Serotonergic effects of dotarizine in coronary artery and in oocytes expressing 5-HT2 receptors.
In strips of pig coronary arteries incubated in oxygenated Krebs-bicarbonate solution at 37 degrees C, dotarizine blocked the phasic contractions evoked by 5-HT (0.5 microM) or K+ depolarization (35 mM K+) with an IC50 of 0.22 and 3.7 microM, respectively. Flunarizine inhibited both types of contractions with IC50 values of 1.7 microM for 5-HT and 2.4 microM for K+ responses. In Xenopus oocytes injected with in vitro transcribed RNA encoding for 5-HT2A or 5-HT2C receptors, 5-HT (100 nM for 20 s) applied every 10 min caused, in both cases, a reproducible inward current through Ca2(+)-activated Cl- channels (ICl). Dotarizine inhibited the 5-HT2A response in a concentration-dependent manner, with an IC50 of 2.2 nM. In contrast, the 5-HT2C response was unaffected by 1 microM dotarizine and blocked around 62% by 10 microM of this drug. The ICl activated either by intracellular injection of inositol 1,4,5-trisphosphate (IP3) in oocytes or by direct photorelease of Ca2+ in DM-nitrophen-injected oocytes was unaffected by 10 microM dotarizine. It is concluded that dotarizine blocks 5-HT2A receptors with a high affinity; the compound is devoid of intracellular effects on any further steps of the transduction pathway (i.e., IP3 receptor). Contrary to flunarizine that blocks equally well the serotonergic and the K+ vascular responses, dotarizine exhibits 17-fold higher affinity for vascular 5-HT receptors. These findings might be relevant to an understanding of the mechanism involved in the use of dotarizine and flunarizine as prophylactic agents in migraine.
Montiel
C
C
Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
Herrero
C J
CJ
García-Palomero
E
E
Renart
J
J
García
A G
AG
Lomax
R B
RB
D000818:Animals; D001158:Arteries / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005444:Flunarizine / Q000494:pharmacology; D008297:Male; D008845:Microinjections; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D014982:Xenopus laevis
D001559:Benzhydryl Compounds; D002121:Calcium Channel Blockers; D010879:Piperazines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014665:Vasodilator Agents; C083946:dotarizine; D005444:Flunarizine