European journal of pharmacology
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We studied the function of autoinhibitory muscarinic M2 receptors on vagal nerve endings in the airways of conscious, unrestrained, ovalbumin-sensitized guinea pigs after the early and late allergic reaction. For this purpose, the effects of the selective muscarinic M2 receptor antagonist gallamine were examined on unilateral vagus nerve stimulation-induced bronchoconstriction, which was determined as an increase in basal respiration amplitude, measured as changes in pleural pressure. Under control conditions, i.e., before antigen challenge, a significant increase in the pleural pressure was found after inhalation of 0.1 mM and, even more pronounced, 1.0 mM gallamine, at medium stimulation frequencies (2-16 Hz), leading to a leftward shift of the frequency-response curve. ⋯ The results clearly demonstrate that prejunctional muscarinic M2 receptors control bronchoconstriction in conscious, unrestrained guinea pigs in vivo. Furthermore, these autoinhibitory receptors appear to be completely dysfunctional after the early allergic phase, but their function is largely restored after the late phase. The results indicate that dysfunction of autoinhibitory muscarinic M2 receptors might contribute to the strongly enhanced responsiveness to histamine after the early allergic response.
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We investigated the influence of endothelial nitric oxide (NO) on the pulmonary pressor activity of the stable thromboxane A2 analogue, U-46619 (9,11-dideoxy-9 alpha-(methanoepoxy) prostaglandin F2 alpha), in anesthetized open-chest Sprague-Dawley rats (n = 6-9 per group). NO synthase inhibition, as obtained by N omega-nitro-L-arginine methyl ester (L-NAME; 0.63 mg/kg i.v. + 20 mg/kg/h), induced sustained systemic hypertension (mean maximal increase, delta, in mean systemic arterial pressure = 38 +/- 6 mmHg; P < 0.05 vs. vehicle) associated with slight bradycardia (delta heart rate = -42 +/- 8 beats/min; P < 0.05 vs. vehicle) and delayed- (> 30 min) onset pulmonary hypertension (delta mean pulmonary arterial pressure = 10 +/- 3.4 mmHg; P < 0.05 vs. vehicle). In separate experiments, when mean systemic arterial pressure was maximally increased by L-NAME, the difference between mean pulmonary arterial pressure and mean left atrial pressure was greater in L-NAME-treated rats (41 +/- 16% compared to 10 +/- 1% in the vehicle group; P < 0.05), strongly suggesting that spontaneously released NO modulated pulmonary vascular resistance. ⋯ U-46619 in control rats). These results indicate that, under normal circumstances, pulmonary vasomotor tone is regulated by spontaneously released NO. Moreover, pulmonary vascular NO attenuates TP receptor-mediated pressor responses, strongly suggesting that in addition to mediating pulmonary vasoconstriction, TP receptor activation also concomitantly releases NO within the pulmonary vasculature.
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Effects of the local anesthetic, n-butyl-p-aminobenzoate, at a concentration of 100 microM, were investigated using the whole-cell voltage clamp on dorsal root ganglion neurons cultured from neonatal rat in a serum-enriched medium. During current clamp conditions, the drug either increased the firing threshold or blocked tetrodotoxin-sensitive and tetrodotoxin-resistant Na+ action potentials. These actions were reversible. ⋯ The amplitudes of only F3 and S2 currents were reduced by n-butyl-p-aminobenzoate to 24 and 11%, respectively, of their control values. These results show that the local anesthetic has a differential mode of action on the 5 types of Na+ currents, which are apparently present in cultured sensory neurons. This differential action can play an important role in the selective analgesic effect observed after epidural administration of a 10% n-butyl-p-amino-benzoate suspension.
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The influence of substance P 3 (microgram/kg) and (+)-tubocurarine (850 micrograms/kg) on the Bezold-Jarisch reflex in urethane-anaesthetized rats was studied. The Bezold-Jarisch reflex was induced by the 5-HT3 receptor agonist phenylbiguanide (0.3, 1, 3 and 10 micrograms/kg i.v.) and by capsaicin (10 micrograms/kg i.v.). The 5-HT3 receptor antagonist ondansetron (10 micrograms/kg) abolished the phenylbiguanide- but not the capsaicin-stimulated bradycardia, indicating that phenylbiguanide and capsaicin act via different trigger mechanisms (5-HT3 receptor-dependent and -independent, respectively). ⋯ Also, when the phenylbiguanide-induced response was amplified by substance P, it was abolished by ondansetron. (+)-Tubocurarine inhibited the phenylbiguanide-induced bradycardia, but did not affect the capsaicin-stimulated decrease in heart rate. Our results demonstrate that substance P potentiates but (+)-tubocurarine inhibits the 5-HT3 receptor-mediated Bezold-Jarisch reflex. Both effects are probably due to direct influences of the drugs on the 5-HT3 receptors on sensory vagal nerves in the heart.
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The effects of bepridil, a potent antiarrhythmic agent, on the Na+ current (INa) of single guinea-pig ventricular myocytes were studied using the whole-cell patch-clamp technique. Bepridil inhibited INa in a dose-dependent manner without causing any change in the I-V. relationship for INa. Bepridil suppressed INa with Kd values of 342 and 40 microM when cells were clamped to holding potentials of -140 and -90 mV, respectively. 10 microM bepridil shifted the steady-state inactivation curve for INa toward more negative potentials by 7.7 mV (n = 6). ⋯ Recovery of INa from inactivation was retarded (time constant 290 ms) at a holding potential of -140 mV in the presence of 10 microM bepridil. When the onset of INa block was studied in experiments using a double-pulse protocol, bepridil blocked INa by 11.5% after a 4-ms pre-pulse, but significantly blocked it after pre-pulses longer than 16 ms. These results suggest that: (1) bepridil has a higher affinity for the inactivated state than the resting state of Na+ channel; (2) the drug also produces an open channel block; and (3) the drug shows a lidocaine-like fast kinetic block of Na+ current.