The BP effects of aspirin were studied in two models of renovascular hypertension: in one kidney, one clip (1K1C)-hypertensive rats, and in two kidney, one clip (2K1C)-hypertensive rats. Male SD rats were treated twice a day with aspirin 100 mg/kg or vehicle and, four days after beginning treatment, their left renal artery was clipped (2K1C rat model). In another group, besides left renal artery clipping, the right kidney was also removed in all animals (1K1C rat model). BP was measured three weeks after surgery. In comparison with vehicle-treated 2K1C rats, aspirin-treated 2K1C rats exhibited higher BP values (160 mmHg vs. 140 mmHg, p<0.05). Interestingly, aspirin treatment attenuated the BP increase in 1K1C rats (153 mmHg vs. 208 mmHg, p<0.05). Since 1K1C and 2K1C rats displayed different profiles in response to AA administration, with 1K1C rats exhibiting an enhanced vasodepressor response to AA, the authors suggested that aspirin decreases BP in hypertensive rats with increased activity of the COX pathway and raises BP in hypertensive rats that have a ‘normal’ COX pathway.55

Tuttle et al. also assessed the antihypertensive effect of aspirin in SHR and WKY. They first demonstrated that prolonged administration of aspirin (100 mg/kg/daily) to young SHR prevents the development of hypertension.56 Since aspirin loses its antihypertensive effect in adult SHR, they investigated whether the loss of aspirin's effect on BP was associated with aging or with the duration of exposure to aspirin treatment. A loss of aspirin's antihypertensive effect was found in all treated groups when SHR and WKY reached 110 days of age. Furthermore, since changes in PGF2α, used as an index of COX activity, did not parallel the BP alterations, the authors assumed that the age of the animal, and not a change in enzymatic activity or process over time, was responsible for the loss of aspirin's antihypertensive effect.56 Similar results were obtained by Wu et al., who observed significant attenuation of the development of hypertension in young SHR treated with aspirin (100 mg/kg/day for 53 days) but not in older aspirin-treated SHR or WKY.41 Nevertheless, aspirin treatment significantly reduced aortic O2− production in both old SHR and WKY.41

The effect of aspirin on BP in SHR also appears to depend on baseline systolic BP (SBP) values. In four-to-six-month old SHR, a three-day treatment with aspirin (100 mg/kg/day) reduced SBP in the SHR group exhibiting SBP values above 161 mmHg before treatment. In contrast, in other SHR with baseline SBP below 160 mmHg, aspirin significantly increased SBP, and this elevation was more marked in SHR that had baseline normotensive SBP values. Although the authors found no differences in the aortic production of TXA2 and PGI2, they speculated that the BP effects of aspirin were caused by inhibiting production of vasoconstrictor or vasodilator prostanoids.57

In Ang II-infused rats, concurrent aspirin treatment (100 mg/kg/day for 12-14 days) completely prevented Ang II-induced production of O2− in cardiovascular tissues, BP rise and cardiac hypertrophy. These effects were not shared by other NSAIDs.42 When aspirin was given to Ang II-infused rats after the establishment of hypertension, BP was significantly reduced after three days of treatment.42 In chronically glucose-fed rats with elevated BP, treatment with aspirin (100 mg/kg/day for three weeks) also prevented rises in SBP, glucose levels and aortic O2− production, and attenuated insulin resistance.58

The aspirin dose (100 mg/kg) used in these studies is high, being equivalent to a 1-g dose for a 70-kg man. Nevertheless, a lower dose (10 mg/kg/day), which would be equivalent to 100 mg/day in a man, was shown to significantly reduce vascular O2− production.42 These antioxidative properties may account for the cardiovascular benefits of low-dose aspirin.

The impact of lower aspirin doses on BP has been tested in some studies. In young male SHR, the administration of aspirin (10 mg/kg) twice a week for 10 weeks had no effect on SBP.59,60 In male Wistar rats, 50 mg/kg aspirin elicited a pressor response that was markedly enhanced by pretreatment with celecoxib, a COX-2 inhibitor, or with zileuton, a 5-LOX inhibitor, or with Boc-2, a LXA4 receptor antagonist.30 Furthermore, aspirin increased the serum concentration of ATL 20-fold and the administration of LXA4 alone significantly decreased BP. Thus, the formation of ATL attenuates the pressor response to aspirin, and drugs that inhibit ATL production enhance the aspirin-induced BP rise.30 In another study, treatment with aspirin (53.5 mg/kg/day) for seven days did not alter BP in male Wistar rats but significantly reduced BP in stroke-prone SHR compared to vehicle-treated animals.61 Our group recently assessed the effect of low-dose aspirin (10 mg/kg/day for eight days) alone or in combination with losartan in male WKY and SHR. Regarding the effect of aspirin alone, no significant changes were observed in SBP of WKY or SHR compared to their respective controls.62 Recently, another study also confirmed the lack of effect of low-dose aspirin (10 mg/kg/day for seven days) on the BP of normotensive WKY.63

