The hypotensive effect of BMY 7378 involves central 5-HT_1A receptor stimulation in the adult but not in the young rat

Background

Stimulation of central 5-hydroxytryptamine-1A (5-HT_1A) receptors produces hypotension and bradycardia. We describe BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9 dione) effects in cardiovascular function and [³H] 8-OH-DPAT (8-hydroxy-2-(di-n-propyl-amino) tetralin) binding sites in rat brain of different ages.

Methods

BMY 7378 was administered to anesthetized male Wistar rats (1, 3 and 6 months old) and blood pressure and heart rate were continuously recorded. Saturation of [³H] 8-OH-DPAT binding to 5-HT_1A sites in brain membranes was determined.

Results

Basal diastolic blood pressure increased with age, 85 ± 2, 106 ± 3, and 113 ± 2 mmHg for 1-, 3- and 6-month-old rats, respectively (p <0.05 among groups). BMY 7378 induced significant dose- and age-dependent hypotension. The selective 5-HT_1A receptor antagonist, WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexanecarboxamide), antagonized BMY 7378 effects in 6 month-old but not in younger rats. [³H] 8-OH-DPAT binding sites decreased in hippocampi and brainstem with maturation.

Conclusions

Data suggest that BMY 7378 is a hypotensive agent in the rat, but that its actions are mediated, in part, by central 5-HT_1A receptor stimulation in the adult and by a nonserotonergic mechanism in the young rat.

Key words: 5-HT_1A Receptors, BMY 7378, WAY 100635, Anesthetized rats, Blood pressure, Aging