6-ketoprostaglandin-f1-alpha and rofecoxib

To assess the influence of low dose rofecoxib on inflammatory mediators and prostacyclin synthesis in patients with acute coronary syndromes (ACS) in a short-term follow up.. Twenty nine patients with ACS without ST elevation were randomized to simvastatin alone or together with low dose rofecoxib. Serum levels of interleukin 6 (IL-6), 6-keto-PGF-1alpha--stable product of prostacyclin (PGT2) and hs-C-reactive protein (hs-CRP) were assessed on enrollment and after 30-day follow up.. Combination of rofecoxib with statin significantly decreased levels of hs-CRP after one month therapy (5.21 mg/l +/- 4.12 vs 2.11 mg/l +/- 2.1; p=0.0092). This effect was not evident in a group on statin alone (3.95 mg/l +/- 3.33 vs 2.48 mg/l +/- 2.39; p=0.31). 6-keto-PGF-1alpha increased not significantly in both groups. IL-6 concentration has not changed during follow up.. Low dose of selective COX-2 inhibitor exerts significant anti-inflammatory effect and does not diminish PG12 synthesis in study group of patients with ACS.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticholesteremic Agents; C-Reactive Protein; Coronary Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoprostenol; Female; Follow-Up Studies; Humans; Inflammation Mediators; Interleukin-6; Lactones; Male; Middle Aged; Simvastatin; Sulfones; Syndrome

Balance between vasoactive prostanoids that contribute to homeostasis of the circulatory system can be affected by cyclooxygenases inhibitors. Results of a recent large clinical trial show that myocardial infarction was more frequent among patients with rheumatoid arthritis treated with the selective cyclooxygenase-2 inhibitor rofecoxib compared with those treated with naproxen. Whether this difference was attributable to deleterious cardiovascular effects of rofecoxib or cardioprotective effects of naproxen has not been determined. We tested the hypothesis that naproxen, contrary to rofecoxib, exerts antithrombotic effects.. Forty-five healthy men were randomized to receive a 7-day treatment with rofecoxib (50 mg/d), naproxen (1000 mg/d), aspirin (75 mg/d), or diclofenac (150 mg/d). Formation of thromboxane, prostacyclin, and thrombin in the bleeding-time blood at the site of standardized microvascular injury was assessed before and after treatment. Naproxen, like aspirin, caused significant reduction of both thromboxane and prostacyclin, whereas diclofenac depressed prostacyclin synthesis but had no effect on tromboxane formation. Naproxen and aspirin significantly suppressed thrombin generation. Diclofenac showed a similar tendency, which did not reach statistical significance. Rofecoxib had no effect on any variables measured.. In healthy men, naproxen exerts an antithrombotic effect at least as potent as aspirin, whereas rofecoxib does not affect hemostatic balance.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Bleeding Time; Blood Platelets; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Double-Blind Method; Endothelium, Vascular; Fibrinolytic Agents; Humans; Isoenzymes; Lactones; Male; Membrane Proteins; Naproxen; Prostaglandin-Endoperoxide Synthases; Sulfones; Thrombin; Thromboxane B2

Conventional nonsteroidal anti-inflammatory drugs inhibit both cyclooxygenase (Cox) isoforms (Cox-1 and Cox-2) and may be associated with nephrotoxicity. The present study was undertaken to assess the renal effects of the specific Cox-2 inhibitor, MK-966. Healthy older adults (n = 36) were admitted to a clinical research unit, placed on a fixed sodium intake, and randomized under double-blind conditions to receive the specific Cox-2 inhibitor, MK-966 (50 mg every day), a nonspecific Cox-1/Cox-2 inhibitor, indomethacin (50 mg t.i.d.), or placebo for 2 weeks. All treatments were well tolerated. Both active regimens were associated with a transient but significant decline in urinary sodium excretion during the first 72 h of treatment. Blood pressure and body weight did not change significantly in any group. The glomerular filtration rate (GFR) was decreased by indomethacin but was not changed significantly by MK-966 treatment. Thromboxane biosynthesis by platelets was inhibited by indomethacin only. The urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto prostaglandin F1alpha was decreased by both MK-966 and indomethacin and was unchanged by placebo. Cox-2 may play a role in the systemic biosynthesis of prostacyclin in healthy humans. Selective inhibition of Cox-2 by MK-966 caused a clinically insignificant and transient retention of sodium, but no depression of GFR. Inhibition of both Cox isoforms by indomethacin caused transient sodium retention and a decline in GFR. Our data suggest that acute sodium retention by nonsteroidal anti-inflammatory drugs in healthy elderly subjects is mediated by the inhibition of Cox-2, whereas depression of GFR is due to inhibition of Cox-1.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Blood Platelets; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Double-Blind Method; Eicosanoids; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Indomethacin; Isoenzymes; Lactones; Male; Membrane Proteins; Middle Aged; Prostaglandin-Endoperoxide Synthases; Sodium; Sulfones; Thromboxane B2; Water-Electrolyte Balance

