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PubMed1989

The effect of theophylline and cyclic adenosine 3',5'-monophosphate on renin release by afferent arterioles.

The effects of theophylline and cyclic adenosine 3',5'-monophosphate (cAMP) on renin release by afferent arterioles were studied. Rabbit afferent arterioles (seven to 10), obtained by a microdissection technique, were incubated for three consecutive 20 min periods in 100 microliters of Medium 199 with 0.1% bovine serum albumin (BSA). Afferent arterioles exposed to theophylline, 1 x 10(-4) mol/l, produced a greater than 100% increase in renin release (0.18 +/- 0.04 to 0.42 +/- 0.05 ng angiotensin l/h per arteriole per h incubation). The renin release stimulated by theophylline was completely abolished by indomethacin and meclofenamate. The stimulation of renin secretion was also blocked when extracellular calcium concentration was decreased to 10(-7) mol/l and the arterioles were permeabilized with calcium ionophore. Dibutyryl cAMP (db-cAMP), 1 x 10(-4) mol/l, and forskolin, 1 mumol/l or 100 mumol/l, failed to stimulate renin release by afferent arterioles. The results of this study therefore suggest that theophylline-stimulated renin release may be mediated through a prostaglandin pathway. The stimulation of renin secretion is also dependent on the extracellular concentration of calcium.

Animals↗
PubMed1992

Control of renal hemodynamics during intrarenal and systemic blockade of nitric oxide synthesis in conscious dogs.

Systemic blockade of nitric oxide (NO) synthesis results in marked increases in the renal vascular resistance (RVR) and decreases in the glomerular filtration rate (GFR) and renal plasma flow (RPF). The renal hemodynamic effect of systemic NO blockade is most likely due to an integration of direct and indirect renal actions. The quantitative importance of local intrarenal blockade of NO synthesis on renal hemodynamics has not been fully elucidated. Therefore, the purpose of this study was to compare the renal hemodynamic effects of intrarenal vs. systemic NO synthesis blockade on renal hemodynamics. Nitro-L-arginine methyl ester (L-NAME) was infused intrarenally at a rate of 3 micrograms/kg/min for 180 min in conscious chronically instrumented dogs (n = 7). Intrarenal infusion of L-NAME for 180 min resulted in a 12% decrease in RPF, 14% increase in RVR, and no effect on mean arterial pressure (MAP) or GFR. In contrast, infusion of L-NAME intravenously at a rate of 10 micrograms/kg/min for 180 min increased the RVR by 124% and decreased the RPF by 55% and GFR by 45%. The MAP and heart rate both increased in response to intravenous administration of L-NAME. The results of this study suggest that the renal hemodynamic effects of systemic administration of L-NAME may, in large part, be secondary to extrarenal effects of NO synthesis blockade, possibly via activation of the sympathetic nervous system.

Animals↗
PubMed1996

Cyclooxygenase inhibition and vascular reactivity in a rat model of hyperdynamic sepsis.

We postulated that the attenuated pulmonary and systemic vascular contractility observed in sepsis was secondary to the release of vasodilator prostaglandins. We used the cyclooxygenase inhibitor meclofenamate to inhibit prostaglandin synthesis in an unanesthetized, chronically instrumented model of hyperdynamic sepsis. Sixteen male Sprague-Dawley rats (300-350 g) were randomized to either sepsis induced by cecal ligation and perforation (CLP, n = 8) or a sham procedure (Sham, n = 8). Vascular reactivity was assessed by measuring the hypoxic (FiO2 = 0.08) pulmonary pressor response (HPV), and the systemic pressor response to an intravenous infusion of phenylephrine (1.5-7.5 micrograms/kg/min) before and after the administration of meclofenamate (5 mg/kg intravenously, i.v.). Twenty-four hours postoperatively, CLP animals had significantly increased cardiac output (CO) as compared with Sham animals (204 +/- 12 vs. 148 +/- 5 ml/min, p < 0.05), slightly decreased mean arterial pressure (MAP) (109 +/- 4 vs. 118 +/- 3 mm Hg, p < 0.05), and decreased total systemic vascular resistance (TSVR) (0.546 +/- 0.046 vs. 0.805 +/- 0.030 mm Hg.min.ml-1, p < 0.05). Mean pulmonary artery pressure (MPAP) and total pulmonary vascular resistance (TPVR) were similar in both groups (p > 0.05). In response to hypoxia, the change in MPAP (delta MPAP) was 3.6 +/- 1.0 and 6.9 +/- 0.8 (mm Hg) in CLP and Sham animals, respectively (p < 0.05). Similarly, the change in TPVR (delta TPVR) during hypoxia was 0.012 +/- 0.006 and 0.038 +/- 0.009 mm Hg.min.ml-1 in CLP and Sham (p < 0.05). The pulmonary and systemic blood pressure (BP) response to phenylephrine was also attenuated in CLP as compared with Sham animals. After treatment with meclofenamate, differences were no longer apparent in the HPV response between CLP and Sham animals, due to a slight increase in the HPV response of CLP animals and a slight decrease in the HPV response in Sham animals. The attenuated pressor response to phenylephrine was not changed in either the pulmonary or the systemic circulation after the administration of meclofenamate. These data suggest that vasodilator prostaglandins may contribute to the attenuated pulmonary pressor response in sepsis. However, the mechanism of the attenuated HPV may be different than the attenuated response to exogenous catecholamines since meclofenamate had no effect on either the pulmonary or systemic response to a phenylephrine infusion in septic animals.

