Differing Administration Time-Dependent Effects of Aspirin on Blood Pressure in Dipper and Non-Dipper Hypertensives

Abstract

Abstract-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), 44.6Ϯ12.5 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; PϽ0.028). 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; PϽ0.001). 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; PϽ0.001). 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 Ⅲ hypertension, mild Ⅲ nitric oxide Ⅲ circadian rhythm A cetylsalicylic 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 p...

Aspirin, Non-Aspirin Analgesics and the Risk of Hypertension in the SUN Cohort

“…22,23 On the other hand, Hermida et al reported an inverse association between aspirin intake (100 mg/day) given before bed-time and mean 24 hour BP levels (-6/-4 mm Hg reduction of systolic BP/ diastolic BP) 10 especially in non-dippers. 11 24 Two meta-analyses assessing the association of aspirin and other NSAIDs with BP levels have been published. The first meta-analysis found that among a total of 771 participants, NSAIDs increased mean blood pressure by 5 mm Hg overall (95% CI, 1.2-8.7).…”

“…4 Results from different prospective studies conducted in the United States assessing the association between use of aspirin, NSAIDs and other analgesics and the risk of hypertension suggest that chronic users of aspirin, NSAIDS, and acetaminophen have a higher risk of hypertension. [5][6][7][8][9] However, some clinical trials conducted in Spain have shown the opposite effect 10,11 and no previous prospective study has assessed this potential relationship in a European cohort, where a different health system probably means different access to medication and a different pattern of drug use. 12 Our objective was to assess the association between regular use of aspirin and non-aspirin analgesic drugs and the incidence of HTN in a prospective dynamic cohort study consisting of Spanish university graduates, the SUN (Seguimiento Universidad de Navarra, University of Navarra Follow-up) project.…”

Time-Dependent Effects of Low-Dose Aspirin on Plasma Renin Activity, Aldosterone, Cortisol, and Catecholamines

“…Subjects were eligible for participation if they had an untreated grade 1 hypertension, defined as systolic blood pressure between 140 and 159 mm Hg and/or diastolic blood pressure between 90 and 99 mm Hg, 1 and were Ͼ18 years old and capable to give informed consent, which are the same inclusion criteria as used by Hermida et al 8,9 Subjects were excluded if they had grade 2 or 3 hypertension (blood pressure Ն160/100 mm Hg), evidence of secondary arterial hypertension, any history of cardiovascular disease, diabetes mellitus, or rheumatoid arthritis or known contraindications to the use of aspirin (defined as history of asthma, any bleeding disorder, gastrointestinal tract bleeding, or known allergy to acetylsalicylic acid). Other exclusion criteria were severe renal or hepatic dysfunction, pregnancy, concurrent participation in other research projects or blood donation, and use of blood pressure-lowering medication, nonsteroidal anti-inflammatory drugs, or anticoagulant medication.…”

“…3 Notably, in studies addressing this association, it was not reported at what time of the day aspirin was ingested by the participants. [5][6][7] In contrast, 2 recent randomized, controlled trials by Hermida et al 8,9 have shown that 100 mg of aspirin strongly decreased blood pressure in subjects with grade 1 essential hypertension when it was administered at bedtime, whereas (if anything) blood pressure might be slightly increased when aspirin was taken on awakening. In the subjects allocated to aspirin at evening, reductions of systolic and diastolic blood pressures of, respectively, 7.2/4.9 and 6.8/4.6 mm Hg (systolic/diastolic blood pressure) were recorded, whereas in the participants using aspirin at morning, a slight elevation of, respectively, 1.5/1.0 and 2.6/1.6 mm Hg was observed.…”

“…In the subjects allocated to aspirin at evening, reductions of systolic and diastolic blood pressures of, respectively, 7.2/4.9 and 6.8/4.6 mm Hg (systolic/diastolic blood pressure) were recorded, whereas in the participants using aspirin at morning, a slight elevation of, respectively, 1.5/1.0 and 2.6/1.6 mm Hg was observed. 8,9 An important yet unanswered question is by which mechanism(s) aspirin could time-dependently lower blood pressure. 10 Because the main regulators of blood pressure behave according to circadian rhythms, these may be potential targets of time-dependent aspirin therapy.…”