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Biomedical subjects

J R Docherty

Publications and source records attributed to J R Docherty.

At least 91 records · Page 5Linked to original sources
PubMed1984

The actions of cirazoline on the rat vas deferens.

The pre- and postsynaptic effects of the alpha 1-agonist cirazoline were assessed in epididymal and prostatic portions of the rat isolated vas deferens. Cirazoline produced a postsynaptic alpha 1-adrenoceptor mediated potentiation of the isometric contraction to single pulse field stimulation in both prostatic and epididymal portions. In epididymal portions, nifedipine (10 microM) greatly attenuated the postsynaptic alpha 1-receptor mediated potentiation of nerve mediated contractions, uncovering a presynaptic inhibitory action of cirazoline . No evidence was found for alpha 2-antagonism by cirazoline . It is concluded that the previously reported antagonism of the presynaptic inhibitory effects of clonidine was due to postsynaptic potentiation of nerve-mediated responses by cirazoline .

Adrenergic alpha-Agonists↗
PubMed1984

An investigation of presynaptic alpha-adrenoceptor subtypes in the pithed rat heart and in the rat isolated vas deferens.

The presynaptic cardio-inhibitory effects of the alpha-adrenoceptor agonists xylazine, cirazoline and amidephrine and their interaction with the antagonists yohimbine and prazosin were investigated in the pithed rat. The presynaptic inhibitory effects of the alpha 2-selective agonist xylazine were antagonized by the alpha 2-antagonist yohimbine but not by the alpha 1-antagonist prazosin, thus demonstrating the lack of alpha 2-adrenoceptor antagonism by prazosin. The presynaptic inhibitory effects of cirazoline were antagonized equally by yohimbine and prazosin, and the presynaptic inhibitory effects of the selective alpha 1-agonist amidephrine were antagonized by prazosin more potently than by yohimbine. In the nifedipine-treated isolated epididymal portion of the rat vas deferens, both xylazine and amidephrine produced concentration-dependent inhibition of the isometric contraction to single pulse electrical stimulation. The alpha 2-antagonist rauwolscine antagonized the inhibitory effects of xylazine but not of amidephrine . It is concluded that inhibitory alpha 1-adrenoceptors, as well as the already established alpha 2-receptors, are present presynaptically in the pithed rat heart and in the rat vas deferens.

Adrenergic alpha-Agonists↗
PubMed1983

An examination of age-related changes in pre- and postsynaptic alpha-adrenoceptors in the rat isolated vas deferens.

Age-related changes in pre- and postsynaptic alpha-adrenoceptors were investigated in prostatic and epididymal portions of vasa deferentia from young adult (2-3 month) and 24 month old Sprague-Dawley rats, using the selective alpha 1-agonist amidephrine and the selective alpha 2-agonist xylazine. Effects of agonists were assessed against the isometric contraction to single pulse field stimulation. There was no change in the pre- or postsynaptic potency of amidephrine, but the presynaptic inhibitory potency of xylazine was significantly reduced in old rats. Therefore, in old rats there is a reduced sensitivity of presynaptic alpha 2- but no change in pre- or postsynaptic alpha 1-adrenoceptors and this may result in increased peripheral sympathetic neurotransmission.

Aging↗
PubMed1983

An investigation of presynaptic alpha-adrenoceptor subtypes in the pithed rat heart.

1 The presynaptic cardio-inhibitory and postsynaptic pressor responses to the alpha-adrenoceptor agonists xylazine and cirazoline, and the interaction with the antagonists yohimbine and prazosin, were examined in the pithed rat.2 Evidence was found to suggest that, as well as the already established pre- and postsynaptic alpha(2)- and postsynaptic alpha(1)-receptors, presynaptic alpha(1)-receptors are present.

Animals↗
PubMed1983

Separation of adrenergic and non-adrenergic contractions to field stimulation in the rat vas deferens.