Animals↗
PubMed1999

Pulmonary artery contractility in pneumonia: role of cyclooxygenase products and nitric oxide.

The purpose of this study was to determine the effects of aminoguanidine (AG) and meclofenamate (MEC) on depressed contractility of small pulmonary artery (PA) rings isolated from a rat model of acute Pseudomonas pneumonia. Contractility of PA rings from lungs of control or pneumonia rats was assessed in vitro by obtaining cumulative concentration-contraction curves to potassium chloride (KCl), phenylephrine (PE), and prostaglandin F2alpha (PGF2alpha) on rings treated with or without MEC (1.0 microM), AG (100 microM), or AG + MEC. Vessels from pneumonia rats exhibited significant attenuation of the contractile responses to KCl, PE, and PGF2alpha. MEC restored the KCl and PGF2alpha contractile responses to control values, but had no effect on the attenuated PE contractile response. In contrast, AG restored the PE contractile response, and only partially affected contractile responses to KCl and PGF2alpha, MEC + AG restored the contractile responses of all three agonists. We conclude that both excess nitric oxide (NO) and cyclooxygenase products contribute to the depressed pulmonary vascular contractility observed in rats with acute pneumonia. The relative importance of NO and cyclooxygenase products in this phenomenon depends on the contractile agonist studied.

Analysis of Variance↗
PubMed2002

Cyclic adenosine monophosphate-dependent vascular responses to purinergic agonists adenosine triphosphate and uridine triphosphate in the anesthetized mouse.

The mechanism by which purinergic agonist adenosine triphosphate (ATP) and uridine triphosphate (UTP) decrease systemic arterial pressure in the anesthetized mouse was investigated. Intravenous injections of adenosine triphosphate (ATP) and uridine triphosphate (UTP) produced dose-dependent decreases in systemic blood pressure in the mouse. The order of potency was ATP > UTP. Vasodilator responses to ATP and UTP were altered by the cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor rolipram. The vascular responses to ATP and UTP were not altered by a nitric oxide synthase inhibitor, a cyclooxygenase inhibitor, a cGMP phosphodiesterase inhibitor, or a particular P2 receptor antagonist. These data suggest that ATP and UTP cause a decrease in systemic arterial pressure in the mouse via a cAMP-dependent pathway via a novel P2 receptor linked to adenylate cyclase and that nitric oxide release, prostaglandin synthesis, cGMP, and P2X1, P2Y1, and P2Y4 receptors play little or no role in the vascular effects of these purinergic agonists in the mouse.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Early aging and anatomic heterogeneity determine cyclooxygenase-mediated vasoconstriction to angiotensin II in mice.

We previously reported that angiotensin II (AngII)-induced vasoconstriction involves activation of cyclooxygenase (COX) in murine aorta and carotid artery. The aim of this study was to investigate the roles of early aging and COX in AngII-induced vasoconstriction in different vascular beds. Aortic, carotid, renal, and femoral artery rings of 19- and 34-week-old C57BL/6 mice were pretreated with the nitric oxide synthase inhibitor L-NAME (300 micromol/L) to exclude effects of NO. Contractions to AngII (100 nmol/L) were recorded in the presence or absence of meclofenamate (10 micromol/L), a nonselective COX inhibitor. The results indicate a pronounced heterogeneity in the vascular responsiveness to AngII. Renal and femoral artery rings showed stronger contractions than aorta or carotid artery (P < 0.01 for both). In all vessels of young animals COX inhibition with meclofenamate only partially blocked vasoconstriction to AngII, whereas contractions were completely abolished in the aorta and carotid artery of older mice (P < 0.05 vs untreated for both). These data demonstrate that COX determines AngII-induced vasoconstriction in the mouse aorta and carotid artery during the early physiological aging process, independent of endothelial NO bioactivity. AngII-induced vasoconstriction in vessels more distal to the heart such as femoral and renal arteries is only in part mediated by COX-dependent mechanisms that remain unaffected by early aging.

