Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 47-year-old renal transplant recipient came to the transplant clinic with a serum creatinine level that was elevated above her baseline value. She had been taking celecoxib for arthritic pain. She was told to discontinue the drug, and shortly after, her serum creatinine level returned to baseline. Several case reports describe nephrotoxicity with cyclooxygenase (COX)-2 inhibitors. However, only two of these reports involved renal transplant recipients, and in both, rofecoxib was the COX-2 inhibitor of concern. To our knowledge, this is the first case report of a renal transplant recipient who developed nephrotoxicity while taking celecoxib. The potential renal effects of COX-2 inhibitors have received little attention, even though nonsteroidal anti-inflammatory drugs are considered to carry the risk of nephrotoxicity in patients with comorbidities such as diabetes mellitus and hypertension. Further studies are necessary to determine the safety of COX-2 inhibitors in transplant recipients and other patient groups that may be at heightened risk of nephrotoxicity.
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PMID:Celecoxib-induced nephrotoxicity in a renal transplant recipient. 1589 41

Suppression of prostacyclin (PGI2) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase (COX)-2 inhibitors. Herein, we examine if COX-2-derived PGI2 might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity. Deletion of the PGI2 receptor (IP) or suppression of PGI2 with the selective COX-2 inhibitor, nimesulide, both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow-induced vascular remodeling. Moreover, nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild-type mice. Generation of both thromboxane (Tx)A2 and the isoprostane, 8, 12 -iso iPF(2alpha)-VI, are increased in the setting of flow reduction and the latter increases further on administration of nimesulide. Deletion of the TxA2 receptor (TP) reduces the hyperplastic response to nimesulide and carotid ligation, despite further augmentation of TP ligand production. Suppression of COX-2-derived PGI2 or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress. Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of COX-2.
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PMID:COX-2-derived prostacyclin modulates vascular remodeling. 1590 61

The aim of the present study was to analyze the possible involvement of vasoconstrictors prostanoids on the reduced endothelium-dependent relaxations produced by chronic administration of aldosterone in Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). For this purpose, acetylcholine (ACh) relaxations in aortic segments from both strains were analyzed in absence and presence of the cyclooxygenase-1 (COX-1) and COX-2 inhibitor indomethacin, the specific COX-2 inhibitor NS-398, the TP receptor antagonist (SQ 29 548), the thromboxane A2 (TXA2) synthase inhibitor furegrelate, and the prostacyclin (PGI2) synthesis inhibitor tranylcypromine (TCP). In addition, COX-2 protein expression was studied by Western blot analysis. Release of prostaglandin E2 (PGE2) and the metabolites of PGF2alpha, TXA2, and PGI2, 13,14-dihydro-15-keto PGF2a, TXB2, and 6-keto-PGF1alpha, respectively, were measured. Treatment with aldosterone did not modify blood pressure levels in any strain. However, aldosterone markedly reduced (P<0.05) ACh-induced relaxations in segments from both strains in a similar extent. Indomethacin, NS-398, SQ 29 548, and TCP enhanced (P<0.05) ACh relaxations in both strains treated with aldosterone. Aortic COX-2 protein expression was higher in both strains of rats treated with aldosterone. In normotensive animals, aldosterone increases the ACh-stimulated aortic production of 13,14-dihydro-15-keto PGF2a, PGE2, and 6-keto-PGF1alpha (P<0.05). In SHR, ACh only increased the 6-keto-PGF1alpha production (P<0.05). It could be concluded that chronic treatment with aldosterone was able to produce endothelial dysfunction through COX-2 activation in normotensive and hypertensive conditions. PGI2 seems to be the main factor accounting for endothelial dysfunction in hypertensive rats, whereas other prostanoids besides PGI2 appear to be involved in endothelial dysfunction under normotensive conditions.
Hypertension 2005 Jul
PMID:Participation of prostacyclin in endothelial dysfunction induced by aldosterone in normotensive and hypertensive rats. 1595 9

The nonsteroidal anti-inflammatory drugs (NSAIDs) cover a wide range of selectivity, from the nonselective cyclooxygenase (COX) inhibitors to the preferential COX-2, and the newest coxibs, selective COX-2, with 1000-fold selectivities for COX-2. Coxibs belong to the distinct classes of sulphonamides, methylsulphones, and phenylacetic acid derivatives. The affinity of an inhibitor for COX-1 and COX-2 determinates its relative selectivity. Minor changes in the amino acid structure between the 2 enzymes results in different forms of their active sites. However, the primitive hypothesis of a dualism between an isoform totally inducible (COX-2) and the other isoform constitutive (COX-1) was not completely true. Thus, also selective COX-2 inhibitors have been shown to interact with gastrointestinal, renal, and cardiovascular systems. New insights into pharmacological data and side effect profile of coxibs have been reported in this review. They may reduce gastrointestinal-related risks, but when administered with low-dose aspirin, they could create an ulcerogenic dual-COX inhibitor. Moreover, by inhibiting COX-2, they could delay ulcer healing. Similarly to traditional NSAIDs, coxibs compromise the glomerular filtration rate in patients at increased risk, and may cause peripheral oedema and hypertension. According to the traditional ''COX-2 hypothesis'', they should not impair efficacy of coagulation. However, in combination with an oral anticoagulant they increase the International Normalized Ratio (INR) and, in some cases, cause bleeding. The altered balance between prostacyclin and thromboxane, due to selective inhibition of COX-2 without reducing COX-1, could promote a prothrombotic state and explain the observed increased cardiovascular risk. Finally, the role of COX-2 expression in the ischemic preconditioning mechanism and the recent discovery of a pro-oxidant activity of sulphones has been analysed.
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PMID:COX-2 inhibitors: pharmacological data and adverse effects. 1601 20

