SEROTONERGIC EFFECTS OF DOTARIZINE IN CORONARY-ARTERY AND IN OOCYTES EXPRESSING 5-HT2 RECEPTORS

In strips of pig coronary arteries incubated in oxygenated Krebs-bicar bonate solution at 37 degrees C, dotarizine blocked the phasic contrac tions evoked by 5-HT (0.5 mu M) or K+ depolarization (35 mM K+) with a n IC50 of 0.22 and 3.7 mu M, respectively. Flunarizine inhibited both types of contractions with IC50 values of 1.7 mu M for 5-HT and 2.4 nM for K+ responses. In Xenopus oocytes injected with in vitro transcrib ed RNA encoding for 5-HT2A or 5-HT2C receptors, 5-HT (100 nM for 20 s) applied every IO min caused, in both cases, a reproducible inward cur rent through Ca2+-activated Cl- channels (I-Cl). 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 mu M d otarizine and blocked around 62% by 10 mu M Of this drug. The l(Cl) ac tivated either by intracellular injection of inositol 1,4,5-trisphosph ate (IP3) in oocytes or by direct photorelease of Ca2+ in DM-nitrophen -injected oocytes was unaffected by 10 mu M dotarizine. It is conclude d that dotarizine blocks 5-HT2A receptors with a high affinity; the co mpound is devoid of intracellular effects on any further steps of the transduction pathway (i.e., IP3 receptor). Contrary to flunarizine tha t blocks equally well the serotonergic and the K+ vascular responses, dotarizine exhibits 17-fold higher affinity for vascular 5-HT receptor s. These findings might be relevant to an understanding of the mechani sm involved in the use of dotarizine and flunarizine as prophylactic a gents in migraine. (C) 1997 Elsevier Science B.V.