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PubMed1990

Resistance of the renal biosynthesis of prostaglandin E2 to the inhibitory effect of indomethacin in the rat in vivo.

Our recent observation that the chronic administration of indomethacin (3.0 mg.kg-1.day) to hypertensive rats, while profoundly inhibiting the urinary excretion of 6-oxo-PGF1 alpha, dinor-6-oxo-PGF1 alpha and thromboxane B2, failed to reduce the urinary levels of PGE2, prompted us to study in more details the influence of indomethacin and of meclofenamate on the urinary excretion of prostaglandins in normal rats. A dose of 1.5 mg.kg-1 of indomethacin administered intraperitoneally was sufficient to cause a 70-75% reduction in the urinary excretion of dinor-6-oxo-PGF1 alpha and of 6-oxo-PGF1 alpha for a period of at least 12 hours. Doses of indomethacin lower than 2.5 mg.kg-1.12h beta 1 or a dose of meclofenamate equal to 5 mg.kg-1.12h beta 1 did not influence the urinary excretion of PGE2. Doses of indomethacin equal to or higher than 2.5 mg.kg-1 were needed to obtain a 50% reduction in the urinary levels of PGE2 for a period of 10-14 h. During these experiments, no circadian rhythm for the urinary excretion of 6-oxo-PGF1 alpha and of dinor-6-oxo-PGF1 alpha could be observed whereas the urine volume and the urinary excretion of PGE2 were found to be greater at night than during the day.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗

PubMed1994

PGE2 inhibits acetylcholine release from cholinergic nerves in canine but not equine airways.

The effects of exogenous prostaglandin E2 (PGE2) and endogenous prostanoids on cholinergic neurotransmission were determined by measurement of acetylcholine (ACh) release from canine and equine airway tissues. Trachealis strips and bronchial segments were suspended in 2 ml tissue baths. ACh release was induced by electrical field stimulation (EFS), and its content in tissue bath liquid was measured by high pressure liquid chromatography (HPLC) with electrochemical detection. In canine airways, exogenous PGE2 (10(-9) to 10(-7) M) inhibited ACh release concentration-dependently, whereas inhibition of endogenous prostanoid production by indomethacin (3 x 10(-6) M) augmented ACh release. By contrast, in equine airways, exogenous PGE2 had no effect on ACh release in bronchi but at 10(-7) M augmented ACh release in the trachea. Cyclooxygenase inhibition by either indomethacin or meclofenamate (10(-6) M) did not influence ACh release. We conclude that exogenous PGE2 and endogenous prostanoids inhibit ACh release from cholinergic nerves in canine but not equine airways.

Acetylcholine↗

PubMed2004

Myogenic reactivity is enhanced in rat radial uterine arteries in a model of maternal undernutrition.

OBJECTIVES: The purpose of this study was to determine if maternal undernutrition during pregnancy altered myogenic tone in small radial uterine arteries. STUDY DESIGN: Myogenic tone of radial uterine arteries was studied from late pregnant rats (day 20) that were fed either ad libitum or globally restricted diet (moderately severe dietary restriction) throughout pregnancy. RESULTS: Myogenic tone was enhanced in the radial uterine arteries from the diet-restricted compared with the ad libitum group. Nitric oxide synthase inhibition enhanced myogenic tone in the arteries from the ad libitum group only. Prostaglandin H synthase inhibition had no effect on myogenic tone in either group. CONCLUSION: Diet restriction during pregnancy enhances myogenic tone in the radial uterine arteries partly as a result of impairment of the nitric oxide synthase pathway. Enhanced myogenic tone in turn may reduce uteroplacental blood flow and, thus, contribute to reduced birth weight, and lead to effects of fetal programming in utero that can have long-term consequences into adulthood.

Animals↗

PubMed2003

Endothelial-dependent vasodilation is reduced in mesenteric arteries from superoxide dismutase knockout mice.

