Pharmacological analysis of the haemodynamic effects of 5-HT1B/D receptor agonists in the normotensive rat.
1 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). 2 Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 microg 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-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). 4 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). 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 (-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. 7 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.
Pagniez
F
F
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.
Valentin
J P
JP
Vieu
S
S
Colpaert
F C
FC
John
G W
GW
D000818:Animals; D001341:Autonomic Nervous System / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects*; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D010080:Oxazoles / Q000494:pharmacology; D023303:Oxazolidinones; D010275:Parasympathetic Nervous System / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014363:Tryptamines
D010080:Oxazoles; D023303:Oxazolidinones; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D014363:Tryptamines; C089750:zolmitriptan; C093622:rizatriptan; D018170:Sumatriptan