The aim of the study was to investigate the effects of the cylooxygenase (COX)-2 specific inhibitor rofecoxib, on blood pressure (BP) and heart rate (HR) in patients with well-controlled hypertension and osteoarthritis via 24-h ambulatory monitoring. Thirty patients with well controlled hypertension were included. Fifteen patients had osteoarthritis and were recommended by their rheumatologists to take rofecoxib 12.5 mg/day (rofecoxib group). The control group consisted of 15 patients who had hypertension but no clinical osteoarthritis and did not receive any anti-inflammatory drugs. Twenty-four-hour ambulatory monitoring of BP and HR were performed on the day before initiation of rofecoxib therapy and on days 3 and 14 of COX-2 therapy. The control group underwent 24-h monitoring three times at similar intervals. Antihypertensive medications were continued. On day 3 of rofecoxib therapy, mean HR for both daytime and nighttime were lower than those at baseline. On day 14, the changes in mean HR did not differ from baseline values. Similarly, diastolic BP (daytime and nighttime) on day 3 appeared to be lower than at baseline. However this difference was not observed on day 14, and mean daytime and nighttime diastolic BP returned to baseline values. There was no statistically significant difference in the mean arterial pressure or systolic BP recordings on days 3 or 14 than at baseline. Rofecoxib 12.5 mg/day did not significantly increase BP during 24-h ambulatory BP monitoring in patients with well-controlled hypertension and osteoarthritis.
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PMID:The effects of rofecoxib on 24-h ambulatory blood pressure and heart rate monitoring in patients with hypertension and osteoarthritis. 1603 51

Cyclooxygenase-2 selective inhibitors (COXIBs) were developed with the prime object of minimizing gastrointestinal adverse effects, which are seen with the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Their long-term use is limited by the development of hypertension, edema, and congestive heart failure in a significant proportion of patients. NSAIDs block the activity of both COX isozymes, COX-1 and COX-2, which mediate the enzymatic conversion of arachidonate to prostaglandin H2 (PGH2) and other prostaglandin (PG) metabolites. It is well established that the cardiovascular profile of COX-2 inhibitors can be accounted for by inhibition of COX-dependent PG synthesis. Following the COX-mediated synthesis of PGH2 from arachidonate, PGH2 is metabolized to one of at least five bioactive PGs, including PGE2, PGI2, PGF2, PGD2, or thromboxane A2 (TXA2). These prostanoids have pleiotropic cardiovascular effects, altering platelet function and renal function, and they are acting either as vasodilators or vasoconstrictors. Although COX-1 and COX-2 exhibit similar biochemical activity in converting arachidonate to PGH2 in vitro, the ultimate prostanoids they produce in vivo may be different due to differential regulation of COX-1 and COX-2, tissue distribution, and availability of the prostanoid synthases. PGs have been established as being critically involved in mitigating hypertension, helping to maintain medullary blood flow (MBF), promoting urinary salt excretion, and preserving the normal homeostasis of thrombosis, and the researchers found that the use of COX-2 inhibitors caused many serious complications in altering the normal body homeostasis. The purpose of the present research is to explain briefly the side effects of COX-2 inhibitors on the renal and cardiovascular system.
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PMID:Adverse effects of COX-2 inhibitors. 1611 40

Specific inhibitors of COX-2 have been associated with increased risk for cardiovascular complications. These agents reduce prostacyclin (PGI2) without affecting production of thromboxane (Tx) A2. While this abnormal pattern of eicosanoid generation has been implicated in the development of vascular disease associated with COX-2 inhibition, its role in the development of hypertension, the most common cardiovascular complication associated with COX-2 inhibition, is not known. We report here that mice lacking the receptor for PGI2 (IPKOs) develop salt-sensitive hypertension, cardiac hypertrophy, and severe cardiac fibrosis. Coincidental deletion of the TxA2 (TP) receptor does not prevent the development of hypertension, but cardiac hypertrophy is ameliorated and fibrosis is prevented in IPTP double knockouts (DKOs). Thus, deletion of the IP receptor removes a constraint revealing adverse cardiovascular consequences of TxA2. Our data suggest that adjuvant therapy that blocks unrestrained Tx actions might protect against end-organ damage without affecting blood pressure in patients taking COX-2 inhibitors.
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PMID:Prostacyclin protects against elevated blood pressure and cardiac fibrosis. 1633 Mar 15