OBJECTIVE: Oxidative stress has increasingly been implicated in the development and progression of many vascular diseases. Previous work from our laboratory indicated that peroxynitrite alters vasoactive pathways in endothelial cells, which could potentially reduce vascular relaxation. To test this hypothesis in vivo, we utilized an animal model of endogenous oxidative stress, the CuZn superoxide dismutase (SOD) knockout mouse, to assess vascular function. METHODS: Vascular reactivity of mouse mesenteric arteries was assessed in the presence or absence of inhibitors to nitric oxide synthase (NOS) and/or prostaglandin H synthase (PGHS). Endothelial-dependent function was also measured after the addition of exogenous SOD. Peroxynitrite formation was detected by nitrotyrosine immunofluorescence in mesenteric arteries. RESULTS: Our data indicate that endothelial-dependent relaxation responses to methacholine are highly reduced in SOD-/- mice (P<0.01, ANOVA). In only the wild-type mice, NOS or PGHS inhibition significantly blunted relaxation, suggesting that vasodilators from these pathways are present only in the controls and not in SOD-/- mice. A combination of NOS and PGHS inhibitors reduced methacholine relaxation in both wild type and SOD-/- mice. This residual EDHF-like relaxation was not different between groups. After incubation with exogenous SOD, endothelial-dependent relaxation could be partially restored in SOD-/- mice, due to increased NOS-mediated vasodilation. In addition, peroxynitrite formation was significantly elevated in mesenteric arteries from SOD-/- mice. CONCLUSION: Our data suggest that in a novel animal model of oxidative stress, vessel function is compromised due to alterations in NOS and PGHS-dependent relaxation responses.

Animals↗

PubMed2004

Effects of chronic PGHS-2 inhibition on PGHS-dependent vasoconstriction in the aged female rat.

OBJECTIVE: In menopause, aging and decreased estrogen levels are risk factors contributing to impaired vascular function. Previously, in a young ovariectomized rat model, we demonstrated an increase in prostaglandin H synthase (PGHS)-dependent vasoconstriction that could be prevented by estrogen replacement. Subsequently, we found that, with aging, estrogen acts through suppression of the PGHS-2 isoform. HYPOTHESIS: Chronic PGHS-2 inhibition reduces PGHS-dependent vasoconstriction in aging. METHODS: Ovariectomized, aged (12 months) Sprague-Dawley rats were treated with a placebo (n=7), or the PGHS-2 inhibitor (NS-398, s.c. 3 mg/kg) for 1 week (n=6) or 4 weeks (n=6). Methacholine (endothelium-dependent dilator) and phenylephrine (adrenergic constrictor) were used to assess vascular function in the absence or presence of the nonselective PGHS inhibitor, meclofenamate (1 micromol/l) or the specific PGHS-2 inhibitor NS-398 (10 micromol/l). RESULTS: One week of chronic PGHS-2 inhibition abolished a PGHS-dependent shift in methacholine-induced relaxation, while modulation was still observed in phenylephrine constriction. Surprisingly, 4 weeks of PGHS-2 inhibition enhanced PGHS-dependent modulation of vasoconstriction (P<0.05). PGH2/thromboxane inhibition (U-51605, 50 micromol/l) mimicked the results observed with PGHS inhibition among the groups. PGHS-2 expression increased with chronic PGHS-2 inhibition compared to control (P<0.05). CONCLUSIONS: Our data indicate a paradoxical increase in PGHS-dependent vasoconstriction and PGHS-2 expression with prolonged inhibition of PGHS-2 activity. Hence, inhibitors of PGHS-2 activity may not be beneficial in counteracting the vascular dysfunction seen with aging and menopause.

Animals↗

PubMed2003

In vivo coronary effects of endothelin-1 after ischemia-reperfusion. Role of nitric oxide and prostanoids.

To examine the effects of reperfusion after short and prolonged ischemia on the coronary action of endothelin-1, left circumflex coronary artery flow was electromagnetically measured, and 15- or 60-min occlusion of this artery followed by reperfusion was induced in anesthetized goats. In non-treated animals, during reperfusion after 15-min occlusion, the duration but not the peak of endothelin-1-induced coronary effects (0.01-0.3 nmol) was increased, and the effects of acetylcholine (3-100 ng) were unchanged. During reperfusion after 60-min occlusion, the peak and duration of endothelin-1-induced effects were increased whereas those of acetylcholine were decreased. N(w)-nitro-L-arginine methyl esther (L-NAME) treatment did not modify the peak and duration of the coronary effects of endothelin-1 during reperfusion after both durations of occlusion. This treatment inhibited the effects of the two higher doses but not those of the two lower doses of acetylcholine during reperfusion after 15-min occlusion, and it did not modify the effects of any dose of this drug during reperfusion after 60-min occlusion. Meclofenamate treatment did not modify the coronary effects of endothelin-1 and acetylcholine during reperfusion after both durations of occlusion. These results suggest that ischemia-reperfusion increases the coronary response to endothelin-1, which is more pronounced during reperfusion after prolonged than after brief ischemia, and that this increased response is probably related to inhibition of nitric oxide release, without involvement of prostanoids.

