The extracellular calcium antagonists, nifedipine and verapamil, the mixed extra/intracellular calcium antagonist diazoxide and the intracellular calcium antagonist TMB-8 were studied for their effects on histamine-induced bronchospasm in guinea pigs and on antigen-induced bronchospasms in guinea pigs and rats when administered directly to the tracheobronchial tree. Nifedipine and verapamil inhibited histamine and antigen-induced bronchoconstriction in guinea pigs, and verapamil was effective in preventing antigen-induced bronchospasms in rats. However, using doses of the extracellular blockers which produce these pulmonary effects, significant reduction of blood pressure occurred in both guinea pigs and rats. Diazoxide was inactive against histamine and antigen-induced bronchoconstrictions in guinea pigs. TMB-8 was inactive against histamine and antigen-induced bronchospasm in guinea pigs and rats. These studies demonstrate the antibronchoconstrictor activity of extracellular Ca²⁺ antagonists in guinea pigs and rats, but indicate that intracellular Ca²⁺ antagonists are not antibronchospastic agents in these species in vivo.

No abstract

The purpose of this study was to investigate the pulmonary effects of hyperventilation in anesthetized, mechanically ventilated guinea pigs. Airway resistance (Raw), dynamic lung compliance (C_Dyn), blood pressure (BP), heart rate (HR), arterial blood gases (PaO₂, PaCO₂), pH and arterial plasma HCO₃^–– were measured before and after a 10-min period of hyperventilation produced by increasing the respiratory rate from 60 to 120 breaths/min while maintaining tidal volume at 4 ml. There was a significant increase in R_aw and decrease in C_Dyn lasting up to 20 min after hyperventilation was stopped with no change in BP and HR. PaO₂ was reduced from 109 ± 3 mm Hg before to 53 ± 7 mm Hg at 5 min after hyperventilation. The R_aw and C_Dyn changes were prevented and reversed with the bronchodilators salbutamol and aminophylline indicating that reversible bronchospasms are induced in guinea pigs following a period of hyperventilation. Additional studies demonstrated that the pulmonary mechanical responses to hyperventilation were not changed by vagotomy, ventilation with high CO₂ or by pretreatment with chlorpheniramine, methysergide, atropine, indomethacin, FPL 55712 or calcium-influx blockers. These results indicate that neither vagal reflexes, airway hypocapnia, receptors of histamine, serotonin, acetylcholine nor the products of arachidonic acid metabolism were involved in hyperventilation-induced bronchospasm in guinea pigs.

We examined the effect of the potent and selective GABA-B agonists, baclofen, 3-aminopropylphosphinic acid (3-APPi) and 3-aminopropyl (methyl) phosphinic acid (SKF 97541), and the GABA-B antagonists, 3-aminopropyl (diethoxymethyl) phosphinic acid (CGP 35348), 2-hydroxysaclofen and 3-aminopropylphosphonic acid (3-APPA) on cholinergic and peptidergic contractile responses in the airways of guinea pigs. Electrical field stimulation of the isolated guinea pig trachea produced cholinergic contractions that were inibited by baclofen (EC50 = 5 μmol/l), 3-APPi (EC₅₀ = 0.3 μmol/l) and SKF 97541 (EC₅₀= 0.4 μmol/l). The inhibition by baclofen (30 μmol/l) was reduced by CGP 35348 (IC₅₀ = 65 μmol/l), 2-hydroxysaclofen (IC50 = 273 μmol/l) and 3-APPA (IC50 = 355 μmol/l). The in vivo cholinergic bronchoconstrictor response to vagal nerve stimulation (5 V, 20 Hz, 0.5 ms for 5 s) was attenuated by intravenous baclofen (ED₅₀ = 1.7 mg/kg), 3-APPi (ED₅₀ = 0.9 mg/kg) and SKF 97541 (ED₅₀ = 0.2 mg/kg). The inhibition of vagally induced bronchoconstriction by baclofen was blocked by CGP 35348 (1-10 mg/kg, i.v.) and 2-hydroxysaclofen (10 mg/kg, i.v.). A cholinergic bronchoconstriction induced by CNS stimulation (400 μA, 2 ms, 32 Hz for 5 s) was inhibited by baclofen (ED₅₀ = 5.1 mg/kg, i.v.) and 3-APPi (ED₅₀ = 0.6 mg/kg, i.v.). The effect of baclofen was attenuated by 3-APPA (5 mg/kg, i.v.). A peptidergic bronchoconstriction was evoked by intravenous nicotine (1 mg/kg) in animals treated with ipratropium and phosphoramidon. This bronchoconstriction was inhibited by baclofen (ED₅₀ = 1.2 mg/kg, i.v.) and 3-APPi (ED₅₀ = 0.6 mg/kg, i.v.), and the effect of baclofen was attenuated by 3-APPA (5 mg/ kg, i.v.). Therefore, a GABA-B receptor-mediated inhibition of neurally induced cholinergic and peptidergic airway constriction was demonstrated by using baclofen and the newer GABA-B agonists, 3-APPi and SKF 97541. The effects of baclofen were reduced by GABA-B antagonists including CGP 35348, the most potent antagonist available. These results support the hypothesis that a peripheral GABA-B receptor is an inhibitory neuromodulator in the airways.

