1 The effect of (R)-a-methylhistamine, a selective H3-histamine receptor agonist, was examined on the neurogenic hypertension and tachycardia that is induced by stimulation of areas in the medulla oblongata of guinea-pigs. Electrical medullary stimulation (32 Hz, 3-5 s trains, 0.5-1.0 ms square pulse, 25-400 juA) produced intensity-dependent increases in blood pressure and a more variable tachycardia.2 (R)-ac-methylhistamine inhibited the hypertension and tachycardia due to submaximal CNS stimulation. The inhibition of hypertension by (R)-x-methylhistamine was dose-dependent (1O-300 tg kg-', i.v.) and was not seen at high intensities of stimulation. 3 (R)-o-methylhistamine (300 ptg kg-', i.v.) did not attenuate the pressor response to adrenaline (1 and 3 fLg kg-', i.v.), indicating that the effect of (R)-x-methylhistamine was not mediated by a postjunctional action on smooth muscle. 4 The inhibition of CNS-induced hypertension by (R)-x-methylhistamine (300 yg kg-', i.v.) was blocked by the H3 antagonists, thioperamide (ID50 = 0.39 mg kg-', iv.), impromidine (ID50 = 0.22 mg kg-, i.v.) and burimamide (ID50 = 6 mg kg-', i.v.). The rank order potency of these antagonists is consistent with activity at the H3B receptor subtype. Chlorpheniramine (30 ptg kg-', i.v.) and cimetidine (3 mg kg-', i.v.) did not antagonize the inhibition of CNS-hypertension by (R)-a-methylhistamine. 5 These results suggest that (R)-a-methylhistamine inhibits sympathetic hypertensive responses in guinea-pigs by activation of prejunctional H3-receptors, possibly located on postganglionic nerve terminals. Furthermore, on the basis of the rank order potency to different H3-antagonists, it appears that the H3B-receptor subtype is involved with H3-receptor responses on vascular sympathetic nerves.

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The CNS depressant effects of H1 antihistamines are promethazine approximately diphenhydramine >> loratadine = placebo. Of the non-sedating antihistamines, loratadine was devoid of adverse cardiovascular effects whereas terfenadine caused a pronounced disruption of the normal ECG, characterized by a torsades de pointes-like effect.

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.

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