Pharmacology
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The aims of the present study were to determine the angiotensin II (AngII) receptor subtype(s) involved in vasoconstriction and enhancement of sympathetic neurotransmission in rat isolated mesenteric arteries. Vasoconstriction was assessed in mesenteric artery ring preparations suspended under 0.5 g of tension in a myograph. In control arteries, with an intact endothelium, AngII (1 nmol/l-3 micromol/l) caused a concentration-dependent contraction. ⋯ Losartan (30 nmol/l) competitively blocked the AngII-induced enhancement of plateau EJP amplitude, with an estimated pA(2) of 8.6. PD 123319 did not alter the enhancement of plateau EJP amplitude by AngII. The results from the present study show that both the vasoconstriction and enhancement of plateau EJP amplitude by AngII in rat mesenteric arteries are blocked by the AT1 receptor antagonist losartan and are unaffected by the AT2 receptor antagonist PD 123319.
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Comparative Study
Meloxicam inhibits prostaglandin E(2) generation via cyclooxygenase 2 in the inflammatory site but not that via cyclooxygenase 1 in the stomach.
We studied the effects of meloxicam on prostanoid levels, both in the inflammatory site in rat carrageenin-induced pleurisy and in the rat stomach injected with 1 mol/l NaCl solution, to clarify the relationship between its low gastric toxicity and its relative cyclooxygenase (COX) 2 selectivity. NS-398 (3 mg/kg), a highly selective COX-2 inhibitor, and meloxicam (3 mg/kg) exhibited anti-inflammatory effects in the pleurisy model. Prostaglandin (PG) E(2) thromboxane (TX) B(2) and 6-keto-PGF(1alpha) were detectable in the inflammatory site. ⋯ Nimesulide (3 mg/kg), another selective COX-2 inhibitor, however, never affected this increase, suggesting that the gastric PGE(2) may be produced via COX-1. The anti-inflammatory dose of meloxicam caused statistically nonsignificant suppression of the PGE(2) level, by approximately 50%. These results suggest that the potent anti-inflammatory effect of meloxicam, accompanied with low gastric toxicity, may be related to its relative selectivity for COX-2 over COX-1.
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Inhaled nitric oxide (NO), a selective pulmonary vasodilator, increases intracellular cyclic guanosine monophosphate. In contrast, adenosine, another selective pulmonary vasodilator, increases intracellular cyclic adenosine monophosphate. There has been only limited study on effects of inhaled NO combined with other pulmonary vasodilators. ⋯ Inhaled NO decreased pulmonary artery pressure and pulmonary vascular resistance at all doses of adenosine, but had no significant pulmonary vasodilator effects at doses of SNP >0.5 microg/kg/min. We conclude that inhaled NO does not produce additional pulmonary vasodilation over that achieved at higher doses of SNP, but does produce additional vasodilation when combined with a vasodilator having different mechanisms of action. Since both inhaled NO and adenosine produce selective pulmonary vasodilation, such combination therapy may be effective in patients with pulmonary hypertension.
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We studied the anti-inflammatory activity of meloxicam on rat carrageenin-induced pleurisy and its toxicity for rat gastric mucosa, relative to its in vitro inhibitory potency against partially purified cyclooxygenase (COX)-1 and COX-2 preparations in order to clarify the pharmacological profile of the compound as an anti-inflammatory agent. In rat carrageenin-induced pleurisy, the plasma exudation rate peaked at 5 h, at which time COX-2 was detectable in cells from the pleural exudate. Meloxicam and piroxicam (1 and 3 mg/kg) and NS-398 (3 mg/kg) showed almost equal anti-inflammatory potency against 5-hour pleurisy. ⋯ These results indicate that meloxicam is a potent anti-inflammatory agent with low gastric toxicity. One reason for its in vivo pharmacological profile may be related to its relative selectivity for COX-2 over COX-1. Thus, meloxicam may belong to a group of COX-2 selective anti-inflammatory agents with a better safety profile than conventional COX-1 and COX-2 nonselective anti-inflammatory agents.
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(+/-)-4-(2-Chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dime thy l-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (Y-24180) is a platelet-activating factor (PAF) antagonist, being similar to WEB 2086. One of the structural differences between the two PAF antagonists is the presence of a methyl substituent in Y-24180 at the 6-position of its ring system. Orally administered Y-24180 and WEB 2086 both dose-dependently prevented PAF-induced airway hyperresponsiveness (ED50: 0.0010 and 0.019 mg/ kg, respectively) and bronchoconstriction (ED50: 0.0014 and 0.024 mg/kg, respectively) in guinea pigs. ⋯ Compared with desmethyl-Y-24180 and WEB 2086, Y-24180 and methyl-WEB 2086, both of which have a methyl substituent on the 6-position of their thienodiazepine ring, exhibited a longer acting suppressive effect on PAF-induced bronchoconstriction and significantly more stable binding to the PAF receptor after the washing-out procedure of the test compounds from platelets. Therefore, the 6-methyl substituent should be responsible for the PAF receptor binding stability of Y-24180, namely, for its long-acting anti-PAF effects in vivo. These results indicate that Y-24180 possesses the specific and long-acting PAF antagonistic effects in the airway.