thromboxane-b2 and flosulide

Nephrotoxicity of nonsteroidal anti-inflammatory drugs is associated with other risk factors (volume-depletion) and may be secondary to functional changes mediated by the inhibition of renal cyclooxygenases. Acute anti-inflammatory doses of flosulide and indomethacin were determined on carrageenan paw edema and its effects on renal plasma flow (RPF) and glomerular filtration rate (GFR) were studied in normovolemic and hypovolemic rats. In normovolemic rats, flosulide increased RPF and GFR (25 mg/kg) and indomethacin (5-10 mg/kg) was without effect. Volume-depleted rats were obtained by oral furosemide (32 mg/kg), urinary eicosanoids were determined. After furosemide, plasma volume, RPF and GFR and PGE2 decreased. Treatment of hypovolemic rats with flosulide (5-25 mg/kg) or indomethacin 10 mg/kg reduced RPF and GFR. Flosulide at 5 mg/kg reduced 6-keto-PGF1alpha whereas at 25 mg/kg and after indomethacin at 10 mg/kg a fall in 6-keto-PGF1alpha and TXB2 appeared. Our data suggest that acute COX-2 selective inhibition may alter renal function.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Female; Glomerular Filtration Rate; Indans; Indomethacin; Isoenzymes; Kidney; Membrane Proteins; Plasma Volume; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Renal Plasma Flow; Thromboxane B2

Interleukin-1beta has been reported to induce airway hyperresponsiveness in several animal models. In this study, we have investigated whether interleukin-1beta was able to potentiate the contractions of human isolated small bronchi (internal diameter < or = 1 mm) provoked by a specific tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P. Pre-incubation of human isolated small bronchi with interleukin-1beta (10 ng/ml, in Krebs-Henseleit solution, at 21 degrees C for 15 h) potentiated the contractile response to [Sar9,Met(O2)11]substance P. It also increased the [Sar9,Met(O2)11]substance P-induced release of thromboxane B2, the stable metabolite of thromboxane A2. Indomethacin (10(-6) M), a non-specific cyclooxygenase inhibitor, or GR 32191 ((1R-(1alpha(Z)),2beta,3beta,5alpha))-(+)-7-(5-(((1,1' -biphenyl)-4-yl)-methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-hept enoic acid, hydrochloride) (10(-6) M), a prostanoid TP-receptor antagonist, blocked the contractions induced by [Sar9,Met(O2)11]substance P both in control experiments and after interleukin-1beta pre-treatment, indicating that prostanoids and thromboxane receptors are directly implicated in the [Sar9,Met(O2)11]substance P-induced contractile response. The thromboxane mimetic U-46619 (10(-8)-10(-6) M) (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F2alpha)-induced contractions of human isolated small bronchi were not enhanced by interleukin-1beta pre-treatment, suggesting that no up-regulation of thromboxane receptors occurred. Furthermore, the cyclooxygenase-2 inhibitor CGP 28238 (6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanon e) (10(-6) M) had no direct effect on [Sar9,Met(O2)11]substance P-provoked contractions, but inhibited the interleukin-1beta-induced potentiation of [Sar9,Met(O2)11]substance P response. In conclusion, our results show that interleukin-1beta pre-treatment is able to potentiate the contractions of isolated human small bronchi provoked by [Sar9,Met(O2)11]substance P both by increasing prostanoid synthesis and by inducing a cyclooxygenase-2 pathway.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aged; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Bronchi; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Heptanoic Acids; Humans; In Vitro Techniques; Indans; Indomethacin; Interleukin-1; Male; Muscle Contraction; Muscle, Smooth; Prostaglandin Antagonists; Receptors, Tachykinin; Substance P; Thromboxane B2; Time Factors; Vasoconstrictor Agents