Effect of azepexole (B-HT 933) on pre- and postsynaptic α-adrenoceptors at peripheral and central nervous sites

Abstract

Azepexole (B-HT 933, 2-amino-6-ethyl-5,6,7,8-tetrahydro-4H-oxazolo-[4,5-d]-azepine dihydrochloride) is chemically different from clonidine but has been characterized pharmacologically as a typical clonidine-like drug. In this study the stimulating effect on presynaptic α-adrenoceptors was shown in pithed rats by a decrease of the tachycardia produced by electrical stimulation within the spinal canal (0.2 Hz; 50 V, 2 msec; 25 sec). The 50% inhibitory dose (D 50) was 236 μg/kg i.v. (clonidine: 4.9 μg/kg). Compared with the effect on postsyanptic α-adrenoceptors in spinal rats (blood pressure increase 30 mm Hg, D 30) this resulted in a pre/postsynaptic activity ratio D 30/D 50 = 2.24 (clonidine 1.9; methoxamine 0.13). The question of wether this relatively high presynaptic activity was responsible for the central nervous sympathoinhibition and vagally mediated baroreceptor reflex facilitation was tested in noradrenaline-depleted cats and dogs. Cats were pretreated with reserpine (5 mg/kg i.p., 18 h) and 2 × 3 mg/kg i.p. α-methyl-p-tyrosine and 2 h); intracisternal injection of 30 μg/kg B-HT 933 decreased significantly the rate of spontaneous sympathetic discharges of splanchnic nerve fibres. Dogs were pretreated with reserpine (5 mg/kg i.p., 18 h) and α-methyl-p-tyrosine (300 mg/kg i.p., 18 h), resulting in radioenzymatically determined noradrenaline concentrations of 2.3 ± 0.6 ng/g, n = 6 as compared with controls, 396 ± 46.8 ng/g, n = 6. Antiotensin i.v. increased blood pressure and reflexly decreased heart rate. In noradrenaline-depleted dogs intracisternal injection of 30 μg/kg B-HT 933 significantly facilitated the angiotensin-induced reflex bradycardia and this facilitation was antagonized by additional intracisternal injection of 50 μg/kg piperoxan. These results clearly demonstrate that both central effects are mediated by stimulation of ‘functional’ postsynaptic α-adrenoceptors.