Acetylcholine↗

PubMed2005

Enhanced response of pig coronary arteries to endothelin-1 after ischemia-reperfusion. Role of endothelin receptors, nitric oxide and prostanoids.

To analyse the coronary effects of endothelin-1 after ischemia-reperfusion, the left anterior descending coronary artery of anesthetized pigs was subjected to 30-min occlusion followed by 60-min reperfusion. Then, rings distal (ischemic arteries) and proximal (control arteries) to the occlusion were taken from this artery and prepared for isometric tension recording. The sensitivity of the contraction in response to endothelin-1 (3 x 10(-10)-3 x 10(-7) M) and the endothelin ET(B) receptor agonist IRL-1620 (3 x 10(-10)-3 x 10(-7) M) was greater in ischemic vessels. The endothelin ET(A) receptor antagonist BQ-123 (10(-7)-3 x 10(-6) M) decreased the sensitivity of the response to endothelin-1 similarly in ischemic and control arteries. The endothelin ET(B) receptor antagonist BQ-788 (10(-6) M), endothelium removal or the inhibitor of nitric oxide synthesis N(omega)-nitro-L-arginine methyl ester (L-NAME 10(-4) M) potentiated the response to endothelin-1 and IRL-1620 in control arteries only. The cyclooxygenase inhibitor meclofenamate (10(-5) M) augmented the maximal response to endothelin-1 in control arteries, and reduced it in ischemic arteries. In precontracted arteries, IRL-1620 (3 x 10(-11)-3 x 10(-10) M) relaxed control but not ischemic arteries, and L-NAME or meclofenamate abolished this relaxation. Therefore, ischemia-reperfusion increases the coronary vasoconstriction in response to endothelin-1 probably due to impairment of endothelin ET(B) receptor-induced release of nitric oxide and prostacyclin, augmentation of the contractile response to activation of endothelin ET(B) receptors, and increased release of vasoconstrictor prostanoids.

Animals↗

PubMed2006

Vasoconstrictor prostanoids may be involved in reduced coronary reactive hyperemia after ischemia-reperfusion in anesthetized goats.

To examine coronary vasodilator reserve after ischemia-reperfusion, reactive hyperemia was determined during reperfusion after partial and total, brief and prolonged ischemia. To this, left circumflex coronary artery flow was electromagnetically measured, and partial (60 min) or total (15 and 60 min) occlusions of this artery were induced, followed in each case by 60-min reperfusion in anesthetized goats untreated and treated with N(W)-nitro-l-arginine methyl ester (l-NAME) or meclofenamate. In untreated and treated animals, coronary flow was decreased during reperfusion after the three types of ischemia. In hyperemic responses to 5- and 10-s coronary occlusions, repayment of debt decreased during reperfusion after the three types of ischemia in untreated animals, and this decrease was not affected by l-NAME. This decrease during reperfusion after partial and total, 60-min ischemia, but not after total, 15-min ischemia, reversed with meclofenamate. Peak hyperemic flow/control flow ratio decreased only during reperfusion after total 60-min occlusion in untreated animals and it was normalized by meclofenamate. These results show that ischemia-reperfusion reduces hyperemic response (vasodilator reserve); this diminution being dependent on duration and severity of ischemia. The hyperemic responses reduction during reperfusion after prolonged ischemia, but not after brief ischemia may be related at least in part to increased production of vasoconstrictor prostanoids.

Anesthesia↗

PubMed2005

Coronary effects of endothelin-1 and vasopressin during acute hypotension in anesthetized goats.