Aging↗
PubMed1986

Effect of anti-inflammatory agents on the haemorrhagic response of mouse skin to Bordetella pertussis heat-labile toxin.

Bordetella pertussis heat-labile toxin (HLT) was assayed by the haemorrhagic response produced by subcutaneous injection into weaned mice. Young mice, 3-5 weeks old of either sex, were highly responsive but they became resistant to HLT as they matured. Two anti-inflammatory agents, prednisolone and meclofenamate, inhibited the skin reactions in young mice. When given intraperitoneally, prednisolone was most inhibitory if it was injected just before, or at the same time as, HLT challenge. Prednisolone given 3 h after challenge, when the skin reactions had started to develop, did not significantly attenuate the final response. Both drugs were even more effective when mixed with the HLT challenge and injected subcutaneously. These findings are discussed in relation to the possible mechanism of action of HLT and to the reported beneficial effects of corticosteroids in the treatment of whooping cough.

Animals↗
PubMed1996

Influence of closure of the reticular groove on the bioavailability and disposition kinetics of meclofenamate in sheep.

Sodium meclofenamate is a non-steroidal anti-inflammatory drug with anaphylactic protective activity in cattle. The objectives of this study were to describe the pharmacokinetic behaviour of sodium meclofenamate after intravenous and oral administration to sheep and to determine the influence of closure of the reticular groove on the bioavailability of the drug. Sodium meclofenamate was administered by the intravenous (2.2 mg/kg) and oral (20 mg/kg) routes to sheep (n = 6). During the oral study the reticular groove was closed by intravenous administration of lysine vasopressin (0.3 IU/kg) or left open (saline solution). The closure of the reticular groove was assessed by determination of the blood glucose curves after oral administration of a glucose solution. After intravenous administration of meclofenamate, the distribution and elimination half-lives of the drug were 7.2 min and 542 min respectively, Vss was 1.68 L/kg and ClB was 2.47 mliter/min kg. Two different patterns of the plasma concentration curves were observed after oral administration of sodium meclofenamate. When the reticular groove was closed, two peaks were observed (tmax-1 12-15 min, Cmax-1 3.30-24.01 micrograms/mliter; and tmax-2' 52.50-75 min, Cmax-2, 6.45-11.08 micrograms/mliter).

Administration, Oral↗
PubMedDate not supplied

The effects of meclofenamate on renal and peripheral vascular beds in conscious rabbits.

1. Meclofenamate caused a dose-dependent increase in renovascular resistance in conscious rabbits. 2. This effect was greatest in inner cortical zones at the highest dose (6 mg/kg) but at the lowest dose (0.75 mg/kg) vascular resistance in the outer cortex was preferentially increased. 3. In contrast, meclofenamate increased cerebral perfusion and the proportion of cardiac output received by the testis. No effect was demonstrated on other organs studied. 4. The results suggest a local vasodilator influence of renal prostaglandins in normal conscious rabbits.

Animals↗
PubMedDate not supplied

Effects of meclofenamate and captopril on blood flow to the kidney and spleen in conscious rabbits subjected to mild haemorrhage.

1. Regional haemodynamic responses to mild haemorrhage were studied in three groups each of seven conscious rabbits, in the presence of either buffer, the prostaglandin cyclo-oxygenase inhibitor meclofenamate, or the kininase II inhibitor captopril. 2. Renal and splenic vasoconstriction occurred with meclofenamate in haemorrhaged animals, and were accentuated by the subsequent administration of captopril. 3. Captopril alone caused mild renal vasodilatation, but subsequent administration of meclofenamate again caused vasoconstriction. 4. Flow to the adrenal coronary, cerebral and hepatic artery circulations was unaffected by meclofenamate or captopril after haemorrhage. 5. The results indicated that the enhanced vasopressor activity occurring during haemorrhage greatly increased the dependence on vasodilator prostaglandins of flow to the renal and splenic vascular beds. 6. The vasoconstrictor effect of meclofenamate does not appear to be due to unopposed action of angiotensin II when prostaglandin synthesis is suppressed.

