Some pharmacological properties of Wy 27127 a more selective alpha 2:alpha 1-adrenoceptor antagonist than idazoxan in vitro.

Wy 27127 and idazoxan were approximately equipotent as antagonists at alpha 2-adrenoceptors as estimated by their ability to block clonidine-induced inhibition of electrically-evoked contractions of the rat isolated vas deferens. Idazoxan was seven times as potent as Wy 27127, as an antagonist at alpha 1-adrenoceptors as indicated by blockade of methoxamine-induced contractions of the rat isolated anococcygeus muscle. Thus, the alpha 2:alpha 1 selectivity ratio, as calculated from these tests was 407 for Wy 27127 and 76 for idazoxan. Wy 27127 and idazoxan were equipotent in enhancing stimulation-evoked overflow of tritium from rabbit isolated pulmonary arteries preloaded with [3H]-noradrenaline as expected for alpha 2-adrenoceptor antagonists. At higher concentrations both compounds reduced the stimulation-evoked contraction of the pulmonary artery but idazoxan was 15 times as potent as Wy 27127 in this respect. Neither compound had marked antagonist actions at 5-hydroxytryptamine (D), muscarinic, presynaptic dopamine or histamine (H1) receptors or at beta 1-adrenoceptors. Thus, idazoxan and Wy 27127 were equipotent alpha 2-adrenoceptor antagonists in vitro, however, the alpha 2:alpha 1 selectivity of Wy 27127 was considerably greater than that of idazoxan by virtue of weaker alpha 1-adrenoceptor antagonism.

The effect of age on the sensitivity of pre- and postsynaptic alpha-adrenoceptors to agonists and antagonists in the rat.

Age-related changes in presynaptic alpha-2 and postsynaptic alpha-1 adrenoceptors have been determined using the rat isolated vas deferens and the thoracic aorta, respectively. The IC50 values of clonidine, B-HT 933 and UK 14,304 for inhibition of the electrically evoked contractions of the vas deferens were significantly higher in 50 week old rats when compared with rats of 5 weeks. Similarly, EC50 values for the contraction of the thoracic aorta by noradrenaline, methoxamine and phenylephrine were significantly increased in 50 week old rats compared with 5 week old rats. No age-related changes in the potency of the selective alpha-2 adrenoceptor antagonists yohimbine and Wy 26392 were detected in the vas deferens. Similarly, there were no age-related changes in the alpha-1 adrenoceptor antagonist potency of indoramin or prazosin on the aorta. The results of the present study suggest that the potency of both alpha-1 and alpha-2 adrenoceptor agonists, as measured by their respective EC and IC50 values decreases with increasing age.

Alpha 2-adrenoceptor antagonism and other pharmacological antagonist properties of some substituted benzoquinolizines and yohimbine in vitro.

Comparison of pA2 values for antagonism of clonidine induced inhibition of the electrically evoked contraction of the rat isolated vas deferens (alpha 2-adrenoceptor) and antagonism of contractions to methoxamine on the rat isolated anococcygeus (alpha 1-adrenoceptor) showed a group of substituted benzoquinolizines (Wy 25309, 26392 and 26703) to be more potent and more selective alpha 2-adrenoceptor antagonists than yohimbine. The benzoquinolizines and yohimbine enhanced stimulation-evoked overflow of tritium from rabbit isolated pulmonary arteries preloaded with [3H]-noradrenaline, as expected for alpha 2-adrenoceptor antagonists. In contrast to the results on the rat vas deferens, yohimbine was more potent than the benzoquinolizines. At higher concentrations all the alpha-adrenoceptor antagonists reduced the stimulation-evoked contraction of the pulmonary artery. The benzoquinolizines were competitive antagonists of 5-hydroxytryptamine on the rat isolated ileum. Wy 25309 showed only weak activity (pA2 = 5.21) whereas Wy 26703 was more potent (pA2 = 7.25). Yohimbine was a potent antagonist of 5-hydroxytryptamine. Wy 26703 was the only compound to have histamine antagonist effects in the guinea pig isolated ileum and to antagonise the chronotropic effect of isoprenaline on the isolated atria of the guinea pig and in both instances activity was weak (pA2 values 5.3 and 5.5 respectively). Yohimbine reduced the spontaneous beating of the atria at 3 X 10(-6) M. No compound at 10(-5) M antagonised acetylcholine on the guinea pig ileum. These novel substituted benzoquinolizines should be useful experimental compounds for the study of alpha 2-adrenoceptor mediated responses.

The effect of temperature on the alpha-adrenoceptor antagonist potency of indoramin and labetalol in the rat perfused mesenteric vascular bed.

The effect of reduction in temperature of perfusion from 37 to 27 degrees C and 20 degrees C on the ability of the adrenoceptor antagonists indoramin and labetalol to block pressor responses to noradrenaline in the perfused mesenteric vascular bed of the rat was examined. The results suggest that in rat mesenteric bed, antagonist potency of both agents is increased at low temperatures.