Pharmacological analysis of the haemodynamic effects of 5-HT(1B/D) receptor agonists in the normotensive rat

Abstract

1. The receptors involved in mediating the haemodynamic effects of three 5-HT(1B/D) receptor agonists were investigated in pentobarbitone anaesthetized rats (n = 6-17 per group). 2. 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). 3. A high dose of the 5-HT(1B/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). 4. The selective 5-HT(1A) 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). 5. 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). 6. In bilaterally vagotomized and atropine-treated (1 mg kg-1, i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (-3 ± 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. 7. In conclusion, the 5-HT(1B/D) receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5-HT(1A) receptors, and a consequent reduction in sympathetic outflow.