Antagonism of the antidiarrhoeal effect of clonidine and the lethal effect of noradrenaline in rats: a reliable procedure to evaluate the in-vivo alpha 1- and alpha 2-blocking activity of drugs?
Eight compounds with alpha-adrenergic blocking activity were tested for their ability to antagonize the antidiarrhoeal effect of clonidine (clonidine test) and the lethal effect of noradrenaline (noradrenaline test). Six of the compounds studied are alpha-adrenergic blocking agents with known alpha 2/alpha 1 selectivity. Two compounds, ketanserin (R 41 468) and butanserin (R 53 393), are 5-hydroxytryptamine S2-antagonists. The ED50-values (mg kg-1) obtained in the clonidine test were: phentolamine (0.34), RX781094 (0.34), yohimbine (0.51), piperoxan (9.36), butanserin (greater than 5.0), prazosin (greater than 10.0), phenoxybenzamine (greater than 40.0), and ketanserin (greater than 80.0). In the noradrenaline test the ED50's (mg kg-1) were: butanserin (0.014), prazosin (0.032), phentolamine (0.59), phenoxybenzamine (1.02), ketanserin (4.69), RX781094 (12.4), piperoxan (21.5), and yohimbine (25.0). The selectivity alpha 2/alpha 1-ratios (ED50 clonidine/ED50 noradrenaline were: yohimbine (0.020), RX781094 (0.027), piperoxan (0.44), phentolamine (0.58), ketanserin (greater than 39), prazosin (greater than 312), and butanserin (greater than 357). These results show that yohimbine and RX781094 are equipotent and relatively selective alpha 2-antagonists; piperoxan and phentolamine block both alpha 1- and alpha 2-receptors at closely related doses; ketanserin, prazosin and butanserin are selective blockers of alpha 1-receptors, ketanserin being very weak, prazosin and butanserin being very potent compounds in this respect. The potent and selective alpha 1-blocking activity of butanserin, combined to its 5-HT S2-antagonism makes butanserin a very interesting experimental drug in view of earlier reported data concerning the amplifying effects between 5-hydroxytryptaminergic and noradrenergic vascular mechanisms.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000930:Antidiarrheals / Q000037:antagonists & inhibitors*; D003000:Clonidine / Q000037:antagonists & inhibitors*; D007928:Lethal Dose 50; D008297:Male; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains
D000317:Adrenergic alpha-Antagonists; D000930:Antidiarrheals; D003000:Clonidine; D009638:Norepinephrine