New look at myocardial infarction: toward a better aspirin

Bing, Richard J.; Yamamoto, Tohru; Yamamoto, Masahide; Kakar, Rani; Cohen, Anna

doi:10.1016/s0008-6363(99)00074-7

Cited by 16 publications

(14 citation statements)

References 61 publications

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“…Therefore, inhibition of TXA 2 counteracts these effects. Reduction of PGI 2 synthesis by celecoxib could interfere with the coronary vasodilator effect of PGI 2 [16]. Since macrophages are located at the border area of the infarcted region, the activity of prostanoids on the infarcted region is secondary.…”

Section: Discussionmentioning

confidence: 99%

Effect of Cyclooxygenase-2 Inhibitor (Celecoxib) on the Infarcted Heart in situ

Yamamoto¹,

Kakar²,

Vina³

et al. 2001

Pharmacology

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Several attempts have been made to replace aspirin with compounds without gastric toxicity; a cyclooxygenase-2 (COX-2) inhibitor, celecoxib, and a nitric oxide-aspirin, NCX-4016, have been developed for this purpose. This paper compares effects of celecoxib, NCX-4016 and aspirin on production of prostacyclin (PGI₂) and thromboxane A₂ (TXA₂) and activation of the inducible form of nitric oxide synthase (iNOS) in infarcted heart in situ. Aspirin was most effective in reducing myocardial PGI₂ synthesis and formation of TXA₂. Myocardial effects of celecoxib resemble those of NCX-4016, although the two compounds have different modes of action.

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Section: Discussionmentioning

confidence: 99%

Effect of Cyclooxygenase-2 Inhibitor (Celecoxib) on the Infarcted Heart in situ

Yamamoto¹,

Kakar²,

Vina³

et al. 2001

Pharmacology

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“…10 B-NOD accomplishes this through NO release, which increases prostaglandin formation. 15 B-NOD has potential clinical relevance because the release of NO counters the diminution of prostacyclin by aspirin and thereby inhibits platelet aggregation (Figures 1 and 2, Table). Deterioration of renal function by selective COX-2 inhibitors has been repeatedly demonstrated.…”

Section: Nsaids and B-nodmentioning

confidence: 99%

Nitric Oxide, Anti-Inflammatory Drugs on Renal Prostaglandins and Cyclooxygenase-2

Miyataka

Rich²,

Ingram³

et al. 2002

Hypertension

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Abstract-Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used as analgesics. They inhibit cyclooxygenases (COX), preventing the formation of prostaglandins, including prostacyclin and thromboxane. A serious side effect of COX-1 and COX-2 is renal damage. We report here that both a nonselective NSAID (aspirin, acetylsalicylic acid) and COX-2 selective NSAIDs (celecoxib and NS-398) diminished renal prostacyclin and thromboxane concentration in the renal medulla. NSAIDs failed to change COX-2 and iNOS (the inducible form of NO synthase) expression. A NO donor, B-NOD, preserved renal prostacyclin and thromboxane after administration of aspirin. PGI 2 and COX-2 protein were mainly expressed in the renal medulla, whereas iNOS expression was greater in the cortex. NSAIDs act by inhibition of cyclooxygenases. 2 Two isoforms of COX have been identified: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). They are homodimers, heme-containing glycosylated proteins with 2 catalytic sites. 2 Aspirin, the classical nonselective NSAID, inhibits platelet thromboxane A2 formation through inhibition of COX-1; this forms the basis for the therapeutic and preventive effects in coronary artery disease.Inhibition of COX can cause severe gastric disturbances because of diminished prostacyclin synthesis in the gastric mucosa. 3 To overcome this side effect, selective COX-2 inhibitors, such as rofecoxib (VIOXX), celecoxib (Celebrex), and NS-398 have been developed. 2,4 These selective COX-2 inhibitors protect the gastric mucosa but, like nonselective COX inhibitors, cause renal damage, which is expressed as a reduction in glomerular filtration rate, renal blood flow, and diminished sodium and potassium excretion. 4 The decline in renal function is especially pronounced in the elderly and in patients with preexisting renal disease. 5 The renal effects are related to depletion of prostacyclin. 6 On the other hand, Wang et al 7 found that chronic administration of a selective COX-2 inhibitor decreased proteinuria and inhibited development of glomerular sclerosis in rats with reduced functional renal mass. The decrease in proteinuria was comparable to that seen with an ACE inhibitor. 7 Prostanoids result from the activity of cyclooxygenases on arachidonic acid. 2 Prostaglandins modulate renal microvascular hemodynamics, renin release, and tubular salt and water reabsorpotion. 8 Prostaglandins diminish vascular resistance in the renal vascular bed, increase perfusion, and mediate natriuretic processes; their presence maintains glomerular filtration rate. 9 Diminution of renal prostacyclin results in papillary necrosis or in interstitial nephritis. 9 Urinary sodium excretion is also reduced after application of celecoxib. 9 The role of COX-2 in the mammalian kidney has been thoroughly investigated. It was found that it is constitutionally expressed and that COX-2 mRNA is present at detectable concentrations in normal adult rat kidneys, particularly in microsomes, cortex, and papilla. Immunoreactivity of COX-2 mRNA was also loc...

