Vascular effects of ketanserin (R 41 468), a novel antagonist of 5-HT2 serotonergic receptors.
The serotonergic receptor antagonist 3-(2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl)-2,4-[1H,3H]quinazolinedione Ketanserin (R 41 468) caused a dose-dependent inhibition on the contractile responses to 5-hydroxytryptamine of isolated rat caudal artery, canine basilar, carotid, coronary and gastrosplenic arteries, canine gastrosplenic veins (threshold 10(-10)-10(-9) M) and canine saphenous veins (threshold 10(-8) M). In concentrations up to 2.5 X 10(-5) M, it did not have agonistic properties. From 10(-8) M on, R 41 468 inhibited the contractions of rat caudal arteries and canine saphenous veins caused by postjunctional alpha adrenergic activation. In the rat caudal artery, R 41 468, in concentrations which did not affect the contractile response to norepinephrine, abolished the amplifying effect of low concentrations of 5-hydroxytryptamine on alpha adrenergic activation. In the canine saphenous vein, R 41 468 did not affect the prejunctional inhibitory effect of 5-hydroxytryptamine during sympathetic nerve stimulation. In the perfused guinea-pig stomach, R 41 468 depressed and in certain experiments reversed the vasoconstrictor response to 5-hydroxytryptamine. In isolated perfused kidneys from both normotensive and spontaneously hypertensive rats, R 41 468, in concentrations which did not depress vasoconstrictor responses to exogenous norepinephrine, inhibited those to 5-hydroxytryptamine. The compound caused a dose-related reduction in aortic blood pressure in unanesthetized spontaneously hypertensive rats, which was larger and occurred at lower concentrations, than in control animals. These results demonstrate that R 41 468 is a potent antagonist of the vasoconstrictor effects of 5-hydroxytryptamine, in particular of its amplifying effect on threshold amounts of norepinephrine, which may help explain its antihypertensive properties.
D000316:Adrenergic alpha-Agonists / Q000037:antagonists & inhibitors; D000818:Animals; D001158:Arteries / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000037:antagonists & inhibitors; D004285:Dogs; D006168:Guinea Pigs; D006973:Hypertension / Q000503:physiopathology; D066298:In Vitro Techniques; D007650:Ketanserin; D007668:Kidney / Q000098:blood supply; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D009928:Organ Specificity; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013045:Species Specificity; D013270:Stomach / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects; D014680:Veins / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D010880:Piperidines; D012702:Serotonin Antagonists; D007650:Ketanserin; D002118:Calcium; D009638:Norepinephrine