The impact on BP of the combination of aspirin with antihypertensive drugs has been little studied. Tuttle et al. studied the antihypertensive efficacy of the BB metoprolol, aspirin (75-100 mg/kg/day), and their combination for 56 days, in young SHR and WKY. Treatment with metoprolol or aspirin alone prevented BP rise in both WKY and SHR. In contrast, when the drugs were co-administered, a loss of the antihypertensive effect was observed in SHR but not in WKY. Renal PGs were also measured after 56 days of treatment. Whereas renal PG content was higher in older SHR than in age-matched WKY, lower levels were found in SHR receiving aspirin or metoprolol. SHR treated with both drugs also exhibited reduced renal PG content, despite the loss of antihypertensive efficacy. The authors concluded that aspirin and metoprolol attenuate each other's antihypertensive effect, but could not explain the underlying mechanism based on the changes observed in renal PGs.11

Our group assessed the effects of combined treatment with low-dose aspirin (10 mg/kg/day for eight days) and the ARB losartan in male SHR and WKY. Although aspirin treatment did not modify the antihypertensive effect of losartan in WKY, it significantly improved the BP-lowering efficacy of losartan in SHR. This effect was associated with a significant reduction in renal COX-2 expression and in the production of vasoconstrictive eicosanoids, compared to SHR treated with losartan alone.62,64

The interaction between aspirin and ACEIs was studied in SHR and in rats with methylprednisolone-induced hypertension. In male SHR, treatment with aspirin (200mg/kg/day for seven days) did not alter the antihypertensive effect of captopril, although it markedly inhibited the formation of vasodilator prostanoids. Thus, these prostanoids do not appear to contribute to the antihypertensive effect of captopril in SHR.65 However, in another study in older SHR, combined treatment with captopril and aspirin (200 mg/kg/day) for seven days enhanced the antihypertensive effect of captopril, apparently by inducing an increase in diuresis. The inhibition of renal PG excretion by aspirin was a transient effect and it was concluded that the enhancement of captopril's antihypertensive efficacy by aspirin was independent of renal PG excretion.66 In male Wistar rats with methylprednisolone-induced hypertension, treatment with 25 mg/kg/day or 100 mg/kg/day aspirin did not modify the hypotensive effect of lisinopril. However, cardiac and renal degenerative changes were found even with the lower aspirin dose, and the combination of the higher aspirin dose and lisinopril was associated with a significant increase in mortality compared to hypertensive rats treated with lisinopril alone.67 A summary of these studies is presented in Table 1.

The influence of aspirin on BP in healthy subjects was investigated in a study designed to assess the effects of captopril, aspirin and the combination of both drugs on BP and on the excretion of prostanoids, nitrates and cyclic guanosine monophosphate (cGMP). A crossover trial was performed in 13 healthy females aged 24.9±0.5 years who were randomized to receive captopril (25 mg twice a day), aspirin (100 mg/day) or both drugs for one week, separated by a two-week washout. Aspirin did not change BP when given alone and did not modulate the hypotensive effect of captopril when co-administered. Urinary excretion of PGI2 metabolite, PGE2, nitrate and cGMP was not altered by either treatment but aspirin significantly reduced the excretion of TXA2 metabolite, when given alone or in combination with captopril.68

Hermida et al. investigated the administration time- and dose-dependent effects of aspirin on BP in healthy individuals. In their first study, 55 healthy subjects aged 20.9±1.8 years were randomized to receive aspirin (500 mg/day) for one week on awakening (n=18), during the afternoon (n=26) or at bedtime (n=11). There was a significant reduction in BP only when aspirin was administered during the afternoon.69 The same authors also conducted a double-blind, randomized clinical trial with 73 healthy participants (21.3±0.3 years of age) assigned to one of six groups defined according to placebo/aspirin dose (100 or 500 mg/day) for one week and to the circadian time of administration (awakening, afternoon and bedtime). In subjects receiving 500 mg aspirin, there was a small (approximately 2 mmHg) but significant reduction in SBP and diastolic blood pressure (DBP) when aspirin was given in the afternoon. Treatment with the lower dose in the afternoon elicited a significant SBP and DBP reduction, comparable to that obtained with 500 mg aspirin administered at the same time. However, the BP reduction was larger when 100 mg aspirin was given at bedtime. The higher impact on BP for 100 mg aspirin compared to 500 mg may be related to the selective inhibition of TXA2 but not PGI2 with the lower dose. The time dependency of BP reduction by aspirin could be due to circadian rhythms in circulating platelets, platelet aggregation, clotting and fibrinolytic inhibitors, and also in aspirin's inhibition of platelet aggregation.70

