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.