The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Feb 1993
Pulmonary antiallergic and bronchodilator effects of isozyme-selective phosphodiesterase inhibitors in guinea pigs.
The effectiveness of theophylline (aminophylline) in treating asthma may result in part from nonselective inhibition of multiple isozymes of cyclic nucleotide phosphodiesterase (PDE). The roles for inhibition of different PDE isozymes in the pulmonary antiallergic and bronchodilator effects of theophylline were investigated in anesthetized and ventilated guinea pigs by using the PDE-III-selective inhibitor Cl-930, the PDE-IV-selective inhibitor rolipram and the PDE-V-selective inhibitor zaprinast. Aminophylline, Cl-930 and rolipram inhibited aerosol ovalbumin-induced full [leukotriene (LT) + histamine] and LT-dependent bronchoconstriction, but zaprinast was inactive. ⋯ In contrast, Cl-930 failed to inhibit airway hyperreactivity, but produced substantial residual bronchodilation. The results indicate that PDE-IV inhibition produces pulmonary antiallergic effects in vivo, including the apparent inhibition of LT release, which may contribute to the antiasthmatic actions of theophylline. The results also support previous suggestions that PDE-III inhibition contributes to the bronchodilator effect of theophylline.
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J. Pharmacol. Exp. Ther. · Nov 1992
General anesthetics potentiate gamma-aminobutyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium.
Potentiation of the gamma-aminobutyric acid (GABAA) receptor-gated Cl- channel response has been suggested to be a primary action of some anesthetic agents. We asked whether the GABAA receptor is a target site common for general anesthetics that are chemically and structurally diverse. This hypothesis was tested in Xenopus oocytes expressing mouse cortical mRNA, and GABA-activated Cl- currents were measured using two-electrode voltage clamping. ⋯ We found that intracellular injection of the Ca++ chelator, EGTA, did not change the enhancement by anesthetics. In addition, these anesthetics alone did not produce significant currents, suggesting that the Ca(++)-dependent Cl- current was not activated by these anesthetics per se. Thus, we found that diverse anesthetics potentiate GABA-induced Cl- currents, but this action is not mediated by a release of intracellular Ca++.
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J. Pharmacol. Exp. Ther. · Oct 1992
Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat.
Subcutaneous injection of formalin into the dorsal surface of the hindpaw evoked a two-phased flinching (phase 1:0-9 min; phase 2: 10-60 min) of the injected paw. Intrathecal administration of the nonsteroidal anti-inflammatory drugs (NSAID) produced minimal effects upon phase 1, but showed a significant, though submaximal, dose-dependent suppression of the phase 2 response. Ordering of i.t. potency was (ID50 in nmol): indomethacin (1.9) > or = flurbiprofen (2.1) > ketorolac (5.2) > or = zomepirac (5.9) > S(+)ibuprofen (16) > or = ibuprofen(racemic) (19) > acetylsalicylic acid (27) > acetaminophen (250) > R(-)ibuprofen (> 270) = 0. ⋯ Pretreatment at longer intervals indicated that the duration of the antinociceptive effect was between 3 to 6 hr after the i.t. injection. The i.t. injection of the highest doses of the several NSAID were without significant effect upon the 52.5 degrees C hot plate test. These studies indicate that NSAID have a powerful effect upon spinal nociceptive processing evoked by the s.c. injection of formalin.
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Nalbuphine is a mixed opioid agonist/antagonist analgesic. It labels mu receptors most potently where it acts as an antagonist. Nalbuphine is analgesic in the tail-flick assay after systemic (ED50, 41.8 mg/kg s.c.), i.c.v. (ED50, 21.3 micrograms) or intrathecal administration (ED50, 11.2 micrograms). ⋯ The presence of analgesic cross-tolerance between nalbuphine and both naloxone benzoylhydrazone and nalorphine indicated an analgesic role for kappa 3 receptors, which act supraspinally. Additional studies revealed synergistic interactions between spinal kappa 1 and supraspinal kappa 3 receptors when nalbuphine was given both intrathecally and i.c.v. In conclusion, these studies suggest that nalbuphine elicits analgesia through a complex interaction of supraspinal kappa 3 and spinal kappa 1 mechanisms.
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J. Pharmacol. Exp. Ther. · Aug 1992
Alfaxalone, pentobarbital and diazepam potentiate gamma-aminobutyric acid-induced depolarizations in single myenteric neurons of guinea pig intestine.
Intracellular electrophysiological recordings were made from myenteric neurons of guinea pig ileum maintained in vitro. gamma-Aminobutyric acid (GABA), applied by superfusion (1-300 microM) or by pressure ejection from a fine-tipped pipette positioned near the impaled neuron, depolarized some neurons. GABA-induced depolarizations were mimicked by muscimol (1-100 microM) applied by superfusion and were blocked by bicuculline (30 microM) and picrotoxin (60 microM). The estimated reversal potential for the GABA-induced depolarization was -18 +/- 3 mV when recordings were made with potassium chloride (2 M)-filled microelectrodes. ⋯ Alfaxalone (greater than 1 microM) and pentobarbital (greater than 100 microM) mimicked the GABA-induced depolarization. Cortisol (30-1000 pM) did not alter the amplitude of GABA responses when GABA was applied by pressure ejection (n = 6) or by superfusion (n = 6). These data indicate that GABAA receptors on myenteric neurons contain binding sites for some steroids, barbiturates and benzodiazepines and that responses mediated at enteric GABAA receptors can be modified by drugs acting at these allosteric binding sites.