Suppression of Thromboxane A2 But Not of Systemic Prostacyclin by Controlled-Release Aspirin

Clarke, Robert; Mayo, Gail; Price, Peter M.; FitzGerald, Garret A.

doi:10.1097/00006254-199204000-00004

Cited by 77 publications

(113 citation statements)

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“…10 PGI 2 receptor-deficient animals showed enhanced injury-induced vascular proliferation and platelet activation that was abolished in mice deficient of both PGI 2 and TXA 2 receptor, suggesting that PGI 2 inhibition with relatively unopposed platelet TXA 2 generation may lead to increased thrombotic risk. Because increased PGI 2 biosynthesis seen in atherosclerosis seems to reflect the activity of both COX isoforms, 14 the selective reduction of PGI 2 that potentially may increase the risk of atherosclerosis remains a concern regarding COX-2 inhibitors. Although PGI 2 potently inhibits aggregation, its role in vivo remains still elusive, because endogenous plasma levels are presumably below the threshold for a systemic effect.…”

Section: Discussionmentioning

confidence: 99%

Selective COX-2 Inhibition Improves Endothelial Function in Coronary Artery Disease

et al. 2003

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Background— There is an ongoing debate as to whether the gastrointestinal safety of COX-2 inhibition compared with nonsteroidal antiinflammatory drugs (NSAIDs) may come at the cost of increased cardiovascular events. In view of the large number of patients at cardiovascular risk requiring chronic analgesic therapy with COX-2 inhibitors for arthritic and other inflammatory conditions, the effects of selective COX-2 inhibition on clinically useful surrogates for cardiovascular disease, particularly endothelial function, need to be determined. Methods and Results— Fourteen male patients (mean age, 66±3 years) with severe coronary artery disease (average of 2.6 vessels with stenosis >75%) undergoing stable background therapy with aspirin and statins were included. The patients received celecoxib (200 mg BID) or placebo for a duration of 2 weeks in a double-blind, placebo-controlled, crossover fashion. After each treatment period, flow-mediated dilation of the brachial artery, high-sensitivity C-reactive protein, oxidized LDL, and prostaglandins were measured. Celecoxib significantly improved endothelium-dependent vasodilation compared with placebo (3.3±0.4% versus 2.0±0.5%, P =0.026), whereas endothelium-independent vasodilation, as assessed by nitroglycerin, remained unchanged (9.0±1.6% versus 9.5±1.3%, P =0.75). High-sensitivity C-reactive protein was significantly lower after celecoxib (1.3±0.4 mg/L) than after placebo (1.8±0.5 mg/L, P =0.019), as was oxidized LDL (43.6±2.4 versus 47.6±2.6 U/L, P =0.028), whereas prostaglandins did not change. Conclusions— This is the first study to demonstrate that selective COX-2 inhibition improves endothelium-dependent vasodilation and reduces low-grade chronic inflammation and oxidative stress in coronary artery disease. Thus, selective COX-2 inhibition holds the potential to beneficially impact outcome in patients with cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Selective COX-2 Inhibition Improves Endothelial Function in Coronary Artery Disease

et al. 2003

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“…1 Prostaglandin generation is catalyzed by the enzyme cyclooxygenase (COX), and the increase in PGI 2 reflects in part the induction of 2 COX isoforms, COX-1 and COX-2, in the vessel wall. 2,3 On the other hand, much of the increase in TXA 2 in atherosclerosis is derived from platelets 4 and therefore is largely generated by COX-1, the only isoform in platelets. 5 This is consistent with and indeed is evidence for enhanced platelet activity in patients with atherosclerosis.…”

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confidence: 99%

Cyclooxygenase Isoforms and Platelet Vessel Wall Interactions in the Apolipoprotein E Knockout Mouse Model of Atherosclerosis

et al. 2003

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Background-Cyclooxygenase (COX) activity is induced in human atherosclerosis, and the products formed may modify the disease directly or through an effect on platelets. We examined the role of COX-1 and -2 on platelet vessel wall interactions and development of atherosclerosis in a murine model. Methods and Results-Apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice fed a 1% cholesterol diet were treated with a selective COX-1 inhibitor (SC-560), a selective COX-2 inhibitor (SC-236), or vehicle. Urinary prostacyclin and thromboxane metabolites (2,3-dinor-6-keto-PGF 1␣ and 2,3-dinor-TXB 2 ) were increased in the apoE Ϫ/Ϫ knockout mouse. There was also induction of both COX isoforms in the vascular lesions formed, which stained for CD41, a platelet-specific marker, and for CD40L. Selective inhibition of COX-2 had no effect on lesion formation and, despite selective reduction in prostacyclin generation, had no effect on platelet activity, as measured by thromboxane formation or platelet deposition. Selective inhibition of COX-1 reduced 2,3-dinor-TXB 2 generation and lesion formation. However, platelet deposition on the vessel wall persisted, with well-defined monolayers seen. There was also persistent expression of the macrophage marker CD68 and increased expression of the cell death protein Bax. In contrast to lesion development, the selective COX-1 inhibitor had no effect on the regression of evolving lesions. Conclusions-COX-1 plays an important role in the early stages of lesion development in the apoEϪ/Ϫ knockout model of atherosclerosis, preventing gross lesion formation in the face of continued vascular injury and inflammation. Despite the inhibition of prostacyclin, COX-2 inhibition had no effect on lesion development or platelet-vessel wall interactions.