Animals↗
PubMed1976

Dual effects of aspirin in guinea-pig lungs.

Dual effects of aspirin were demonstrated in guinea-pig lungs: (a) aspirin (3.3 mg/kg i.v.) antagonized bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A); (b) aspirin produced bronchoconstriction when injected in the presence of propranolol into guinea-pigs in vivo at 330 mg/kg, or into guinea-pig isolated lungs in vitro as a 4% solution (40 mg/ml). 2 The severity of bronchoconstriction following administration of aspirin was directly related to the degree of beta-adrenoceptor blockade and to the age of the guinea-pigs. Aspirin-induced bronchoconstriction was prevented in vivo and in vitro by atropine and it could be reversed in vivo by atropine. Aspirin-induced bronchoconstriction was not inhibited by vagotomy or phenoxybenzamine. 3 These data suggest that the mechanism involved in aspirin-induced bronchoconstriction may be local cholinergic stimulation and that reduced beta-adrenergic drive may be a predisposing factor.

Aging↗
PubMed1977

Renal blood flow autoregulation and renal venous prostaglandins in the pump-perfused canine kidney (in situ).

1. Renal autoregulation of blood flow was re-examined in the pump-perfused canine kidney and concentrations of prostaglandins E and F in the renal venous plasma were measured by radioimmunoassay. 2. At low perfusion pressures, below the range of autoregulation, prostaglandin E and F concentrations rose and calculated prostaglandin E secretion rate fell. 3. Meclofenamate (10 mg/kg i.v.) reduced renal blood flow and prostaglandin E and F secretion rates, but did not abolish autoregulation. 4. Renal prostaglandins do not appear to mediate autoregulation in the kidney but may affect the level at which flow is controlled.

Animals↗
PubMed1977

The possible roles of histamine, 5-hydroxytryptamine and prostaglandin F2alpha as mediators of the acute pulmonary effects of endotoxin.

1 In an attempt to investigate the possible role of released vasoactive substances in mediating the pulmonary pressor responses to E. coli endotoxin, cats were pretreated with histamine, 5-hydroxytryptamine (5-HT) or prostaglandin antagonists, with a histamine depleting agent (compound 48/80) or with an inhibitor of prostaglandin synthetase (sodium meclofenamate).2 The administration of endotoxin (2 mg/kg) resulted in a rapidly developing pulmonary hypertension (pressure twice normal after 2-3 min), increases in right atrial and intratracheal pressures, systemic hypotension and bradycardia. These effects were unaffected by methysergide in a dose sufficient to prevent the effects of intravenously administered 5-HT.3 Endotoxin responses were also unaffected by a combination of mepyramine and burimamide in doses sufficient to reduce markedly the effects of intravenously-administered histamine. In cats pretreated (chronically or acutely) with compound 48/80, endotoxin induced a transient pulmonary pressor response which was not maintained.4 The pulmonary and systemic responses to endotoxin were prevented by the prior administration of the prostaglandin antagonist, polyphloretin phosphate and by pretreatment with the prostaglandin synthetase inhibitor, sodium meclofenamate.5 It is concluded that a pulmonary vasoconstrictor prostaglandin is involved in the acute response to endotoxin in the cat.

Animals↗
PubMed1984

Cyclo-oxygenase inhibitors antagonize indirectly evoked contractions of the guinea-pig isolated ileum by inhibiting acetylcholine release.