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“…The beneficial effects of aspirin are ascribed to its inhibition of platelet aggregation and inhibition of thromboxane generation by COX-1. 4 A mounting body of data, however, suggests that inhibition of COX-2 enhances cell death, particularly apoptotic cell death. 5,6 It has recently been suggested that apoptosis may play a role in ischemia/reperfusion injury.…”

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confidence: 99%

Cyclooxygenase-1 and -2 Knockout Mice Demonstrate Increased Cardiac Ischemia/Reperfusion Injury but Are Protected by Acute Preconditioning

et al. 2001

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Background-The purpose of this study was to examine the effects of cyclooxygenase (COX) deficiency on baseline functional characteristics and on recovery of left ventricular developed pressure (LVDP) after 20 minutes of global ischemia and 40 minutes of reperfusion in untreated and preconditioned hearts. Methods and Results-Compared with hearts from wild-type (WT) and COX-2 Ϫ/Ϫ mice, baseline cardiac prostaglandin (PG) E 2 and 6-keto-PGF 1␣ levels were significantly decreased in hearts from COX-1 Ϫ/Ϫ mice. After ischemia, cardiac PGE 2 levels increased in WT, COX-1 Ϫ/Ϫ , and COX-2 Ϫ/Ϫ mice (PϽ0.05). Recovery of function (LVDP) after global ischemia in hearts from COX-1 Ϫ/Ϫ and COX-2 Ϫ/Ϫ mice was significantly less than in WT hearts. Pretreatment of WT mice with indomethacin for 2 days before ischemia significantly decreased LVDP recovery; however, perfusion of WT hearts with indomethacin for 40 minutes before ischemia did not significantly alter LVDP recovery. Postischemic recovery of LVDP in COX-1 Ϫ/Ϫ and COX-2 Ϫ/Ϫ was unchanged by perfusion with 5 mol/L PGE 2 , PGD 2 , PGF 2␣ , or carboprostacyclin. Hearts from COX-2 Ϫ/Ϫ mice showed an increase in ischemic contracture compared with hearts from WT and COX-1 Ϫ/Ϫ mice; however, hearts did not differ in intracellular pH, ATP, or inorganic phosphate during ischemia. Ischemic preconditioning significantly improved postischemic LVDP recovery in COX-1 Ϫ/Ϫ , COX-2 Ϫ/Ϫ , and WT mice. Conclusions-Genetic disruption or 2-day chemical inhibition of COX-1 and COX-2 decreases recovery of LVDP after ischemia; however, acute perfusion with indomethacin is not detrimental. These data are consistent with protection due to the altered expression of some protein that is modulated by COX or its metabolites.

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New look at myocardial infarction: toward a better aspirin

Cited by 16 publications

References 61 publications

Effect of Cyclooxygenase-2 Inhibitor (Celecoxib) on the Infarcted Heart in situ

Effect of Cyclooxygenase-2 Inhibitor (Celecoxib) on the Infarcted Heart in situ

Nitric Oxide, Anti-Inflammatory Drugs on Renal Prostaglandins and Cyclooxygenase-2

Cyclooxygenase-1 and -2 Knockout Mice Demonstrate Increased Cardiac Ischemia/Reperfusion Injury but Are Protected by Acute Preconditioning

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