Adrenergic and 'non-adrenergic' nerve-induced contractions in rat vas deferens were separated pharmacologically. Responses to single stimuli comprised two components, an alpha-noradrenergic component (IIs), dominant in the epididymal portion, and a 'non-adrenergic' component (Is), dominant in the prostatic portion. Is but not IIs was blocked by nifedipine. A combination of adrenergic blockade and nifedipine virtually abolished all components. After cocaine, a third component (IIIs) emerged which was abolished by either adrenergic blockade or nifedipine. The response to trains of stimuli consisted of 'twitch' and 'secondary' components. This biphasic time course was modified by adrenergic blockade or nifedipine to reveal the time course of the 'non-adrenergic' and adrenergic components, respectively: these did not correspond to the 'twitch' and 'secondary' components. A combination of adrenergic blockade and nifedipine virtually abolished the whole response. Prejunctional alpha 2-adrenoceptor-mediated inhibition of the contractile responses could be blocked by selective alpha 2-adrenoceptor antagonists. The adrenergic contractile response demonstrated this 'feed-back' even on the second pulse at 0.5 Hz. Endogenous inhibition of the 'non-adrenergic' contraction required higher frequencies or enhancement of the extracellular concentration of noradrenaline by blockade of its neuronal uptake. Contractile responses to exogenous noradrenaline were abolished by nifedipine, at a concentration that did not affect the adrenergic (IIs) neurotransmission. These results reinforce the view that part of the motor transmission in rat vas deferens is non-adrenergic and allow the disentanglement of the various postjunctional and prejunctional elements contributing to the complex response to a train of stimuli.

Animals↗
PubMed1982

Types and functions of peripheral alpha-adrenoceptors.

Both in the periphery and in the central nervous system, alpha-adrenoceptors can be subdivided into alpha 1-types. alpha 1-Receptors are sensitive to low concentrations of the agonists phenylephrine and methoxamine, and of the antagonists corynanthine and prazosin. alpha 1-Receptors are sensitive to low concentrations of the agonists clonidine and tramazoline, and of the antagonists yohimbine and rauwolscine. Although it has been shown recently that some smooth muscle tissues contain postsynaptic, contraction-mediating alpha 2-adrenoceptors, the smooth muscle of rabbit aorta and pulmonary artery possesses only alpha 1-receptors. In rabbit portal vein, practically all of the effect of exogenous agonists is mediated by alpha 1-receptors. On the other hand, prazosin resistance and rauwolscine sensitivity of the contractile response to transmural sympathetic nerve stimulation indicates that released noradrenaline may act on a small population of postsynaptic alpha 2-receptors as well.

Animals↗
PubMed1982

An examination of the pre- and postsynaptic alpha-adrenoceptors involved in neuroeffector transmission in rabbit aorta and portal vein.

1 The alpha-adrenoceptor agonists, clonidine and xylazine, reduced and the alpha-antagonists, yohimbine an rauwolscine, increased the stimulation-evoked tritium overflow from rabbit aorta and portal vein pre-incubated with [3H]-noradrenaline. 2 Based on an order of agonist potency of clonidine greater than xylazine greater than phenylephrine and antagonist potency of rauwolscine = yohimbine greater than prazosin, the presynaptic receptor mediating these effects is of the alpha 2 type. 3 In the aorta, stimulation-evoked contractions were abolished by prazosin (0.1 micrometers) and potentiated by rauwolscine and yohimbine in concentrations that increased the stimulation-evoked overflow tritium. 4 In the portal vein, prazosin was less potent in reducing, and rauwolscine and yohimbine failed to potentiate, the stimulation-evoked contraction. 5 In experiments in which tissues were pre-exposed to phenoxybenzamine (30 nM) to block some of the postsynaptic alpha-receptors, rauwolscine in concentrations that increased stimulation-evoked tritium overflow, reduced the evoked contraction in the portal vein but not in the aorta. 6 It is concluded that presynaptic alpha 2-autoreceptors are present in both tissues and that the postsynaptic alpha-receptors which mediate nerve stimulation-evoked contractions are alpha 1 in the aorta but a mixture of alpha 1 and alpha 2 in the portal vein.

Animals↗
PubMed1982

Effects of 4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline Hydrochloride (BE 6143) at pre- and postsynaptic alpha-adrenoceptors in rabbit aorta and pulmonary artery.

