Catecholamine uptake blockade in anaesthetized dogs: influence on cardiovascular responses.

The effects of differential and combined catecholamine uptake antagonism on cardiovascular responses of anaesthetized dogs to isoprenaline, noradrenaline, and electrical stimulation of the left ansa subclavia nerve have been studied. Uptake1 inhibition by cocaine HCl (5 mg kg-1 and 1 mg kg-1 every 45 min) enhanced responses to noradrenaline (0.1 to 2.0 micrograms kg-1 i.v.) and sympathetic nerve stimulation (1 to 20 Hz), but did not affect those to isoprenaline. Uptake2 inhibition by metanephrine (40 micrograms kg-1 min-1) enhanced cardiac responses to isoprenaline (0.05 to 1.0 microgram kg-1 i.v.), but did not significantly alter those to noradrenaline or nerve stimulation. Responses to all agonist interventions were increased by the combined administration of cocaine and metanephrine. Cocaine preferentially enhanced the positive chronotropic cardiac response to noradrenaline, but metanephrine did not differentiate between heart rate and contractility. These results have been discussed in the light of the mechanism of drug action involved.     

Catecholamine uptake blockade in anaesthetized dogs: influence on cardiovascular responses

The effects of differential and combined catecholamine uptake antagonism on cardiovascular responses of anaesthetized dogs to isoprenaline, noradrenaline, and electrical stimulation of the left ansa subclavia nerve have been studied. Uptake 1 inhibition by cocaine HCl (5 mg kg^?1 and 1 mg kg^?1 every 45 min) enhanced responses to noradrenaline (0·1 to 2·0 μg kg^?1 i.v.) and sympathetic nerve stimulation (1 to 20 Hz), but did not affect those to isoprenaline. Uptake 2 inhibition by metanephrine (40 μg kg^?1 min^?1) enhanced cardiac responses to isoprenaline (0·05 to 1·0 μg kg^?1 i.v.), but did not significantly alter those to noradrenaline or nerve stimulation. Responses to all agonist interventions were increased by the combined administration of cocaine and metanephrine. Cocaine preferentially enhanced the positive chronotropic cardiac response to noradrenaline, but metanephrine did not differentiate between heart rate and contractility. These results have been discussed in the light of the mechanism of drug action involved.     

Haemodynamic and coronary vascular responses after beta-adrenoceptor blockade in the anaesthetised dog: a comparison of tolamolol with practolol and propranolol

In anaesthetised dogs, the β-adrenoceptor blocking agent tolamolol had approximately ten times the activity of practolol and twice that of propranolol in antagonising the myocardial responses to injected isoprenaline, adrenaline and noradrenaline and to stimulation of the left stellate ganglion. Tolamolol, like practocol was cardioselective amounts which blocked myocardial responses to exogenous catecholamines andtto sympathetic stimulation, it did not block peripheal vasodilatition caused ay isoprenaline, and isoprenaline and adrenaline continued to cause coronary vasodilatation. In contrast, propranolol blocked myocardial, peripheral vascular and coronary vascular responses to isoprenaline to similar degrees. These results imply that the coronary vascular β-adrenoceptors resemble those of the peripheral vasculature. The coronary dilatation due to noradrenaline and stellate ganglion stimulation was generally abolished afterβ-adrenoceptor blockade and in some experiments was converted to a vasoconstriction. β-Adrenoceptor blockade did not affect peak reactive hyperaemia following coronary artery occlusion.     

THE EFFECT OF β-ADRENORECEPTOR ANTAGONISTS ON THE INHIBITION OF PENDULAR MOVEMENTS OF RABBIT ILEUM PRODUCED BY PERIARTERIAL SYMPATHETIC NERVE STIMULATION AND SOME SYMPATHOMIMETIC AMINES

