Pharmacological analysis of the haemodynamic effects of 5‐HT1B/D receptor agonists in the normotensive rat
Authors: Pagniez Fabrice , Valentin Jean‐Pierre , Vieu Sylvie , Colpaert Francis C , John Gareth W 
Published: January 2005

The receptors involved in mediating the haemodynamic effects of three 5‐HT1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats (n=6–17 per group).
Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 μg kg−1; each dose over 5 min) induced dose‐dependent and marked hypotension (−42±6 and −34±4 mmHg at the highest dose, respectively; both P<0.05 vs vehicle: +5±3 mmHg) and bradycardia (−85±16 and −44±12 beats min−1 at the highest dose, respectively; both P<0.05 vs vehicle: +16±6 beats min−1). Zolmitriptan evoked only moderate hypotension at the highest dose (−19±9 mmHg; P<0.05 vs vehicle).
A high dose of the 5‐HT1B/D receptor antagonist, GR 127935 (0.63 mg kg−1, i.v.), failed to antagonize the hypotension and bradycardia evoked by sumatriptan (−35±6 mmHg and −52±19 beats min−1, respectively; both not significant vs sumatriptan in untreated rats), but moderately reduced the hypotension and bradycardia evoked by rizatriptan (−20±5 mmHg and −30±17 beats min−1, respectively; both P<0.05 vs vehicle and vs rizatriptan in untreated rats).
The selective 5‐HT1A receptor antagonist, WAY 100635 (0.16 and 0.63 mg kg−1, i.v.), dose‐dependently attenuated the haemodynamic responses evoked by rizatriptan and sumatriptan, which were almost abolished by the higher dose of WAY 100635 (−4±3 mmHg and −15±8 beats min−1; both not significant vs vehicle and P<0.05 vs rizatriptan in untreated rats). A slight but statistically significant reduction in mean arterial pressure (MAP) persisted at the highest dose of sumatriptan (−13±4 mmHg following the higher dose of WAY 100635; P<0.05 vs vehicle).
In pithed rats with MAP normalized by angiotensin II, rizatriptan failed to induce hypotension or bradycardia (+5±4 mmHg and −6±16 beats min−1, respectively; both NS vs vehicle and P<0.05 vs rizatriptan in untreated rats). Similarly, sumatriptan failed to induce bradycardia in pithed rats (+5±6 beats min−1; not significant vs vehicle and P<0.05 vs sumatriptan in untreated rats), whereas a slight but statistically significant reduction in MAP, compared to controls, occurred at the highest dose (−9±9 mmHg; P<0.05 vs both vehicle and sumatriptan in untreated rats).
In bilaterally vagotomized and atropine‐treated (1 mg kg−1, i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (−31±4 mmHg and −64 ±9 beats min−1, respectively; both P<0.05 vs vehicle and not significant vs rizatriptan in controls) and sumatriptan (−47±8 mmHg and −56±10 beats min−1, respectively; both P<0.05 vs vehicle and not significant vs sumatriptan in controls) were not statistically significantly different from those observed in controls.
In conclusion, the 5‐HT1B/D receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5‐HT1A receptors, and a consequent reduction in sympathetic outflow.

British Journal of Pharmacology (1998) 123, 205–214; doi:10.1038/sj.bjp.0701593