The effects of indomethacin, sodium meclofenamate and ketoprofen on the contractile responses of the guinea-pig isolated ileum to directly and indirectly evoked stimuli were investigated. The effects of the cyclo-oxygenase inhibitors on acetylcholine (ACh) release from plexus containing longitudinal muscle strips were also studied. The cyclo-oxygenase inhibitors reduced contractile responses to transmural stimulation (TMS) and nicotine at concentrations which had no effect on ACh-induced contractions. In whole ileum preparations (WIP) indomethacin and ketoprofen (40 micrograms ml-1) reduced TMS responses by 17 +/- 1.8% and 12 +/- 1.8% (n = 6), respectively (30 min incubation). In longitudinal muscle strips (LMS) in which Auerbach's plexus is exposed, indomethacin and ketoprofen (1 microgram ml-1) reduced TMS responses by 28 +/- 2.3% and 34 +/- 2.7% (n = 6), respectively (10 min incubation). Thus the cyclo-oxygenase inhibitors were up to 80 times more effective in LMS than in WIP. The drugs were similarly more effective in blocking nicotine contractions in LMS than in WIP. The cyclo-oxygenase inhibitors reduced basal and stimulated ACh release from LMS. For example, indomethacin (1 microgram ml-1) reduced stimulated ACh release by 35% after 10 min incubation. The percentage inhibition increased to 79% after 40 min incubation (n = 6). Prostaglandin E2 (PGE2) (0.1-2.5 ng ml-1) restored the contractile responses and ACh release depressed by the cyclo-oxygenase inhibitors but not the contractile responses depressed by atropine. PGF2 alpha had no effect on mechanical responses or ACh release depressed by the cyclo-oxygenase inhibitors. 6 It is concluded that the cyclo-oxygenase inhibitors studied reduced responses to transmural stimulation and nicotine by inhibiting ACh release. The site of action is the postganglionic parasympathetic nerve. 7 It is suggested that the reason why previous investigators needed to use high doses of cyclooxygenase inhibitor in the ileum is because the action of the inhibitor is limited by diffusion barriers. There was no evidence to support the view that there is more than one pool of cyclo-oxygenase in guinea-pig gut.

Acetylcholine↗
PubMed1990

Receptors involved in mechanical responses to catecholamines in the circular muscle of guinea-pig stomach treated with meclofenamate.

1. In circular muscle strips of the fundus and corpus of guinea-pig stomach, mechanical responses to catecholamines were studied mainly in the presence of a prostaglandin biosynthesis inhibitor, meclofenamate. 2. Normal preparations developed considerable muscle tone, and adrenaline (10-100 microM) in the presence of 3-5 microM propranolol produced a multiphasic response, generally consisting of transient relaxation and contraction, followed by slow relaxation and then contraction. Responses to phenylephrine were similar to those of adrenaline. 3. Meclofenamate (0.3 microM) nearly abolished the muscle tone and under this condition, both adrenaline and phenylephrine produced a simple contraction. This response was strongly inhibited by prazosin, but only weakly by yohimbine. 4. When muscle tone was maintained by prostaglandin E2 (10 nM) in the presence of meclofenamate, phenylephrine (30 microM) produced transient relaxation followed by slow contraction in most preparations. These were strongly inhibited by prazosin. Adrenaline produced a similar response, but the relaxation was only partially reduced by prazosin. The remaining relaxation was more dominant in the middle fundic region and this was considered to be mediated through beta-adrenoceptors. 5. It is concluded that in the circular muscle of the fundic region of guinea-pig stomach, endogenous prostaglandins are involved in maintaining muscle tone and in modifying the response to catecholamines and that both contraction and relaxation are mediated by alpha 1-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1991

Mechanical responses to catecholamines in the longitudinal muscle of guinea-pig gastric fundus.

1. In the longitudinal muscle of guinea-pig gastric fundus, adrenaline and phenylephrine (1-30 microM) both produced a slow contraction preceded by a relaxation. The slow contraction was strongly inhibited by prazosin (0.1 microM), but only weakly by yohimbine (1 microM), suggesting main contribution of alpha 1-adrenoceptors. 2. Most of the slow contraction was blocked by meclofenamate or indomethacin (0.1-0.3 microM). Both these drugs also inhibited spontaneously generated muscle tone. In some preparations, obtained from the apical fundus, a small contraction remained in the presence of meclofenamate. 3. During contraction induced by prostaglandin E2, adrenaline produced sustained relaxation and phenylephrine often transient relaxation, in the presence of meclofenamate. The transient relaxation, but not the sustained relaxation, was suppressed by prazosin. 4. In the presence of prostaglandin E2 (5 nM), after treating with phenoxybenzamine (30 microM) for 30 min, isoprenaline and adrenaline produced concentration-dependent relaxation, with IC50 s of 3.9 nM and 64 nM, respectively. Propranolol shifted these concentration-response curves to the right, with apparent pA2 s of 8.15 and 7.34, respectively. 5. It is suggested that in the fundic longitudinal muscle, adrenaline-induced contraction is mediated mainly by an increase in endogenous prostaglandin production through activation of alpha 1-adrenoceptors and that adrenaline produces transient relaxation through alpha 1-adrenoceptors and sustained relaxation through beta-adrenoceptors. The beta-adrenoceptors in the longitudinal muscle are more sensitive to adrenaline and isoprenaline than those in the circular muscle.

Animals↗