Atherosclerotic plaque rupture is promoted by metalloproteinase (MMP)-2 and MMP-9, enzymes that degrade the fibrous cap leading to plaque erosion. MMP biosynthesis is mediated by prostaglandin (PG)E2, the product of cyclooxygenase (COX)-2/inducible PGE synthase (mPGES) activity. We have recently reported the overexpression of COX-2/mPGES-1 in vulnerable plaques as a basis of MMP-mediated plaque instability. Hypercholesterolemia and hypertension are two important risk factors for atherosclerosis. Recent trial showed that statins and AT1 receptor blockers significantly reduce the incidence of cardiovascular events in humans. Since anti-inflammatory effects have been reported in association to therapy with statins or AT1 receptor blockers, in two different studies we hypothesized that these drugs can stabilize atherosclerotic plaques through modulation of COX-2/mPGES-1-dependent MMP biosynthesis. Our data demonstrated the stabilizing effect of atherosclerotic plaques by simvastatin or irbesartan, that is due, at least in part, to the reduction of inflammatory burden and suppression of PGE2-dependent metalloproteinases release.
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PMID:Pharmacological modulation of plaque instability. 1621 85

We have demonstrated recently [Callera, Touyz, Teixeira, Muscara, Carvalho, Fortes, Schiffrin and Tostes (2003) Hypertension 42, 811-817] that increased vascular oxidative stress in DOCA (deoxycorticosterone acetate)-salt rats is associated with activation of the ET (endothelin) system via ETA receptors. The exact source of ET-1-mediated oxidative stress remains unclear. The aim of the present study was to investigate whether ET-1 increases generation of ROS (reactive oxygen species) in DOCA-salt hypertension through NADPH-oxidase-dependent mechanisms. Xanthine oxidase, eNOS (endothelial nitric oxide synthase) and COX-2 (cyclo-oxygenase-2) were also examined as potential ET-1 sources of ROS as well as mitochondrial respiration. DOCA-salt and control UniNX (uninephrectomized) rats were treated with the ETA antagonist BMS182874 (40 mg.day(-1).kg(-1) of body weight) or vehicle. Plasma TBARS (thiobarbituric acid-reacting substances) were increased in DOCA-salt compared with UniNX rats. Activity of NADPH and xanthine oxidases in aorta, mesenteric arteries and heart was increased in DOCA-salt rats. BMS182874 decreased plasma TBARS levels without influencing NADPH and xanthine oxidase activities in DOCA-salt rats. Increased p22(phox) protein expression and increased p47(phox) membrane translocation in arteries from DOCA-salt by rats were not affected by BMS182874 treatment. Increased eNOS and COX-2 expression, also observed in aortas from DOCA-salt rats, was unaltered by BMS182874. Increased mitochondrial generation of ROS in DOCA-salt rats was normalized by BMS182874. ETA antagonism also increased the expression of mitochondrial MnSOD (manganese superoxide dismutase) in DOCA-salt rats. In conclusion, activation of NADPH oxidase does not seem to be the major source of oxidative stress induced by ET-1/ETA in DOCA-salt hypertension, which also appears to be independent of increased activation of xanthine oxidase or eNOS/COX-2 overexpression. Mitochondria may play a role in ET-1-driven oxidative stress, as evidenced by increased mitochondrial-derived ROS in this model of hypertension.
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PMID:Endothelin-1-induced oxidative stress in DOCA-salt hypertension involves NADPH-oxidase-independent mechanisms. 1632 76

Selective inhibitors of cyclooxygenase (COX)-2, the coxibs, were developed to inhibit inflammatory prostaglandins derived from COX-2, while sparing gastroprotective prostaglandins primarily formed by COX-1. However, COX-2-derived prostaglandins mediate not only pain and inflammation but also affect vascular function, the regulation of hemostasis/ thrombosis, and blood pressure control. All coxibs depress COX-2-dependent prostacyclin (PGI(2)) biosynthesis without effective suppression of platelet COX-1-derived thromboxane (Tx) A(2), unlike aspirin or traditional nonsteroidal anti-inflammatory drugs, which inhibit both COX-1 and COX-2. The actions of PGI(2) oppose mediators, which stimulate platelets, elevate blood pressure, and accelerate atherogenesis, including TxA(2). Indeed, structurally distinct inhibitors of COX-2 have increased the likelihood of hypertension, myocardial infarction and stroke in controlled clinical trials. The detection of these events in patients is related to the duration of exposure and to their baseline risk of cardiovascular disease. Thus, coxibs should be withheld from patients with preexisting cardiovascular risk factors, and exposed patients at low cardiovascular baseline risk should be monitored for changes in their risk factor profile, such as increases in arterial blood pressure.
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PMID:The cardiovascular pharmacology of COX-2 inhibition. 1630 18


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