Antagonism of the antidiarrhoeal effect of clonidine and the lethal effect of noradrenaline in rats: a reliable procedure to evaluate the in-vivo α1- and α2-blocking activity of drugs?

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Abstract
Eight compounds with .alpha.-adrenergic blocking activity were tested for their ability to antagonize the antidiarrheal effect of clonidine (clonidine test) and the lethal effect of noradrenaline [norepinephrine]. Six 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[5-HT S2]-antagonists. The ED50 values (mg/kgkg-1) obtained in the clonidine test were: phentolamine (0.34), RX781094 (0.34), yohimbine (0.51), piperoxan (9.36), butanserin (> 5.0), prazosin (> 10.0), phenoxybenzamine (> 40.0) and ketanserin (> 80.0). In the norepinephrine test the ED50 (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 norepinephrine were: yohimbine (0.020). RX781094 (0.027), piperoxan (0.44), phentolamine (0.58), ketanserin (> 39), prazosin (> 312), and butanserin (> 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 of .alpha.1-receptors, ketanserin being very weak, prazosin and butanserin being very potent componds 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.