Strips of rabbit aorta and pulmonary artery were used to study the effects of 4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline hydrochloride (BE 6143 or BDF 6143) on pre- and postsynaptic alpha-adrenoceptors. BE 6143 caused contraction of both preparations with a potency slightly higher than and an intrinsic activity 0.7-0.8 that of phenylephrine. The effect was competitively antagonized by prazosin and rauwolscine. Conversely, BE 6143 antagonized contractile responses to phenylephrine, alpha-methylnoradrenaline and noradrenaline (norepinephrine) with pA2 values of 7.1-7.4. In strips preincubated with 3H-noradrenaline and then superfused, BE 6143 increased the electrically evoked overflow of tritium. Increases by 30% were produced by concentrations of about 1.5 nmol/l; high concentrations failed to change or even reduced the evoked overflow. BE 614 0.01 mumol/l also increased electrically evoked contractions whereas high concentrations were inhibitory. The drug shifted the log concentration-response curve of clonidine for inhibition of evoked tritium overflow to the right in parallel manner; from the shift, a pA2 value of 8.3 was calculated. When presynaptic alpha-adrenoceptors had been blocked by yohimbine or rauwolscine, BE 6143 0.01-10 mumol/l caused a decrease in evoked tritium overflow which was more pronounced, the higher the concentration of yohimbine or rauwolscine. It is concluded that BE 6143 acts as a partial agonist at the postsynaptic alpha 1-adrenoceptors and as an antagonist at the presynaptic alpha 2-receptors of rabbit aorta and pulmonary artery. It has higher affinity pre- than postsynaptically, and its affinity for the presynaptic receptors exceeds that of yohimbine and rauwolscine. In addition, however, BE 6143 inhibits the release of noradrenaline by a non-alpha-adrenergic mechanism.

Animals↗
PubMed1981

Smooth muscle of rabbit aorta contains alpha 1-but not alpha 2-adrenoceptors.

We have investigated the residual contractile response to noradrenaline remaining after phenoxybenzamine (3 x 10(-7) mol/l) in rabbit aorta, since it has been reported that phenoxybenzamine at low doses completely and irreversibly blocks alpha 1-but not alpha 2-adrenoceptors. The contraction elicited by noradrenaline slowly recovered with time after it had been almost abolished by phenoxybenzamine. This residual response was blocked by the alpha 1-selective antagonist prazosin (3 x 10(-8) mol/l) but not by the alpha 2-selective antagonist rauwolscine (3 x 10(-7) mol/l). The results confirm that the smooth muscle of rabbit aorta contains alpha 2-but not alpha 2-adrenoceptors.

Animals↗
PubMed1980

An examination of factors influencing adrenergic transmission in the pithed rat, with special reference to noradrenaline uptake mechanisms and post-junctional alpha-adrenoceptors.

Adrenergic mechanisms were analysed in the pithed rat to determine to what extent the actions of drugs observed in vitro are relevant in situ. The drugs examined were those which are known to block the neuronal or extraneuronal uptake of noradrenaline (cocaine, desipramine and corticosterone) or to be antagonists at post and/or pre-junctional alpha-adrenoceptors (prazosin and yohimbine) together with the antidepressant, mianserin, which has been implicated in several of these actions. These drugs were tested against the arterial diastolic pressor, cardiac chronotropic and vas deferens responses to sympathetic nerve stimulation, to indirect sympathomimetics or to direct sympathomimetics, which were chosen according to whether they were substrates for noradrenaline uptake processes or selective between adrenoceptors. Pressor and cardiac responses to sympathetic nerve stimulation or to intravenous noradrenaline were potentiated by blockade of neuronal uptake but only the pressor effect of noradrenaline was potentiated by blockade of extraneuronal uptake. The effects of the antagonists suggested that the pressor effects of noradrenaline and of sympathetic nerve stimulation result from a combination of activation of alpha 1- and alpha 2-adrenoceptors, but that the effect of noradrenaline had a relatively greater contribution from the alpha 2-adrenoceptors. Mianserin was found to potentiate adrenergic responses at low doses, to produce limited antagonism at post-junctional alpha 1-adrenoceptors in high doses but to have no detectable effect at post-junctional alpha 2-adrenoceptors.

Animals↗
PubMed1980

Comparison of the cardiovascular actions of ORG NC 45 with those produced by other non-depolarizing neuromuscular blocking agents in experimental animals.

