIT03-PXIB-32201PR), Química Farmacéutica Bayer, and Vicerrectorado de Investigación, University of Vigo.
Received April 27, 2005; first decision May 12, 2005; accepted May 24, 2005.
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References |
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1. Patrono C, Ciabattoni G, Patrignani P, Pugliese F, Filabozzi P, Catella F, Dave G, Forni L. Clinical pharmacology of platelet cyclo-oxygenase inhibition. Circulation. 1985; 72: 1177–1184.
2. Wu R, Lamontagne D, de Champlain J. Antioxidative properties of acetylsalicylic acid on vascular tissues from normotensive and spontaneously hypertensive rats. Circulation. 2002; 105: 387–392.
3. Wu R, Laplante MA, de Champlain J. Prevention of angiotensin II-induced hypertension, cardiovascular hypertrophy and oxidative stress by acetylsalicylic acid in rats. J Hypertens. 2004; 22: 793–801.[CrossRef][Medline] [Order article via Infotrieve]
4. Grosser N, Schroder H. Aspirin protects endothelial cells from oxidant damage via the nitric oxide-cGMP pathway. Arterioscler Thromb Vasc Biol. 2003; 23: 1345–1351.
5. Taubert D, Berkels R, Grosser N, Schroder H, Grundemann D, Schomig E. Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action. Br J Pharmacol. 2004; 143: 159–165.[CrossRef][Medline] [Order article via Infotrieve]
6. Kanabrocki EL, Murray D, Hermida RC, Scott GS, Bremner WF, Ryan MD, Ayala DE, Third JL, Shirazi P, Nemchausky BA, Hooper DC. Circadian variation in oxidative stress markers in healthy and type II diabetic men. Chronobiol Int. 2002; 19: 423–439.[CrossRef][Medline] [Order article via Infotrieve]
7. Kanabrocki EL, George M, Hermida RC, Messmore HL, Ryan MD, Ayala DE, Hoppensteadt DA, Fareed J, Bremmer FW, Third JL, Shirazi P, Nemchausky BA. Day-night variations in blood levels of nitric oxide, T-TFPI, and E-selectin. Clin Appl Thromb Hemost. 2001; 7: 339–345.
8. Angeli A, Gatti G, Masera R. Chronobiology of the hypothalamic-pituitary-adrenal and renin-angiotensin-aldosterone systems. In: Touitou Y, Haus E, eds. Biologic Rhythms in Clinical and Laboratory Medicine. Berlin, Germany: Springer-Verlag; 1992: 292–314.
9. Cornélissen G, Halberg F, Prikryl P, Dankova E, Siegelova J, Dusek J; International Womb-To-Tomb Chronome Study Group. Prophylactic aspirin treatment: the merits of timing. J Am Med Assoc. 1991; 266: 3128–3129.
10. Abacioglu N. Effects of drugs and electroshock on blood angiotensin II concentrations. Ankara University, Department of Pharmacology, PhD. Dissertation; 1982.
11. Hermida RC, Fernández JR, Ayala DE, Iglesias M, Halberg F. Time-dependent effects of ASA administration on blood pressure in healthy subjects. Chronobiologia. 1994; 21: 201–213.[Medline] [Order article via Infotrieve]
12. Hermida RC, Fernández JR, Ayala DE, Mojón A, Iglesias M. Influence of aspirin usage on blood pressure. Dose and administration-time dependencies. Chronobiol Int. 1997; 14: 619–637.[Medline] [Order article via Infotrieve]
13. Hermida RC, Ayala DE, Iglesias M. Administration-time dependent influence of aspirin on blood pressure in pregnant women. Hypertension. 2003; 41: 651–656.
14. Hermida RC, Ayala DE, Calvo C, López JE, Fernández JR, Mojón A, Domínguez MJ, Covelo M. Administration-time dependent effects of aspirin on blood pressure in untreated hypertensive patients. Hypertension. 2003; 41: 1259–1267.
15. Hermida RC, Smolensky MH. Chronotherapy of hypertension. Curr Opin Nephrol Hypertens. 2004; 13: 501–505.[CrossRef][Medline] [Order article via Infotrieve]
16. Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistell M, Guerrieri M, Gatteschi C, Zampi I, Santucci A, Santucci C, Reboldi G. Ambulatory blood pressure: an independent predictor of prognosis in essential hypertension. Hypertension. 1994; 24: 793–801.
17. Staessen JA, Thijs L, Fagard R, O'Brien ET, Clement D, de Leeuw PW, Mancia G, Nachev C, Palatini P, Parati G, Tuomilehto J, Webster J; Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. J Am Med Assoc. 1999; 282: 539–546.
18. Ohkubo T, Hozawa A, Yamaguchi J, Kikuya M, Ohmori K, Michimata M, Matsubara M, Hashimoto J, Hoshi H, Araki T, Tsuji I, Satoh H, Hisamichi S, Imai Y. Prognostic significance of the nocturnal decline in blood pressure in individuals with and without high 24-h blood pressure: the Ohasama Study. J Hypertens. 2002; 20: 2183–2189.[CrossRef][Medline] [Order article via Infotrieve]
19. Pierdomenico SD, Costantini F, Bucci A, De Cesare D, Bucciarelli T, Cuccurullo F, Mezzetti A. Blunted nocturnal fall in blood pressure and oxidative stress in men and women with essential hypertension. Am J Hypertens. 1999; 12: 356–363.[CrossRef][Medline] [Order article via Infotrieve]
20. Higashi Y, Nakagawa K, Kimura M, Noma K, Hara K, Sasaki S, Goto C, Oshima T, Chayama K, Yoshizumi M. Circadian variation of blood pressure and endothelial function in patients with essential hypertension: a comparison of dippers and non-dippers. J Am Coll Cardiol. 2002; 40: 2039–2043.
