Dual Effect of Α‐adrenoceptor Antagonists in Rat Isolated Vas Deferens

Abstract

I In rat isolated vas deferens, the isotonic contractile responses to low doses of noradrenaline or adrenaline were antagonized, and those to high doses were potentiated, by yohimbine, piperoxan, phentolamine and tolazoline. Effects due to intermediate doses were not affected, or were potentiated within about 30 min, following an initial inhibition. 2 The a-adrenoceptor blockers thus caused a shift to the right and an increase of the maximum height of log dose-response curves of a-adrenoceptor stimulants. For a given dose of antagonist, the onset was slower for the potentiating than for the blocking effect. 3 The shift to the right induced by piperoxan and yohimbine on dose-response curves of noradrenaline and adrenaline was analysed with the Schild plot, and the slopes obtained, around 0.3, were lower than expected from receptor theory. When cocaine was used to block neuronal uptake, the slopes were close to 1.0. 4 The increase in maximum response to noradrenaline and adrenaline induced by a-adrenoceptor blockers was dependent on the time of incubation, on the dose of antagonist, and on the initial height of responses to the agonist. A less pronounced potentiation was also obtained when acetylcholine was used as agonist. 5 The findings are explained in terms of receptor theory as being due to a dual effect of aadrenoceptor antagonists; competitive antagonism proper, which may be disclosed after blockade of neuronal uptake, and an interaction at a different locus, which results in potentiation of the effects of noradrenaline and adrenaline.

Increase of angiotensin-converting enzyme activity and peripheral sympathetic dysfunction could contribute to hypertension development in streptozotocin-induced diabetic rats

“…[16][17][18] One end of the vas deferens was fixed to the organ chamber, and the other end was attached by means of a silk surgical suture to a force-displacement transducer (model FT 302; CB FT-302, iWORX, NH, USA) connected through a bridge amplifier to a PowerLab recorder (ADInstruments, Castle Hill, NSW, Australia) coupled to a computer. Contractions were recorded and the data stored in Chart 4.2.1 software (ADInstruments, Warwick, USA).…”

“…Cumulative concentration-response curves were made for the adrenergic agonist noradrenaline (NA) (10 −8 −3.10 −4 M), 16 to quantify for possible alterations of receptors, indicated by the respective pharmacological parameters, 19 such as E am (maximum contraction induced by an agonist A) 16 and pD 2 , as the apparent affinity of the agonists, measured as the negative log of ED 50 . 19 Contractions induced by single concentration of the indirect agonist tyramine (10 −4 M) were also measured, to check for changes on the release of endogenous NA.…”

Study of the mechanism of the relaxant action of (+)‐glaucine in rat vas deferens

“…However, (+)-glaucine did not reduce the accumulation of tritium in tissues exposed to [3H]-noradrenaline and, hence, presumably did not significantly inhibit this uptake mechanism. Other mechanisms are therefore implicated, such as a sensitization to the effects of noradrenaline (see Jurkiewicz & Jurkiewicz, 1976).…”

Different mechanisms of action of agents acting on β‐adrenoceptors in barium‐stimulated and electrically‐stimulated rat vas deferens

“…In the latter case, Iso, Ad, and NA elicited a dose-dependent decrease of the amplitude of twitches, without affecting the baseline (Diaz-Toledo & Jurkiewicz, 1980;1990). However, if the concentrations of these agonists were further increased, an undesirable rise in the baseline occurred, due to a well-known concentrationdependent interaction with postsynaptic a-adrenoceptors (Jurkiewicz & Jurkiewicz, 1976); the minimum concentrations of these agonists to start such an increase in the baseline were about 3 x 10-7M for Ad and NA, and 3 x 10-5M for Iso (Diaz-Toledo, 1983). To overcome this problem, aadrenoceptors had to be inactivated in an essentially irreversible manner by a fi-haloalkylamine.…”

“…As an additional control, it was observed that the presynaptic aadrenoceptor agonist, clonidine, was unable to induce inhibitory effects upon electrically-induced twitches, when added up to a concentration of 3 x 10-5M, while in preparations which were not treated with dibenamine, a complete inhibition of twitches was observed with a dose of clonidine about 300 times lower (Diaz-Toledo, 1983). To block neuronal uptake, cocaine (10puM) was added to the bath (Jurkiewicz & Jurkiewicz, 1976), 30min before the beginning of concentrationresponse curves, and maintained thereafter. In relation to extraneuronal uptake, other drugs were not used, since dibenamine is known to be an irreversible blocker of this type of removal mechanism (Furchgott, 1972;Furchgott et al, 1974 (Arunlakshana & Schild, 1959;Furchgott et al, 1974):…”