We investigated the roles of cyclooxygenase (COX) isozymes and prostaglandin E (PGE) receptor EP1 and EP3 subtypes or prostacyclin IP receptors in the decrease in acid secretion in the damaged mouse stomach. Male C57/BL6 mice, both wild type and animals lacking EP1, EP3, or IP receptors, were used after 18 h of fasting. Under urethane anesthesia, the stomach was mounted on an ex-vivo chamber and perfused with saline, and acid secretion as well as transmucosal potential difference (PD) was measured before and after exposure to 20 mM taurocholate Na (TC) for 20 min. Indomethacin, SC-560 or rofecoxib was given i.d. 30 min before TC. Mucosal exposure to TC in wild-type mice caused a reduction in PD, followed by decrease in acid secretion. Indomethacin attenuated the decrease in acid secretion after exposure to TC in wild-type mice, an effect mimicked by SC-560 but not rofecoxib, yet none of these drugs affected the decrease in PD. An altered acid response after exposure to TC was similarly observed in EP1 (-/-) mice but mitigated in mice lacking either EP3 or IP receptors, although a decrease in PD was observed in all groups. Furthermore, the decreased acid response was also attenuated by prior administration of the EP3- but not EP1- antagonist. Mucosal levels of PGE(2) and 6-keto PGF(1a) increased after exposure to TC in all groups of mice. In conclusion, the decrease in acid secretion in the damaged stomach is mediated by endogenous PGs derived from COX-1, through PGE(2)/EP3 receptors and prostacyclin/IP receptors.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bridged Bicyclo Compounds; Caproates; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Gastric Acid; Gastric Acidity Determination; Gastric Mucosa; Hydrogen-Ion Concentration; Indomethacin; Lactones; Male; Membrane Potentials; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Pyrazoles; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype; Stomach Diseases; Sulfones; Taurocholic Acid

It is known that inhibition of cyclooxygenase (COX) impairs the renal actions of loop diuretics. Recently, we found that cyclosporine A (CsA) inhibits renal COX-2 expression. Therefore, we examined the interferences of CsA with the renal actions of loop diuretics.. We investigated the renal effects of furosemide administration (12 mg/day subcutaneously) in male Sprague-Dawley rats receiving in addition vehicle, CsA (15 mg/kg x day), rofecoxib (10 mg/kg x day), or a combination of both.. CsA, rofecoxib, and their combination lowered the furosemide-induced increase of prostaglandin E(2) (PGE(2)) and of 6-keto prostaglandin F(1 alpha) (6-keto PGF(1 alpha)) excretion by 55% and by 70%. They also lowered furosemide stimulated renal excretion of sodium and water by about 65% and 60%. Basal as well as furosemide-induced stimulation of plasma renin activity (PRA) and of renal renin mRNA was further enhanced by CsA. In contrast, rofecoxib attenuated the furosemide-induced rise of PRA and of renin mRNA, both in the absence and in the presence of CsA. In addition, the increase in plasma 6-keto PGF(1 alpha) levels by furosemide was further enhanced by CsA and was attenuated by rofecoxib.. Taken together, our data suggest that CsA acts as an antinatriuretic, likely by the inhibition of COX-2-mediated renal prostanoid formation. Since the furosemide-induced stimulation of the renin system is not attenuated by CsA but by COX-2 inhibition, we speculate that extrarenal COX-2-derived prostanoids may be involved in the stimulation of the renin system by CsA and by loop diuretics.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calcineurin Inhibitors; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Cyclosporine; Dinoprostone; Diuresis; Diuretics; Drug Interactions; Furosemide; Isoenzymes; Kidney; Lactones; Loop of Henle; Male; Membrane Proteins; Natriuresis; Potassium; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Sulfones