Hermida et al. also assessed the administration time-dependency of the effect of 100 mg/day aspirin for one week on BP reduction in untreated hypertensive subjects. This was performed in 18 volunteers aged 21.8±0.4 years, recently diagnosed with mild hypertension and untreated for hypertension. Aspirin significantly decreased BP when administered in the afternoon and at bedtime, but the effect was larger for bedtime administration.70 The same authors also conducted a trial in 100 untreated volunteers with mild (grade 1) essential hypertension, aged 42.5±11.6 years, who were randomly allocated to three groups to take hygienic-dietary recommendations (HDR) (n=50), HDR plus aspirin (100 mg/day) on awakening (n=24) or HDR plus aspirin (100 mg/day) before bedtime (n=26) for three months. Essentially, in the group that received aspirin before bedtime, but not in the other groups, there were significant reductions in SBP and DBP measured by conventional methods and by ambulatory blood pressure measurement (ABPM). Although the mechanisms responsible for this decrease have not been elucidated, the authors speculate that circadian rhythms in TXA2 production and in plasma renin activity (PRA) could account for the BP lowering effect of aspirin.71 Hermida et al. also conducted a similar study involving a larger sample of 328 untreated grade 1 hypertensive patients aged 44.0±12.6 years. These subjects were randomly distributed to the same groups described above (HDR, n=169; HDR plus aspirin 100 mg/day on awakening, n=77; HDR plus aspirin 100 mg/day before bedtime, n=82). The results obtained corroborated the previously described reduction of SBP and DBP values on ABPM and conventional measurement in the group receiving low-dose aspirin at bedtime.72 They further compared the chronobiological impact of aspirin on BP in dipper and non-dipper subjects with untreated grade 1 hypertension (n=257) randomized to receive aspirin (100 mg/day) on awakening (n=126, 80 dipper and 46 non-dipper) or at bedtime (n=131, 83 dipper and 48 non-dipper) for three months. This study again confirmed that aspirin given at bedtime, but not on awakening, significantly reduced 24-hour SBP and DBP. Of note, aspirin administered at bedtime induced a two-fold higher decrease in nocturnal BP in non-dipper patients compared to dipper patients.73 Interestingly, in another study they also demonstrated the existence of gender differences in BP response to aspirin administration. This trial included 130 men and 186 women with untreated grade 1 hypertension who were randomly assigned to take aspirin 100 mg/day on awakening or at bedtime for three months.74 When aspirin was administered on awakening, BP was not altered in men but was slightly increased in women. In contrast, when aspirin was given at bedtime, BP values were significantly decreased in both men and women. This reduction was significantly larger in women than in men, and gender differences in BP were greater during night-time rest.74

Magagna et al. also assessed the influence of 100 mg/day aspirin on BP control in untreated borderline or mild essential hypertensive subjects. Ten patients aged 47.9±5.1 years received aspirin (100 mg/day) or placebo for four weeks. Aspirin treatment did not modify BP in these patients but significantly reduced serum and urinary TXB2 and PRA.75 Although urinary excretion of PGI2 metabolite was not significantly altered by aspirin treatment, the authors reported that it was slightly decreased and could have contributed to the reduction in PRA.75 The effect on BP of low-dose aspirin in untreated hypertensive patients was further studied by Snoep et al. as a secondary endpoint in a crossover trial designed to assess the mechanisms underlying BP reduction when aspirin was given at bedtime.76 This trial included 16 untreated grade 1 hypertensive individuals aged 58.4±6.8 years who were randomly allocated to one of two groups, one receiving aspirin (100 mg/day) at bedtime and placebo on awakening, and the other receiving aspirin on awakening and placebo at bedtime, for two weeks. After a four-week washout interval, patients again received aspirin and placebo for another two weeks, in the reverse order of the first treatment period. The results of this study indicate that aspirin intake at bedtime compared with the morning significantly reduced PRA over 24 hours, as well as 24-hour urinary excretion of cortisol, dopamine and noradrenaline. The authors suggested that reduced activity of these pressor systems was a plausible explanation for the BP decrease when aspirin is given at night and the lack of effect detected when given in the morning. Although in this study no significant reduction in 24-hour BP was observed when aspirin was given at bedtime, the authors hypothesized that the treatment period was probably too short to translate the effects on BP regulating systems into effective BP reduction. They also underlined that their study was not designed and powered to detect differences in BP response to timed administration of aspirin.76