• 1 The effects of propranolol and of the selective β₁ and β₂-adrenoreceptor blocking drugs atenolol and ICI 118,551 were determined on the inhibitory responses of isolated segments of rabbit ileum to noradrenaline, isoprenaline and salbutamol and to periarterial sympathetic nerve stimulation.
• 2 Responses to isoprenaline (0.04–10.24 μM) and salbutamol (1.4–89.6 μM) were blocked by propranolol in concentrations up to 5.0 and 12.8 μM, respectively. Responses to sympathetic nerve stimulation were reduced but responses to noradrenaline (0.03-1.92 μM) were unaffected by propranolol in concentrations up to 10.0 and 5.0 μM, respectively.
• 3 Atenolol in concentrations up to 30.0 μM blocked responses to isoprenaline (0.04-2.56 μM) but did not affect responses to noradrenaline, salbutamol or sympathetic nerve stimulation in concentrations up to 3.0,3.0 and 1.0 μM, respectively. However, when responses to noradrenaline and sympathetic nerve stimulation were reduced by phentolamine (1.0 μM), atenolol then produced further reductions.
• 4 Responses to isoprenaline (0.04-2.56 μM) and salbutamol (1.4–89.6 μM) were blocked by ICI 118,551 in concentrations up to 0.5 μM. Responses to sympathetic nerve stimulation were reduced but responses to noradrenaline were unaffected by ICI 118,551 in concentrations up to 0.01 and 0.3 μM, respectively.
• 5 Salbutamol (0.1 μM.) increased the inhibitory response to sympathetic nerve stimulation and this effect was blocked by ICI 118,551 (0.01 μM).
• 6 It was concluded that blockade of β₂-adrenoreceptors, presumably located on sympathetic nerve terminals, decreases the release of transmitter noradrenaline and that blockade of β₁-adrenoreceptors, presumably located in longitudinal smooth muscle cells, reduces the response to transmitter noradrenaline when α-adrenoreceptors are also blocked.

     

The postnatal development of adrenoceptor responses to agonists and electrical stimulation in rat isolated atria.

1. Isolated right and left atria from rats of ages ranging from newborn to adult were used to measure chronotropic and inotropic responses to noradrenaline, isoprenaline, tyramine, and electrical stimulation of intramural nerves. 2. Right atria from newborn animals showed increases in rate with noradrenaline, isoprenaline, and tyramine which did not differ significantly from those of atria from adults. The ED50 values for the chronotropic actions of noradrenaline and isoprenaline were not significantly different at any age from the values in adult preparations. 3. Paced left atria from newborn rats showed well developed positive inotropic responses to noradrenaline and isoprenaline. Newborn left atria (and those from 1 and 2 week old animals) were supersensitive to noradrenaline but not to isoprenaline. 4. Left atria from newborn animals showed very small inotropic responses to both tyramine and field stimulation of intramural nerves. These responses developed progressively with age over the first three weeks of life. The results are discussed with respect to the development of cardiac beta-adrenoceptors and of cardiac sympathetic innervation.     

Sympathomimetic effects of pancuronium bromide on the cardiovascular system of the pithed rat: a comparison with the effects of drugs blocking the neuronal uptake of noradrenaline.

1. The effects of pancuronium bromide on the cardiovascular system of the pithed rat were examined. Pancuronium had two effects, a short-lasting cardiovascular stimulation following injection and a longer-lasting potentiation of responses to sympathetic nerve stimulation. 2 The initial effect of pancuronium was compared with that of tyramine. The cardioaccelerator but not the pressor responses to both pancuronium and tyramine were significantly reduced following sympathectomy with 6-hydroxydopamine (6-OHDA). 3 The action of pancuronium in potentiating sympathetic nerve responses was compared with that of known blockers of the neuronal uptake of noradrenaline (NA). Pancuronium (1 mg/kg) and cocaine (0.5 mg/kg) potentiated cardioaccelerator and pressor responses to sympathetic stimulation. These effects of pancuronium could be obtained following adrenalectomy and during neuromuscular blockade with gallamine. Pancuronium and uptake blockers potentiated the cardioaccelerator response to NA, reduced the response to tyramine, but did not affect the response to isoprenaline. Pancuronium and uptake blockers potentiated the pressor response to NA, but did not affect the response to tyramine or clonidine. 4 Following sympathectomy with 6-OHDA, pancuronium failed to potentiate cardioaccelerator and pressor responses to NA. 5 These results are discussed in relation to two main cardiovascular effects of pancuronium; an indirect sympathomimetic action and blockade of the neuronal uptake of NA.     