1 It is known that nonselective cyclo-oxygenase (COX) inhibitors have small but significant effects on blood pressure (BP), most notably in hypertensive patients on antihypertensive medication. Whether selective COX-2 inhibitors also interfere with BP regulation is not well understood. Therefore, we aimed to examine the effect of chronic treatment with a selective COX-2 inhibitor (rofecoxib) on systolic blood pressure (sBP) in normotensive Wistar-Kyoto rats (WKY) and on the developmental changes of sBP in young spontaneously hypertensive rats (SHR). In addition, we investigated a possible influence of salt intake on the effects of COX-2 inhibition on BP in these two rat strains. 2 Rofecoxib dose dependently increased sBP and decreased plasma levels of 6-keto prostaglandin (PG)F(1alpha) in WKY rats fed a normal salt diet (0.6% NaCl, wt wt(-1)), without affecting serum thromboxane (TX)B(2) levels. 3 Rofecoxib significantly elevated sBP in both rat strains fed normal salt or high salt diet (8% NaCl, wt wt(-1)), but not in rats on low salt intake (0.02% NaCl, wt wt(-1)). 4 Rofecoxib significantly decreased plasma levels of 6-keto PGF(1alpha) in both rat strains fed normal or high salt diet, but not in rats during low salt intake. 5 Rofecoxib exerted no influence on the changes of body weight nor on water intake. Plasma renin activity (PRA) and renocortical renin mRNA abundance were not changed by rofecoxib, but plasma aldosterone concentration (PAC) was significantly reduced. 6 These results suggest that chronic inhibition of COX-2 causes an increase of blood pressure that depends on prostacyclin synthesis. Furthermore, this increase is independent on genetic predisposition and can be prevented by salt deprivation. Since water intake and body weight gain were not changed by rofecoxib, fluid retention appears not to be a major reason for the development of hypertension. Similarly, an activation of the renin-angiotensin-aldosterone axis appears to be an unlikely candidate mechanism.

Topics: 6-Ketoprostaglandin F1 alpha; Actins; Aldosterone; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Body Weight; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drinking; Heart Rate; Hematocrit; Kidney Cortex; Lactones; Male; Potassium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; RNA, Messenger; Sodium, Dietary; Sulfones

This study aimed to assess the impact of cyclooxygenase-2 (COX-2) on the secretion and expression of renin in the kidney cortex. For this purpose renocortical COX-2 expression was moderately stimulated by a low-salt diet or strongly stimulated (increase in mRNA about fivefold) by the combination of a low-salt diet and the angiotensin-I-converting enzyme inhibitor ramipril in male Sprague-Dawley rats. None of these manoeuvres changed medullary COX-2 expression or cortical or medullary COX-1 expression. Treatment with low salt plus ramipril but not with low salt alone led to a three- to fourfold increase of the urinary output of all major prostanoids. The selective COX-2 inhibitor rofecoxib (10 mg/kg per day) markedly lowered basal urinary prostanoid excretion and blunted the stimulation of prostanoid excretion during treatment with low salt plus ramipril. The stimulation of renin secretion by the low-salt diet but not by low salt plus ramipril was attenuated by rofecoxib. The low-salt diet led to a moderate increase of renin gene expression, and additional treatment with ramipril caused a 15-fold increase of renin mRNA. However, no effect of rofecoxib on renin gene expression was observed in any group. These findings suggest that stimulation of COX-2 in the renal cortex leads to the increased formation of all major prostanoids. COX-2-derived prostanoids may play a role in the regulation of renin secretion but not in renin gene expression during the intake of a low-salt diet. However, no major relevance of COX-2-derived prostanoids to renin secretion or renin gene expression during ramipril treatment or a combination of ramipril and a low-salt diet was found.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diet, Sodium-Restricted; Dinoprostone; Gene Expression; Isoenzymes; Kidney Cortex; Kidney Medulla; Lactones; Male; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Ramipril; Rats; Rats, Sprague-Dawley; Renin; Sulfones