Coronary effects of endothelin-1 and vasopressin during acute hypotension, and the role of NO and prostanoids in these effects were examined in anesthetized goats. Left circumflex coronary artery flow was measured electromagnetically, and hypotension was induced by constriction of the caudal vena cava in animals non-treated (7 goats) or treated with the inhibitor of NO synthesis N(w)-nitro-L-arginine methyl esther (L-NAME, 5 goats), the cyclooxygenase inhibitor meclofenamate (5 goats) or both drugs (5 goats). Under normotension (22 goats), mean arterial pressure averaged 93 +/- 3 mm Hg and coronary vascular conductance (CVC) 0.37 +/- 0.025 ml/min/mm Hg. Endothelin-1 (0.01-0.3 nmol) and vasopressin (0.03-1 nmol), intracoronarily injected, dose-dependently decreased CVC by up to 56% for endothelin-1 and 40% for vasopressin. During hypotension in every condition tested, mean arterial pressure decreased to approximately 60 mm Hg, and CVC only decreased during hypotension pretreated with L-NAME (23%) or L-NAME + meclofenamate (34%). Under non-treated hypotension, the decreases in CVC by endothelin-1 were augmented approximately 1.5 fold, and those by vasopressin were not modified. This increase in CVR by endothelin-1 was not affected by L-NAME and was reversed by meclofenamate or L-NAME + meclofenamate. The coronary effects of vasopressin were not modified by any of these treatments. Therefore, acute hypotension increases the coronary vasoconstriction in response to endothelin-1 but not to vasopressin. This increased response to endothelin-1 may be related to both inhibition of NO release and release of vasoconstrictor prostanoids.

Acute Disease↗

PubMed2006

Allosteric modulation of [3H]EBOB binding to GABAA receptors by diflunisal analogues.

Allosteric modulatory effects of 12 biphenyl derivatives of diflunisal and two fenamates were studied on A-type receptors of GABA (GABAAR) via [3H]4'-ethynylbicycloorthobenzoate (EBOB) binding to synaptic membrane preparations of rat forebrain. A simplified ternary allosteric model was used to determine binding affinities of the compounds and the extents of cooperativity with GABA. Structure activity analysis revealed that 4-hydroxy substituents of the biphenyls contribute to their micromolar binding affinities more than 3-carboxyl groups. Electron-withdrawing fluorinated substituents, especially in ortho position, were also advantageous. These factors also strongly enhanced the cooperativity with GABA binding. The correlation between displacing potency of the allosteric agents and cooperativity with GABA suggests that these processes are associated with common mechanisms. The pharmacological relevance of these interactions is discussed. These data help to differentiate the structural requirements of these agents to act on GABAergic neurotransmission versus nonsteroidal anti-inflammatory effects.

Affinity Labels↗

PubMed2006

Hemopressin, a hemoglobin fragment, dilates the rat systemic vascular bed through release of nitric oxide.

The present study was undertaken to investigate the effects of intravenous (i.v.) administration of rat hemopressin (rHP), 30-1000 microg/kg, on systemic arterial pressure (SAP), cardiac output (CO) and systemic vascular resistance (SVR) in the anesthetized rat. Bolus i.v. injections of rHP produced mild decreases in SAP that were dose-dependent. Since CO was not altered, the decreases in SAP reflect reductions in SVR. The systemic vasodilator response to rHP was not subject to tachyphylaxis. The systemic vasodilator response to rHP was abolished by L-nitro-arginine methylester (L-NAME) but was not altered by meclofenamate. In addition, rHP lacked direct contractile and relaxant activity on isolated rat aortic rings (AA) and pulmonary arterial rings (PA). The present data suggest rHP dilates the rat systemic vascular bed through the endogenous release of nitric oxide (NO) independent of the formation of cyclooxygenase products including prostacyclin. It is possible rHP acts as an endogenous vasodilator substance to regulate local blood flow during clinical states of altered red cell turnover, microvascular disease and hemolysis.

Animals↗

PubMed2003

Comparison of the in vivo coronary action of endothelin-1 and vasopressin role of nitric oxide and prostanoids.

