Vascular and cardiac effects of DV-7028, a selective, 5-HT2-receptor antagonist in rats.
The effect of 5HT2A-receptor antagonist DV-7028 (3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro - 2H-pyrido[1,2,-a]-1,3,5-triazine-2,4(3H)-dione maleate on the rat cardiovascular system was evaluated. DV-7028 (0.1 and 1.0 mg/kg), given intravenously, caused a significant, dose-dependent decrease in mean arterial blood pressure in anesthetized normotensive rats. In vagotomized rats, administration of DV-7028 resulted in a reduction of mean blood pressure, but this effect was less prominent than that seen in nonvagotomized rats. Intravenous administration of DV-7028 induced bradycardia, which was almost completely abolished by vagotomy. In pithed rats, bradycardia and hypotension were not demonstrated after DV-7028 administration. In pithed rats, serotonin administered intravenously caused a dose-dependent increase in blood pressure. In this experimental model, DV-7028 inhibited the pressor effects of serotonin at doses of 0.01 and 0.1 mg/kg, which caused neither hypotension nor bradycardia in anesthetized rats. DV-7028 strongly inhibited the pressor effects of serotonin in the isolated perfused hindlegs of the rat (IC50 = 0.032 +/- 0.004 microM) and caused a concentration-dependent, almost parallel shift to the right of the concentration-response curve to serotonin for its pressor effect in the rat perfused tail artery (pA2 value for DV-7028 was 7.92, a slope 0.94). These data demonstrate that DV-7028 exhibits 5-HT2A-receptor antagonistic property in the rat cardiovascular system. Besides this peripheral action, DV-7028, when applied in high doses, exerts hypotension and bradycardia via an unknown site and mechanism.
Pawlak
D
D
Department of Pharmacodynamics, University School of Medicine, Bialastrokystok, Poland.
Adamkiewicz
M
M
Malyszko
J
J
Takada
A
A
Mysliwiec
M
M
Buczko
W
W
D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D003326:Coronary Circulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006614:Hindlimb / Q000187:drug effects / Q000502:physiology; D007275:Injections, Intravenous; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects*; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*; D014628:Vagotomy
D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014227:Triazines; C073727:DV 7028; D016713:Ritanserin; D007650:Ketanserin