In vivo and in vitro pharmacological studies of a new hypotensive compound (QF0301B) in rat: comparison with prazosin, a known alpha1-adrenoceptor antagonist.
In this work, we studied the in vivo and in vitro pharmacological effects of the novel compound QF0301B (2-[2-(N-4-o-methoxyphenyl-N-1-piperazinyl)ethyl]-1-tetralone) and compared with those of prazosin. In anaesthetized normotensive rats, both QF0301B and prazosin (0.1-0.2 mg/kg iv) caused a pronounced and prolonged fall in mean arterial blood pressure accompanied by bradycardia. Neither QF0301B nor prazosin (0.2 mg/kg iv) significantly modified the cardiovascular effects of either 5-hydroxytryptamine (serotonin, 5-HT, 75 microg/kg iv) or the selective alpha(2)-adrenoceptor agonist B-HT 920 (0.2 mg/kg iv), but both markedly inhibited the hypertensive effect of noradrenaline (5 microg/kg iv), a nonselective alpha-adrenergic receptor agonist. In isolated rubbed rat aorta rings, QF0301B and prazosin showed marked alpha(1)-adrenoceptor blocking activity, with pA(2) values of 9.00+/-0.12 and 9.75+/-0.14, respectively. In addition, QF0301B reversed and competitively antagonized the inhibitory action produced by clonidine in electrically stimulated rat vas deferens and inhibited the force and rate of contraction in rat isolated atria (pA(2)=5.91+/-0.43), competitively antagonized the contractile effect of 5-HT in rat aorta (pA(2)=6.75+/-0.06) and in rat stomach fundus (pA(2)=7.13+/-0.48) and the contractions induced by histamine in isolated guinea pig longitudinal ileal muscle (pA(2)=7.40+/-0.40). QF0301B showed noncompetitive low action in 5-HT(3), muscarinic and nicotinic receptors, or as Ca(2+) antagonist. These results indicate that a alpha(1)-adrenoceptor blocking lead has been obtained with a new chemical structure and interesting pharmacological properties, which only alpha(1)-adrenoceptor blocking activity seems to be responsible for its cardiovascular effects.
Orallo
Francisco
F
Department of Pharmacology, Faculty of Pharmacy, University of Santiago de Compostela, Campus Universitario Sur, Spain.
Garcia-Ferreiro
Tomas
T
Enguix
Maria Jose
MJ
Tristan
Helena
H
Masaguer
Cristian
C
Ravina
Enrique
E
Cadavid
Isabel
I
Loza
Maria Isabel
MI
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D005748:Gastric Fundus / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D044024:Tetralones / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C479524:2-(2-(n-4-o-methoxyphenyl-N-1-piperazinyl)ethyl)-1-tetralone; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D044024:Tetralones; D011224:Prazosin