Characterization of alpha-adrenoceptors participating in the central hypotensive and sedative effects of clonidine using yohimbine, rauwolscine and corynanthine.

The central alpha-adrenoceptors responsible for mediating the clonidine-induced central hypotension in anaesthetized cats and sedation in mice have been characterized according to their sensitivities to the alpha-adrenoceptor antagonist yohimbine and its two diastereomeric congeners rauwolscine and corynanthine. Yohimbine and rauwolscine (1-10 microgram/kg) dose-dependently antagonized the central hypotensive response to clonidine (1 microgram/kg) applied 15 min later. Greater amounts of corynanthine (30-100 micrograms/kg) had to be administered to diminish the central depressor effect of clonidine. In these studies the drugs were infused via the left vertebral artery. The prolongation of the hexobarbitone-induced loss of the righting reflex in mice by clonidine (0.3 mg/kg, i.p.) was inhibited by previous treatment with yohimbine and rauwolscine (0.04-5 mg/kg, i.p.) in a dose-dependent manner, but not by corynanthine. Binding experiments with rat isolated cerebral membranes demonstrated the higher affinity of yohimbine and rauwolscine for the [3H] clonidine- than for the [3H]prazosin-specific binding sites. The reverse was found for corynanthine. The relative potencies of yohimbine, rauwolscine and corynanthine in inhibiting these central effects of clonidine are comparable to their order of efficacies in blocking peripheral alpha 2-adrenoceptors. Accordingly, clonidine-induced central hypotension and sedation are mediated by alpha 2-adrenoceptors.

Possible subdivision of postsynaptic alpha-adrenoceptors mediating pressor responses in the pithed rat.

Additional evidence has been obtained indicating a possible subclassification of postsynaptic alpha-adrenoceptors into alpha 1 - and alpha 2 -subtypes. The pressor responses to the alpha-adrenoceptor agonists L-phenylephrine and guanfacine were quantified after i.v. administration to pithed rats. The alpha-sympatholytic drug yohimbine (1 mg/kg) displaced both dose-response curves to the right, but the effect was greatest for guanfacine. After prazosin (0.1 mg/kg) a 53-fold shift to the right was noticed for the dose-response characteristic of L-phenylephrine. Prazosin antagonized the effect of only the higher doses of guanfacine. The findings indicate that L-phenylephrine and prazosin preferentially interact with alpha 1 -adrenoceptors as agonist and antagonist, respectively. Yohimbine proved less selective than prazosin, but preferentially blocks postjunctional alpha 2 -adrenoceptors in the vascular wall. The results obtained with guanfacine may be interpreted to indicate that this drug acts on alpha 2 -adrenoceptors at lower doses and additionally stimulates alpha 1 -adrenoceptors at higher ones. Preliminary findings with corynanthine and rauwolscine support this interpretation.

Expert systems integrated with information systems.

Amongst the users of the AIDA applications there is a rapidly growing interest in the use of expert systems, not as independent systems, but as logical extensions of their already existing information systems. In this paper a prototype system (IDEA) will be described that consists of a set of utilities for the construction of an expert system within the context of an AIDA application. Although IDEA does not excel in sophisticated knowledge representations nor in search strategies (the development of which was not our primary concern) it is able to demonstrate that the facilities provided by AIDA together with the IDEA facilities result in an expert system which is characterized by a high degree of integration with the already operational information system.

Inhibition of R 28935- and R 29814-induced hypotension by prazosin in anaesthetized normotensive rats.

The intravenous administration of erythro 1-(1-[2-(1,4-benzodioxane-2-yl)-2-hydroxyethyl]-4-piperidyl)-2-benzimidazolinone R 28935) and the threo from R 29814 to anaesthetized normotensive rats showed a dose-dependent decrease in mean arterial pressure. Previous (-1 hr) intraperitoneal (0.1 mg/kg) as well as subcutaneous (0.03 mg/kg) treatment with the alpha 1-adrenoceptor blocking drug prazosin antagonized the hypotensive responses to R 28935 and R 29814. The selective antagonist of alpha 2-adrenoceptors yohimbine (0.5 mg/kg) was ineffective. On the other hand, the hypotensive action of clonidine was hardly affected by this prazosin treatment, whereas yohimbine now significantly impaired it. R 28935 and R 29814 showed no direct alpha-adrenoceptor stimulating properties and were moderately active in inhibiting the pressor response to (-)-phenylephrine in pithed normotensive rats when compared with phentolamine and prazosin. The results confirm and extend previous findings in cats. It is concluded that in some way central alpha 1-adrenoceptors are involved in the hypotensive mechanism of R 28935 (R 28914). However, central alpha 1-adrenoceptors are probably not the common sites of interaction, since any alpha 1-adrenoceptor-stimulating potency is lacking for R 28935 (R 29814) and their (moderate) affinity for alpha 1-adrenoceptors bears no relationship to their hypotensive activity.