To compare the coronary effects of endothelin-1 and vasopressin, as well as the role of nitric oxide (NO) and prostanoids in these effects, blood flow in the left circumflex (73 animals) or left anterior descending (19 animals) coronary artery (coronary flow) was electromagnetically measured, and both peptides were intracoronarily injected in anesthetized goats under control conditions and after intravenous administration of the inhibitor of NO synthesis NW-nitro-L-arginine methyl ester (L-NAME, 47 mg/kg, nine animals) or the inhibitor of cyclooxygenase meclofenamate (6-8 mg/kg, seven animals). In every animal, both endothelin-1 and vasopressin reduced coronary flow in a dose-dependent way, but these reductions by 0.03, 0.1 and 0.3 nmol of endothelin-1 (16%, 33% and 66%, respectively) were significantly higher than those by the equimolar doses of vasopressin (11%, 22% and 35%, respectively). After L-NAME treatment, the reductions of coronary flow by both peptides were augmented, and this augmentation was about two times higher for endothelin-1 than for vasopressin. Meclofenamate treatment did not affect the reductions of coronary flow caused by both peptides. Therefore, we suggest that endothelin-1 is more effective than vasopressin for producing coronary vasoconstriction, but vasopressin also produces remarkable coronary vasoconstriction. Also, it is suggested that NO may play a more relevant role for modulating the coronary vasoconstriction by endothelin-1 than by vasopressin, and that cyclooxygenase products may not be involved in the coronary effects of these two peptides.

Animals↗

PubMed1984

Review of ibuprofen for osteoarthritis.

Pain is the predominant reason for seeking treatment in patients with osteoarthritis. Management is multifactorial, involving psychological, physical, pharmaceutical, and sometimes surgical measures. Nonsteroidal anti-inflammatory agents play a valuable role in the overall treatment program. A review of 28 clinical trials involving ibuprofen for osteoarthritis shows sometimes conflicting results in efficacy, often because of inadequacies in study design or dosage. In fact, 17 of these 28 studies employed doses of less than 1,600 mg/day. Nonetheless, several trends are clear. Ibuprofen at a dose of over 1,200 mg daily was superior to placebo and at doses of 1,200 to 1,800 mg/day was as effective or more effective than 3,200 to 3,600 mg/day of aspirin or 4,500 mg/day of aspirin plus acetaminophen. In trials with a wide variety of other nonsteroidal anti-inflammatory drugs, ibuprofen was often as effective as the comparison agent. Tolerability was consistently excellent with ibuprofen, and adverse reactions were few.

Acetaminophen↗

PubMed1987

Simultaneous objective and subjective evaluation of meclofenamate sodium in the treatment of primary dysmenorrhea.

Eighteen patients participated in a double-blind, placebo-controlled, single-dose, crossover study of meclofenamate sodium in women with primary dysmenorrhea. Simultaneous evaluations of pain intensity and pain relief, sampling of continuous intrauterine pressure recording, and monitoring of blood meclofenamate levels were carried out. Improvements in pain intensity and pain relief were observed at 45 minutes and reached statistical significance at and beyond 1 hour 45 minutes after meclofenamate therapy. Ten of 14 uterine pressure parameters showed statistically significant responses after drug therapy and 12 of the 14 parameters showed statistically significant differences in time-response patterns. Statistically significant changes were noted as early as 45 minutes after meclofenamate therapy. Statistically significant correlations were found between and among the parameters of blood drug level and the subjective and objective measures. No drug-related adverse effects were found.

Adult↗

PubMed1987

Treatment of menorrhagia with meclofenamate sodium.

A double-blind, placebo-controlled crossover trial was undertaken to determine the efficacy of meclofenamate sodium in the treatment of menorrhagia. Twenty-nine patients who had a baseline menstrual blood loss greater than 60 ml received 2 months' each of meclofenamate sodium, 100 mg by mouth, three times a day, or a placebo. The mean menstrual blood loss was reduced from 141.6 +/- 15.9 ml at baseline to 69.0 +/- 6.3 ml during treatment cycles but remained increased during placebo cycles (135.6 +/- 11.3 ml). The symptoms of dysmenorrhea, backache, and headache were significantly reduced only during active drug periods. The number of days of flow and pads or tampons used was also reduced during drug cycles but not during placebo cycles. Overall, 26 of the 29 patients evaluated had a reduction in menstrual blood loss with the use of meclofenamate sodium. It appears that many women with unexplained menorrhagia may benefit from this treatment.

Adolescent↗

PubMed2003

Relaxation by urocortin of rat renal arteries: effects of diabetes in males and females.