Comparison of noradrenaline and isoprenaline removal in the canine hindlimb and kidney

Because isoprenaline is not a substrate for neuronal uptake (Uptake-1, U-1), the difference in regional removal of isoprenaline from regional removal of the sympathetic neurotransmitter noradrenaline has been proposed as an index of regional U-1 activity. U-1 activity has not been assessed in the kidney, where decreased U-1 may account for increased renal spillover of noradrenaline into plasma in disorders such as essential hypertension. Tracer-labelled noradrenaline and isoprenaline were simultaneously infused intravenously into anaesthetized dogs, and the regional removal of noradrenaline and isoprenaline was measured in the hindlimb and kidney after administration of the U-1 blocker desipramine, hydrocortisone, which inhibits extra-neuronal uptake of noradrenaline (Uptake-2, U-2), or no drug. Hindlimb removal of noradrenaline (51%) exceeded that of isoprenaline (36%). Desipramine abolished this difference by decreasing removal of noradrenaline without affecting removal of isoprenaline. Renal removal of isoprenaline exceeded that of noradrenaline (74% vs 54%) even after U-1 blockade. Hydrocortisone did not affect removal of noradrenaline or isoprenaline in either bed. The results suggest that differences in removal of noradrenaline and isoprenaline reflect U-1 activity in the hindlimb but not in the kidney; U-1 is much more important than U-2 in the regional removal of noradrenaline; and one mechanism of noradrenaline removal in the kidney is by neuronal uptake.     

Effect of (±) dihydroxy ephedrine and (±) dihydroxy pseudoephedrine on adrenergic transmission in mesenteric arteries

1. The effect of (+/-) dihydroxy ephedrine (DHE), (+/-) dihydroxy pseudoephedrine (DHPE) and isoprenaline on the vasoconstrictor responses of the perfused mesenteric arteries of the rat produced by stimulation of their periarterial sympathetic fibres, and in the responses to injected noradrenaline, has been studied.2. DHE and DHPE inhibited the responses to nerve stimulation and increased the responses to injected noradrenaline.3. Isoprenaline slightly decreased the basal perfusion pressure and reduced the responses to both nerve stimulation and injected noradrenaline. Since these effects of isoprenaline were abolished by propranolol, they are presumably mediated by beta-receptors.4. The inhibitory effect of DHE and DHPE on the responses to nerve stimulation was not abolished by propranolol.5. The results suggest that DHE and DHPE impair adrenergic transmission by partially replacing the adrenergic neurotransmitter, thereby acting as a false neurotransmitter.     

EFFECTS OF CA2+ ANTAGONISTS ON CARDIOVASCULAR RESPONSES TO POSTERIOR HYPOTHALAMIC STIMULATION IN THE RAT

The effects of methoxyverapamil or hydralazine on pressor responses to posterior hypothalamic stimulation and injected pressor agents were studied in normotensive male Wistar rats. Methoxyverapamil inhibited both phases of pressor responses to hypothalamic stimulation and pressor responses to injected noradrenaline or angiotensin II. Hydralazine inhibited the secondary phase (due to adrenomedullary catecholamine) and not the primary phase (due to increased sympathetic vasomotor activity) of pressor response to hypothalamic stimulation. However, it inhibited the pressor responses to exogenous noradrenaline or angiotensin II. The data indicate that hydralazine is ineffective in inhibiting the pressor response elicited by noradrenaline endogenously released at the sympathetic nerve endings.     

