Selective vasoconstriction by alniditan in the carotid vascular bed of anaesthetized dogs.
In anaesthetized dogs, alniditan or (-)-(R)-N-[3,4-dihydro-2H-1- benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3- propanediamine dihydrochloride, a new compound with 5-HT1-like receptor ligand effects, dose dependently (0.63-80 micrograms/kg i.v.) reduced common carotid arterial blood flow with comparatively little effect on other cardiovascular variables including coronary, mesenteric and renal arterial blood flow, systemic and pulmonary vascular resistance and airway resistance. The potency of alniditan was higher than that of sumatriptan and comparable to that of ergotamine (dose producing a 50% reduction: alniditan = 5.1 micrograms/kg i.v.; sumatriptan = 13.1 micrograms/kg i.v.; ergotamine = 4.6 micrograms/kg i.v.; median values). The reduction of carotid arterial blood flow by alniditan was accompanied by an increase of carotid arterial vascular resistance and correlated with the increase of the difference in oxygen saturation between arterial and jugular venous blood, suggesting a preferential reduction of extracerebral shunt flow by the compound via constriction of arteriovenous anastomoses in the carotid vascular region. The extent and duration of carotid arterial blood flow reductions after alniditan at 5 micrograms/kg i.v. were similar to those after sumatriptan 15 micrograms/kg i.v. but larger/longer after alniditan at 15 micrograms/kg i.v. than after sumatriptan at 15 micrograms/kg i.v. The dose-dependent increase of carotid arterial vascular resistance by alniditan was similar in dogs premedicated daily for 4 days with solvent or active compound (20 micrograms/kg i.v.), indicating absence of tolerance or resetting of sensitivity to the compound.
Department of Cardiovascular and Pulmonary Pharmacology, Janssen Research Foundation, Beerse, Belgium.
A
A
Van de Water
J
J
D'Aubioul
W
W
Van Gerven
K
K
Van Ammel
F
F
De Clerck
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001784:Blood Gas Analysis; D002339:Carotid Arteries / Q000187:drug effects*; D004285:Dogs; D004878:Ergotamine / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D011437:Propylamines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D001578:Benzopyrans; D011437:Propylamines; D011743:Pyrimidines; D014662:Vasoconstrictor Agents; D018170:Sumatriptan; C100822:alniditan; D004878:Ergotamine