The majority of small, short-term trials have reported that low doses (75-100 mg/day) of aspirin do not interfere with the BP lowering effect of ACEIs (captopril, enalapril), ARBs (losartan), BBs (atenolol) and calcium antagonists (nifedipine).10,14,19,75,81,82 Regarding the interaction of low-dose aspirin and ACEIs, although no change in the antihypertensive effect of ACEIs was detected, significant reductions in serum and/or urinary TXB2 were observed with combined treatment with aspirin compared with treatment with ACEIs alone.14,75,81 Nevertheless, no significant changes were observed in the urinary metabolite of PGI2.75 Studies assessing the effects of higher aspirin doses on the BP of patients treated with ACEIs have reported contradictory results. While Guazzi et al. showed that aspirin (300 mg/day) induced an antagonistic effect on the action of enalapril,10 Nawarskas et al. observed no significant changes in mean arterial pressure, SBP or DBP in patients treated with aspirin (325 mg) and enalapril, compared to enalapril alone.14 Furthermore, Fisman et al. reported that treatment with aspirin 500 mg/day for one week did not influence BP control in hypertensive or in post-infarction patients receiving an ACEI.83 Also of note is the fact that combined treatment with aspirin (100 and/or 300 mg/day) and ACEIs reduced the ACEI-induced increased in PRA.10,75

The interaction of aspirin with ARBs does not appear to negatively influence BP control. No significant BP differences were observed when losartan was associated with aspirin therapy (81 mg or 325 mg/day) for two weeks.14 Of note, a post-hoc subgroup analysis of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study revealed that the combination of aspirin with losartan exerted greater cardiovascular protection than the combination of aspirin with atenolol, despite similar BP reduction.15 Additionally, a significant decrease in cardiovascular events was found in patients using aspirin plus losartan, compared with losartan alone.15 Interestingly, Prikryl et al. showed that the addition of aspirin to telmisartan improved the effects of this ARB on BP, heart rate, intrarenal resistive index and ejection fraction.84

There have also been large and medium- or long-term trials assessing the BP effects of aspirin in patients on antihypertensive monotherapy or combination therapy (Table 2). Avanzini et al. reported that there was no significant change in BP after addition of aspirin (100 mg/day) to antihypertensive therapy.13 Results from the Hypertension Optimal Treatment (HOT) randomized trial also revealed that there were no differences in achieved BP in patients randomized to aspirin or placebo.4 Importantly, the combination of aspirin with antihypertensive treatment reduced the risk of acute myocardial infarction without increasing the risk of cerebral bleeding.4 Furthermore, the BP values achieved, the intensity of the antihypertensive regimen, and the number and type of drugs used were very similar in aspirin and placebo patients, not only in the overall HOT study population, but in all subgroups.85 Of note, Leinonen et al. conducted a large observational study to assess the effect of aspirin treatment (50-250 mg/day) on BP of hypertensive patients receiving antihypertensive monotherapy or combination therapy and observed that aspirin reduced DBP regardless of the antihypertensive therapeutic scheme.22

The chronotherapeutic effects of aspirin have also been investigated in treated hypertensive patients (Table 2). The administration time-dependent effects of aspirin were assessed in patients with long-standing hypertension and treated with aspirin for cardiovascular prevention. Hypertensive patients were randomly assigned to take aspirin (75-160 mg/day) in the morning followed by aspirin in the evening, or in the reverse order, during two one-month periods, with no washout period. No differences were found in mean 24-hour SBP or DBP, or in patients’ dipper/non-dipper status, independently of aspirin administration time.86 The timing effect of aspirin dosing on BP was further studied in a recent crossover trial including patients taking low-dose aspirin for secondary cardiovascular disease prevention. Subjects were randomized to receive aspirin on awakening then at bedtime, or the reverse order, during two three-month periods, with no washout period. No differences were found in mean 24-hour SBP or DBP when aspirin was administered at awakening or at bedtime. However, morning platelet reactivity was significantly reduced when aspirin was taken at bedtime.87 These results86,87 contradict those observed for bedtime aspirin administration in patients with untreated mild hypertension or those at risk of developing hypertension,70–73,77–80 and may be explained by differences in study populations or by a weakened chronopharmacological effect of aspirin in patients taking this drug for a long time.86,87 A summary of studies assessing aspirin's effects in treated hypertensive patients is presented in Table 2.

The authors declare that no experiments were performed on humans or animals for this study.

The authors declare that no patient data appear in this article.

The authors declare that no patient data appear in this article.