title: Study of the in vivo and in vitro cardiovascular effects of four new analogues of ketanserin: implication of 5-HT2A and alpha1 adrenergic antagonism in their hypotensive effect.
abstract: The in vivo and in vitro cardiovascular effects of the novel 5-HT2A/alpha1/H1 antagonist ketanserin analogues QF 0303B, QF 0307B, QF 0311B, QF 0313B were studied in anaesthetized normotensive rats (ANR) and in isolated rubbed rat aorta (IRRA). In ANR, 0.2 mg x kg(-1) i.v. of each compound produced a rapid, remarkable but short-lasting fall in mean arterial blood pressure (MAP) accompanied by bradycardia. All compounds significantly modified the pressor effects induced by 5-hydroxytryptamine (5-HT) and noradrenaline (NA). In IRRA, the compounds inhibited NA- and 5-HT-induced contractions in a competitive fashion. Furthermore, the analogues displayed lower H1-antagonist activity than ketanserin. Compounds tested showed low 5-HT2B affinity and no activity at muscarinic, nicotinic, or 5-HT3 receptors, nor any marked ability to produce smooth muscle relaxation via calcium entry blockade. There is a significant correlation between hypotension reached and inhibition of the 5-HT-induced pressor responses (but not for NA). A certain degree of correlation was observed between hypotensive effect endurance vs. alpha1-adrenoceptor blockade (but not for serotonin). These results indicate that in this series the brief hypotensive activity in ANR is attributed to a 5-HT1A receptor blockade and the duration of the effect is better attributed to an alpha1 adrenoceptor blockade.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Santiago de Compostela, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Orallo
authors.forename: H
authors.initials: H
authors.lastname: Tristan
authors.forename: T
authors.initials: T
authors.lastname: Garcia-Ferreiro
authors.forename: S
authors.initials: S
authors.lastname: De Francisco
authors.forename: C
authors.initials: C
authors.lastname: Masaguer
authors.forename: E
authors.initials: E
authors.lastname: Raviña
authors.forename: J M
authors.initials: JM
authors.lastname: Calleja
authors.forename: I
authors.initials: I
authors.lastname: Cadavid
authors.forename: M I
authors.initials: MI
authors.lastname: Loza
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology*; D001011:Aorta; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007650:Ketanserin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D018340:Receptors, Adrenergic, alpha-1; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D011189:Potassium Chloride; D007650:Ketanserin