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“…4,7 The mechanisms whereby NSAID may increase BP are not fully understood, nor it is known whether the increase in BP is a long-term effect. In any event, the dose of ASA regularly used to show anti-inflammatory effects is markedly larger than the dose used as anticoagulant 10 and recommended for prevention of cardiovascular events. [1][2][3] ASA use in hypertensive patients is expected to increase after the publication of the results from the Hypertension Optimal Treatment (HOT) study, which documented the efficacy of low-dose ASA in preventing major cardiovascular events in hypertensive subjects.…”

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confidence: 99%

Administration Time–Dependent Effects of Aspirin on Blood Pressure in Untreated Hypertensive Patients

et al. 2003

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Abstract-Previous studies on the potential influence of aspirin on blood pressure have not taken into consideration the chronopharmacological effects of nonsteroidal anti-inflammatory drugs. This pilot study investigates the effects of aspirin on blood pressure in untreated hypertensive patients who received aspirin at different times of the day according to their rest-activity cycle. We studied 100 untreated patients with mild hypertension (34 men and 66 women), 42.5Ϯ11.6 (meanϮSD) years of age, randomly divided into 3 groups: nonpharmacological hygienic-dietary recommendations; the same recommendations and aspirin (100 mg/d) on awakening; or the same recommendations and aspirin before bedtime. Blood pressure was measured every 20 minutes during the day and every 30 minutes at night for 48 consecutive hours before and after 3 months of intervention. The circadian pattern of blood pressure in each group was established by population multiple-component analysis. After 3 months of nonpharmacological intervention, there was a small, nonsignificant reduction of blood pressure (Ͻ1.1 mm Hg; PϾ0.341). There was no change in blood pressure when aspirin was given on awakening (Pϭ0.229). A highly significant blood pressure reduction was, however, observed in the patients who received aspirin before bedtime (decrease of 6 and 4 mm Hg in systolic and diastolic blood pressure, respectively; PϽ0.001). Results indicate a statistically significant administration time-dependent effect of low-dose aspirin on blood pressure in untreated patients with mild hypertension. The influence of aspirin on blood pressure demonstrated in this study indicates the need to quantify and control for aspirin effects in patients using this drug in combination with antihypertensive medication. Key Words: antihypertensive agents Ⅲ blood pressure monitoring, ambulatory Ⅲ heart rate Ⅲ hypertension, mild Ⅲ drug therapy Ⅲ circadian rhythm T here is an extensive literature on the effects of acetylsalicylic acid (ASA, or aspirin), one of the most commonly consumed nonsteroidal anti-inflammatory drugs (NSAID), mainly in the prevention of cardiovascular events. 1-3 Although some of these studies reported average values of office blood pressure (BP) measurements for the patients before and after long-term administration of ASA or placebo, the study of a possible effect from ASA on BP was not a primary objective. In fact, the effect of ASA on BP was evaluated only in a few small studies. 4 -6 It has been reported that NSAID may increase BP both in normotensive and hypertensive subjects. 4,[7][8][9] The effects appear more marked in hypertensive subjects under treatment. 4,7 The mechanisms whereby NSAID may increase BP are not fully understood, nor it is known whether the increase in BP is a long-term effect. In any event, the dose of ASA regularly used to show anti-inflammatory effects is markedly larger than the dose used as anticoagulant 10 and recommended for prevention of cardiovascular events. [1][2][3] ASA use in hypertensive patients is expected to inc...

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Suppression of Thromboxane A2 But Not of Systemic Prostacyclin by Controlled-Release Aspirin

Cited by 77 publications

References 0 publications

Selective COX-2 Inhibition Improves Endothelial Function in Coronary Artery Disease

Selective COX-2 Inhibition Improves Endothelial Function in Coronary Artery Disease

Cyclooxygenase Isoforms and Platelet Vessel Wall Interactions in the Apolipoprotein E Knockout Mouse Model of Atherosclerosis

Administration Time–Dependent Effects of Aspirin on Blood Pressure in Untreated Hypertensive Patients

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