1. We examined the effect of exogenously administered tachykinins, neurokinin A (NKA), substance P (SP) and neurokinin B (NKB) on neurally mediated cholinergic bronchoconstrictor responses in guinea-pigs. 2. Electrical stimulation of regions in the dorsal medulla oblongata produced a cholinergic bronchospasm that was not affected by depletion of endogenous tachykinins with capsaicin pretreatment (50 mg kg-1, s.c., 1 week earlier) or by pretreatment with the neutral endopeptidase inhibitor, phosphoramidon (3 mg kg-1, i.v.). 3. Infusion of NKA (0.03-0.1 microgram kg-1 min-1), SP (1 microgram kg-1 min-1) or NKB (1 microgram kg-1 min-1) potentiated the bronchoconstrictor response to electrical stimulation of the dorsal medulla. The doses of tachykinins tested were subthreshold for direct activation of airway smooth muscle, because they were devoid of direct bronchoconstrictor effects. The relative rank order potency for augmentation of centrally induced bronchospasm was NKA > NKB approximately SP, suggesting activation of the NK2 receptor subtype. 4. Infusion of NKA, SP and NKB had no effect on bronchoconstrictor responses to i.v. methacholine (1 microgram kg-1) indicating that a prejunctional neural mechanism of action was responsible for the effects on CNS stimulation-induced bronchospasm. 5. Potentiation of the bronchoconstrictor response to dorsal medullary stimulation produced by infusion of NKA was blocked by pretreatment with the NK2 antagonist SR 48968 (1 mg kg-1, i.v.) but not by the NK1 antagoinst CP 96,345 (1 mg kg-1, i.v.). 6. The potentiation of CNS-induced bronchospasm produced by infusion of SP was partially inhibited by CP 96,345 (1 mg kg-1, i.v.) but not by SR 48968 (1 mg kg-1, i.v.). Treatment with combined SR 48968 (1 mg kg-1, i.v.) and CP 96,345 (1 mg kg-1, i.v.) completely blocked the SP-induced potentiation of CNS-stimulated bronchospasm. 7. These results identify an important modulatory role for NK2 receptors, located at prejunctional sites on parasympathetic nerves, on cholinergic bronchoconstrictor responses in guinea-pigs. 8. It is proposed that substances that release tachykinins from airway sensory nerves, e.g. inflammatory mediators or irritants, may induce hyperresponsiveness of cholinergic bronchomotor responses by activation of NK2-receptors on parasympathetic airway nerves. Furthermore, these studies indicate that endogenous tachykinins are not involved in the maintenance of basal cholinergic bronchomotor tone in the intact guinea-pig.