OBJECTIVE: Urocortin is a peptide structurally related to corticotropin releasing factor (CRF), and the present study was performed to examine the effects of diabetes mellitus on the relaxation by urocortin of renal arteries from males and females. METHODS: The response to urocortin was studied in isolated segments, 2 mm long, from renal arteries, from male and female, control (normoglycemic) and streptozotocin-induced diabetic rats. RESULTS: In the renal arterial segments precontracted with endothelin-1, urocortin produced concentration-dependent relaxation, that was not different between males and females. Diabetes reduced the relaxation in renal arteries from females but not in those from males. The potassium channel blocker charybdotoxin (10(-7) M) reduced the relaxation to urocortin of renal arteries from normoglycemic males and females. The cyclooxygenase inhibitor meclofenamate did not modify the relaxation to urocortin in renal arteries from normoglycemic males or females. The inhibitor of nitric oxide synthesis N(W)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) reduced the relaxation to urocortin in renal arteries from normoglycemic females, but not in renal arteries from normoglycemic males. Neither charybdotoxin, L-NAME or meclofenamate modified the relaxation to urocortin of renal arteries from diabetic females. CONCLUSION: These results suggest that urocortin produces a marked vasodilation of renal arteries, which may be mediated by nitric oxide in females and by activation of potassium channels in both genders, and is reduced by diabetes in renal arteries from females.

Animals↗

PubMed2001

Diabetes abolishes the gender difference in vasopressin-mediated potentiation of sympathetic vasoconstriction.

Electrical field stimulation (4 Hz, 0.2 ms pulse duration, at a supramaximal voltage of 70 V, for 1 s) of isolated rat tail artery segments produced contraction which was lower in female than in male rats, and was reduced by streptozotocin-induced diabetes in both genders. This contraction was potentiated by vasopressin (10(-12)-10(-10) M) more in normoglycemic male than in normoglycemic female rats, and this effect of vasopressin was increased by the cyclooxigenase inhibitor meclofenamate (10(-5) M) in female control rats, but not in diabetic female, or control and diabetic male rats, and it was not modified by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M). Endothelin-1 (10(-10)-3 x 10(-9) M) also potentiated the contraction to electrical stimulation. This potentiation was similar in all experimental groups, and it was not modified by meclofenamate or L-NAME. These results suggest that the potentiating effect of vasopressin, but not that of endothelin-1, on the sympathetic vasoconstriction, is lower in females than in males, probably by an increased release of vasodilating prostanoids, and this release may be reduced by diabetes in females.

Animals↗

PubMed2002

Coronary reactivity to endothelin-1 during partial ischemia and reperfusion in anesthetized goats. Role of nitric oxide and prostanoids.

To examine the coronary reactivity to endothelin-1 and its interaction with nitric oxide or prostanoids during partial coronary ischemia and reperfusion, left circumflex coronary artery flow was electromagnetically measured, and partial occlusion of this artery was induced for 60 min, followed by reperfusion in anesthetized goats (eight non-treated, six treated with N(w)-nitro-L-arginine methyl esther (L-NAME) and five treated with meclofenamate). During partial occlusion, coronary vascular conductance was reduced by 24-37% (P<0.01), and the coronary vasodilatation in response to acetylcholine (3-100 ng) and sodium nitroprusside (1-10 microg) was much decreased in every case; the vasoconstriction in response to endothelin-1 (1-10 microg) was depressed in non-treated animals, and this depression was reversed by L-NAME and was accentuated by meclofenamate. At 30 min of reperfusion coronary vascular conductance remained decreased by 22-27% (P<0.01), and the vasodilatation in response to acetylcholine (3-100 ng) and sodium nitroprusside (1-10 microg), as well as the vasoconstriction with endothelin-1 (1-10 microg), were as in the control and comparable in the three groups of animals. These results suggest: (a) that during ischemia, the coronary vasodilator reserve is greatly reduced, and the vasoconstriction with endothelin-1 is blunted, with preservation of the modulatory role of nitric oxide and involvement of vasoconstrictor prostanoids in this vasoconstriction, and (2) that during reperfusion, the coronary vasodilator reserve and the coronary reactivity to acetylcholine and endothelin-1 recover, but the modulatory role of nitric oxide in this reactivity may be attenuated.

Acetylcholine↗