21. Guidelines Committee. 2003 European Society of Hypertension—European Society of Cardiology guidelines for the management of arterial hypertension. J. Hypertens. 2003; 21: 1011–1053.[CrossRef][Medline] [Order article via Infotrieve]
22. O’Brien A, Asmar R, Beilin L, Imai Y, Mallion JM, Mancia G, Mengden T, Myers M, Padfield P, Palatini P, Parati G, Pickering T, Redon J, Staessen J, Stergiou G, Verdecchia P; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement. J Hypertens. 2003; 21: 821–848.[CrossRef][Medline] [Order article via Infotrieve]
23. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ. Recommendations for blood pressure measurement in humans and experimental animals. Part 1: Blood pressure measurement in humans. Hypertension. 2005; 45: 142–161.
24. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71–86.
25. Smith DH, Neutel JM, Lacourciere Y, Kempthorne-Rawson J. Prospective, randomized, open-label, blinded-endpoint (PROBE) designed trials yield the same results as double-blind, placebo-controlled trials with respect to ABPM measurements. J Hypertens. 2003; 21: 1291–1298.[CrossRef][Medline] [Order article via Infotrieve]
26. Anwar YA, Giacco S, McCabe EJ, Tendler BE, White WB. Evaluation of the efficacy of the Omron HEM-737 Intellisense device for use on adults according to the recommendations of the Association for the Advancement of Medical Instrumentation. Blood Press Monit. 1998; 3: 261–265.[Medline] [Order article via Infotrieve]
27. Hermida RC, Calvo C, Ayala DE, Mojón A, López JE. Relationship between physical activity and blood pressure in dipper and nondipper hypertensive patients. J Hypertens. 2002; 20: 1097–1104.[CrossRef][Medline] [Order article via Infotrieve]
28. Mansoor GA, White WB, McCabe EJ, Giacco S. The relationship of electronically monitored physical activity to blood pressure, heart rate, and the circadian blood pressure profile. Am J Hypertens. 2000; 13: 262–267.[CrossRef][Medline] [Order article via Infotrieve]
29. Staessen J, Fagard R, Lijnen P, Thijs L, Vaa Hoof R, Amery A. Ambulatory blood pressure monitoring in clinical trials. J Hypertens. 1991; 9 (suppl 1): s13–s19.[CrossRef]
30. Fernández JR, Hermida RC. Inferential statistical method for analysis of nonsinusoidal hybrid time series with unequidistant observations. Chronobiol Int. 1998; 15: 191–204.[Medline] [Order article via Infotrieve]
31. Fernández JR, Mojón A, Hermida RC. Comparison of parameters from rhythmometric models with multiple components on hybrid data. Chronobiol Int. 2004; 21: 469–484.[CrossRef][Medline] [Order article via Infotrieve]
32. Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat. 1979; 6: 65–70.
33. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med. 1993; 153: 477–484.
34. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med. 1994; 121: 289–300.
35. Clarke RJ, Mayo G, Price P, FitzGerald GA. Suppression of thromboxane A2 but not systemic prostacyclin by controlled-release aspirin. N Engl J Med. 1991; 325: 1137–1141.[Abstract]
36. Panza JA, Epstein SE, Quyyumi AA. Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstrictor activity. N Engl J Med. 1991; 325: 986–990.[Abstract]
37. Hermida RC, Calvo C, Ayala DE, Domínguez MJ, Covelo M, Fernández JR, Fontao MJ, López JE. Administration-time-dependent effects of doxazosin GITS on ambulatory blood pressure of hypertensive subjects. Chronobiol Int. 2004; 21: 277–296.[Medline] [Order article via Infotrieve]
38. Wang JL, Cheng HF, Harris RC. Cyclooxygenase-2 inhibition decreases renin content and lowers blood pressure in a model of renovascular hypertension. Hypertension. 1999; 34: 96–101.
39. Svensson P, de Faire U, Sleight P, Yusuf S, Östergren J. Comparative effects of ramipril on ambulatory and office blood pressures. A HOPE substudy. Hypertension. 2001; 38: e28–e32.[CrossRef][Medline] [Order article via Infotrieve]
40. Nawarskas JJ, Townsend RR, Cirigliano MD, Spinler SA. Effect of aspirin on blood pressure in hypertensive patients taking enalapril or losartan. Am J Hypertens. 1999; 12: 784–789.[CrossRef][Medline] [Order article via Infotrieve]
41. Avanzini F, Palumbo G, Alli C, Roncaglioni MC, Ronchi E, Cristifari M, Capra A, Rossi S, Nosotti L, Costantini C, Pietrofeso R; Collaborative Group of the Primary Prevention Project (PPP)–Hypertension Study. Effects of low-dose aspirin on clinic and ambulatory blood pressure in treated hypertensive patients. Am J Hypertens. 2000; 13: 611–616.[CrossRef][Medline] [Order article via Infotrieve]
42. Moore JG, Goo RH. Day and night aspirin-induced gastric mucosal damage and protection by ranitidine in man. Chronobiol Int. 1987; 4: 111–116.[Medline] [Order article via Infotrieve]
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