The cardiovascular actions of 1- [(2 beta,3 alpha, 16 beta,17 beta)-3,17-bis(acetyloxy)-2-(1-piperidinyl)-androstan-16-yl]-1-methyl-piperidinium bromide (Org NC 45) are reviewed and compared with those of other non-depolarizing neuromuscular blocking drugs. Results obtained in anaesthetized cats and dogs have demonstrated that, in contrast to other neuromuscular blocking drugs, Org NC 45, even in doses 20 times greater than those required for neuromuscular block, has no effects on heart rate, arterial pressure, autonomic ganglia, adrenoceptors or baroreceptors activity. Studies in pithed rats and on guineapig atria have further shown that Org NC 45 has little effect on cardiac muscarinic receptors or on noradrenaline re-uptake mechanisms. These results suggest that Org NC 45 possesses significant advantages over presently used non-depolarizing neuromuscular blocking drugs, since its clinical use should not be associated with cardiovascular side-effects.

Anesthesia, General↗
PubMed1980

The factors influencing the time course of drug action at alpha-adrenoceptors: an investigation of the effects of clonidine in the pithed rat.

1 The time courses of the pre- and post-junctional effects of clonidine were examined on heart rate and blood pressure and on the isometric tension responses of the vas deferens and anococcygeus in situ in the pithed rat. Plasma levels of clonidine were also monitored. 2 The time courses of the pre-junctional inhibition of sympathetic nerve mediated responses in all tissues monitored were related to the plasma levels of clonidine, but the degree of inhibition which was observed varied with the tissue and with the test stimulus employed. 3 The post-junctional agonist effects of clonidine, expecially at low doses, exhibited an initial 'peak' followed by a decline to a lower plateau. This decline of the response was not due to receptor desensitization but was related to a decline in the plasma clonidine level from an initially high value caused by injection of a bolus. 4 The factors determining the time course of drugs' effects in the preparation are discussed and it is concluded that pre- and post-junctional responses should be compared at a point in time after injection of the-drug, at which equilibration has occurred.

Animals↗
PubMed1980

A comparison of the effects of pancuronium bromide and its monoquaternary analogue, ORG NC 45, on autonomic and somatic neurotransmission in the rat.

1 Potentiation by pancuronium of the effects of adrenergic nerve stimulation, previously shown in cardiovascular tissues, was also found in rat anococcygeus and vas deferens, in vitro or in vivo. 2 In the pithed rat, in the presence of pancuronium, pre-junctional alpha-adrenoceptor-mediated feedback inhibition of cardiac sympathetic transmission was uncovered at relatively low stimulation frequencies by phentolamine or yohimbine. 3 The effects of pancuronium and its mono-quaternary analogue Org NC 45 on autonomic and somatic neuromuscular transmission were compared, in the pithed rat. Org NC 45 was less potent than pancuronium at blocking somatic neuromuscular transmission by a factor of 2.1, at blocking cardiac, parasympathetic transmission by a factor of 538 and at potentiating sympathetic transmission by a factor of 33.

Animals↗
PubMed1979

An analysis of some factors influencing alpha-adrenoceptor feed-back at the sympathetic junction in the rat heart.

1 The effects of the selective prejunctional alpha-adrenoceptor antagonist, yohimbine, on the cardioacceleration responses to sympathetic stimulation were examined in the pithed rat. 2 Yohimbine reversed the inhibitory effects of the alpha-adrenoceptor agonist, clonidine, on the stimulation-induced tachycardia. 3 Yohimbine failed to potentiate significantly responses to stimulation in the absence of clonidine when stimulation was applied at the optimal level for cardiac responses (C6-T1). 4 When the pithing rod electrode was moved to T2-T6, cardioaccelerator responses were smaller and yohimbine produced potentiation at frequencies of greater than or equal to 1 Hz. This potentiation was prejunctional since responses to exogenous noradrenaline (NA) were not increased by yohimbine. 5 In the presence of cocaine, potentiation by yohimbine could be shown at the lower frequency of 0.1 Hz. 6 The possible physiological significance of a negative feed-back effect of noradrenaline on cardiac sympathetic nerves is discussed.

Adrenalectomy↗