Abstract
To investigate whether the hypotensive and bradycardiac effects of B-HT 958 (2-amino-6-(p-chlorobenzyl)-4H-5,6,7,8-tetrahydrothiazolo-(5,4-d) azepine) are due to the stimulation of peripheral prejunctional alpha2-adrenoceptors, the selective alpha2-adrenoceptor antagonist idazoxan was given either intravenously (i.v.) or intracerebroventricularly (i.c.v.) to anaesthetized rats before the administration of i.v. B-HT 958. Plasma noradrenaline was used as an approximate index of peripheral sympathetic nervous activity. B-HT 958 350 micrograms kg-1 i.v. caused significant falls in blood pressure and heart rate which were maximal 5 min after dosing (-29.25 +/- 3.2 mmHg and - 52 +/- 6.8 beats min-1 respectively, mean of all control animals). The hypotension and bradycardia were accompanied by significant falls in plasma noradrenaline concentration of 30-40%. Idazoxan 300 micrograms kg-1 i.v. caused a marked, but transient tachycardia and a large sustained rise in plasma noradrenaline concentration. Idazoxan 300 micrograms kg-1 and 1000 micrograms kg-1 i.v. did not prevent B-HT 958-induced falls in mean arterial pressure, heart rate and plasma noradrenaline concentration. Responses to B-HT 958 were unaffected by idazoxan 20 micrograms i.c.v. B-HT 958-induced falls in mean arterial pressure, heart rate and plasma noradrenaline concentration were significantly attenuated by i.v. administration of the dopamine receptor antagonist, sulpiride 300 micrograms kg-1. Sulpiride 10 micrograms and 50 micrograms i.c.v. caused inhibition of B-HT 958 hypotension and bradycardia similar to that of intravenous sulpiride. After i.c.v. sulpiride, B-HT 958 did not cause a significant fall in plasma noradrenaline concentration. A combination of idazoxan 1000 micrograms kg-1 i.v. and sulpiride 300 micrograms kg-1 i.v. did not cause further significant inhibition of B-HT 958 hypotension and bradycardia compared with sulpiride 300 micrograms kg-1 i.v. alone. This combination however had a significantly greater effect in inhibiting B-HT 958 hypotension than had idazoxan 1000 micrograms kg-1 alone, and almost completely blocked the B-HT 958-induced fall in plasma noradrenaline concentration. These results suggest that in the anaesthetized rat the cardiovascular effects of B-HT 958 are due to stimulation of dopamine receptors, probably located within the central nervous system, and not to stimulation of peripheral prejunctional alpha2-adrenoceptors.