Divergent effects of rofecoxib on endothelial function and inflammation in acute coronary syndromes

Lekakis, John; Vamvakou, G.; Andreadou, Ioanna; Ganiatsos, George; Karatzis, Emmanouil; Protogerou, Athanase D.; Papaioannou, Theodore G.; Ikonomidis, Ignatios; Papamichael, Christos; Mavrikakis, Myron

doi:10.1016/j.ijcard.2005.10.011

Cited by 10 publications

(7 citation statements)

References 36 publications

(58 reference statements)

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“…A number of studies dealing with the presence of isoforms of COX (COX-1 and COX-2), as detected by molecular biology techniques in biopsies of fresh human blood vessels, demonstrate that most native endothelial cells contain COX-1 but not COX-2 (ref. [28][29][30] One exception may be human renal arteries.…”

Section: Nature Of Edcfmentioning

confidence: 99%

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COX-1 and Vascular Disease

Vanhoutte

2009

Clin Pharmacol Ther

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Since the discovery of the pivotal role of cyclooxygenase (COX) in the metabolism of arachidonic acid, vascular biologists have been confronted with the duality of this system. Indeed, one substrate (arachidonic acid) transformed by one enzyme (COX) yields end products (endoperoxides) that exist only very briefly before being metabolized to more stable prostanoids by a set of specific downstream synthases that were initially believed to be tissue specific. For instance, platelets contain mainly the synthase that produces thromboxane A(2) (a potent proaggregatory and vasoconstrictor substance), whereas endothelial cells contain mainly the enzyme that generates prostacyclin (an equally potent antiaggregatory and vasodilator substance). The overproduction of thromboxane A(2) by platelets leads to thrombosis; endothelial cells resist vascular occlusion by producing prostacyclin. This duality of the metabolism of arachidonic acid has dominated our thinking about atherothrombosis for decades, and rightfully still does. As scientific understanding progressed, it became evident that two isoforms of COX exist: COX-1 and COX-2. COX-1 was initially considered to be the "good," constitutive isoform, whereas COX-2 appeared to be mainly a "bad" inducible enzyme involved in inflammatory responses. However, more recently, the unexpected events resulting from the widespread use of selective COX-2 inhibitors has suggested that, from a cardiovascular point of view, the products of COX-2 exert a protective role and that this isoform cannot necessarily be regarded as "bad." Likewise, evidence has emerged that initiation of the metabolism of arachidonic acid by COX-1 is not necessarily a "good" thing in terms of vascular protection. This brief review focuses on the potential contribution of endothelial COX-1 to vascular dysfunction. It is based on a number of review articles, to which the reader will be referred in order to identify the original references to the statements made; these references are not cited here because of space limitations.

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Section: Nature Of Edcfmentioning

confidence: 99%

“…This conclusion is in line with the findings of most in vivo studies that selective COX-2 inhibitors have no effect on endothelial function in the forearms of healthy subjects 27 or patients with coronary disease. [28][29][30]…”

Section: Aging and Vascular Disease Agingmentioning

confidence: 99%

COX-1 and Vascular Disease

Vanhoutte

2009

Clin Pharmacol Ther

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“…Likewise, 8 weeks of rofecoxib therapy in patients with coronary artery disease had no influence on flow-mediated dilatation or inflammatory markers [ 89 ], but in two other studies short-term [ 90 ] or 6 months of therapy [ 91 ] with rofecoxib led to reductions in CRP and IL-6 levels but no changes in brachial artery flow-mediated dilatation. In another study [ 92 ], no change in acetylcholine-induced forearm blood flow response was seen after treatment with either rofecoxib or naproxen in healthy volunteers.…”

Section: Nonsteroidal Anti-inflammatory Drugs and Endothelial Functiomentioning

confidence: 99%

Nitric oxide and cardiovascular effects: new insights in the role of nitric oxide for the management of osteoarthritis

2008

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Nitric oxide (NO) is an important mediator in both health and disease. In addition to its effects on vascular tone and platelet function, it plays roles in inflammation and pain perception that may be of relevance in osteoarthritis. Many patients with osteoarthritis take nonsteroidal anti-inflammatory drugs (NSAIDs) long term for pain control. Over recent years concern has been raised about the possible cardiovascular side effects of NSAIDs. The reasons for this possible increased cardiovascular risk with NSAIDs are not yet entirely clear, although changes in blood pressure, renal salt handling and platelet function may contribute. Recently, drugs that chemically link a NSAID with a NO donating moiety (cyclo-oxygenase-inhibiting NO-donating drugs [CINODs]) were developed. NO is an important mediator of endothelial function, acting as a vasodilator and an inhibitor of platelet aggregation, and having anti-inflammatory properties. The potential benefits of CINODs include the combination of effective analgesic and anti-inflammatory actions with NO release, which might counterbalance any adverse cardiovascular effects of NSAIDs. Effects of CINODs in animal studies include inhibition of vasopressor responses, blood pressure reduction in hypertensive rats and inhibition of platelet aggregation. CINODs may also reduce ischemic damage to compromised myocardial tissue. In addition, endothelial dysfunction is a recognized feature of inflammatory arthritides, and therefore a drug that might provide slow release of NO to the vasculature while treating pain is an attractive prospect in these conditions. Further studies of the effects of CINODs in humans are required, but these agents represent a potential exciting advance in the management of osteoarthritis. IntroductionRecently issued guidelines for the management of osteoarthritis [1] have emphasized the use of lifestyle advice, weight loss, and exercise as first-line interventions in the management of osteoarthritis, followed by the addition of paracetamol or topical nonsteroidal anti-inflammatory drugs (NSAIDs). However, many patients with osteoarthritis will require the use of systemic NSAIDs for control of their pain.Recently, NSAIDs (both traditional and cyclo-oxygenase [COX]-2 selective) were linked to an increased incidence of cardiovascular events, at least in patients at increased baseline cardiovascular risk [2][3][4][5]. The degree of the risk associated with the various NSAIDs and the mechanisms underlying the link with cardiovascular events are still being investigated in large clinical trials. Findings to date have had a major influence on the use of these drugs in the management of chronic arthritic conditions, with regulatory authorities advising against the use of these drugs in patients with known cardiovascular disease or who are at high cardiovascular risk. However, many patients rely on NSAIDs to achieve adequate pain relief, and the risk/benefit ratio must be carefully considered when deciding whether to prescribe these agents. Options to amel...

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“…We enjoyed reading the recently published article by Lekakis and coworkers [1]. This meticulously designed study broadened our horizon about cardiovascular effects of selective cyclooxygenase-2 (COX-2) inhibitors.…”

mentioning

confidence: 99%