Post-junctional mechanisms involved in the potentiation of cardiac adrenergic responses by cocaine

Cocaine cardiotoxicity is partly due to sympathetic activation of the heart resulting from inhibition of catecholamine uptake at the sympathetic nerve terminal and possible central sympathetic stimulation and/or inhibition. This study evaluated the role of postsynaptic mechanisms in potentiation by cocaine of cardiac adrenergic responses. Cardiovascular responses (arterial and left ventricular pressure, contractility and heart rate) to increasing doses of noradrenaline and to isoproterenol were obtained in anesthetized cats during a control period, after irreversible alpha-adrenoceptor blockade with phenoxybenzamine (5 mg/kg i.v.), and after cocaine (5 mg/kg, i.v.). Responses to noradrenaline were significantly reduced by phenoxybenzamine with lowering of the maximal rise of all parameters. Cocaine shifted the dose-response curve of noradrenaline to the left and enhanced its maximal effects. Some responses to isoproterenol, which is not taken up by nerve terminals, were also enhanced by cocaine. Pretreatment with chlorisondamine or verapamil prevented the cocaine-induced enhancement of the maximal response to noradrenaline and the response to isoproterenol, but it did not inhibit potentiation of submaximal doses. Lidocaine did not potentiate the response to noradrenaline or isoproterenol. Use of chlorisondamine instead of cocaine potentiated responses to all noradrenaline doses and enhanced the responses to isoproterenol. These results suggest that the potentiation by cocaine of cardiac responses to adrenergic stimuli involves presynaptic mechanisms to block noradrenaline re-uptake, and postsynaptic mechanisms to raise the maximal responses. The latter may result from inhibition of central sympathetic outflow or from activation of cardiac Ca(+) channels, leading to increased cardiac sensitivity to noradrenaline.     

The beta 1-adrenoceptor antagonist, betaxolol, is not released from the heart of the anaesthetized dog during sympathetic nerve stimulation.

1. We investigated the hypothesis that the beta 1-adrenoceptor antagonist, betaxolol, can be accumulated by cardiac sympathetic nerve endings and then released together with noradrenaline during accelerans nerve stimulation. 2. Dogs were chronically treated with betaxolol (1 mg kg-1 daily, s.c.) for 7 days. Twenty four hours after the last dose, there was a significant retention of betaxolol in the heart of these dogs treated chronically with the beta 1-adrenoceptor antagonist. However, during in vivo accelerans nerve stimulation, the concentration of betaxolol in the coronary sinus was not modified, whereas the noradrenaline concentration increased significantly. 3. Chronic betaxolol treatment antagonized the tachycardia induced by electrical stimulation of the cardiac accelerator nerves or by intravenous isoprenaline. However, the tachycardia induced by nerve stimulation was not antagonized to a greater extent than that induced by isoprenaline. 4. These findings are discussed in relation to a similar in vivo study in dogs treated with propranolol, in which the drug was found to be released into the coronary circulation during stimulation of the accelerans nerve.     

Sympatho-adrenal secretion in humans: factors governing catecholamine and storage vesicle peptide co-release *

1 In postganglionic sympathetic neurones and adrenal chromaffin cells, catecholamines are co-stored in vesicles with soluble peptides, including chromogranin A (CgA) and neuropeptide Y (NPY), which are subject to exocytotic co-release with catecholamines. 2 Plasma catecholamine, CgA and NPY responses to stimulators and inhibitors of sympatho-adrenal catecholamine storage and release were measured in humans. Short-term, high-intensity dynamic exercise, prolonged low-intensity dynamic exercise, and assumption of the upright posture, in decreasing order of potency, predominantly stimulated noradrenaline (NA) release from sympathetic nerve endings. Only high-intensity exercise elevated CgA and NPY, which did not peak until 2 min after exercise cessation. Stimulated NA correlated with plasma CgA 2 min after exercise, and with NPY 5 min after exercise. 3 Insulin-evoked hypoglycaemia and caffeine ingestion, in decreasing order of potency, predominantly stimulated adrenaline (AD) release from the adrenal medulla. During insulin hypoglycaemia AD and CgA rose, but NPY was unchanged. Neither NPY nor CgA were altered by caffeine. The rise in CgA after intense adrenal medullary stimulation was greater than its rise after intense sympathetic neuronal stimulation (1.4-versus 1.2-fold, respectively). 4 Infusion of tyramine, which disrupts sympathetic neuronal vesicular NA storage, elevated systolic blood pressure and NA, while NPY and CgA were unchanged. After reserpine, another disruptor of neuronal NA storage, NA transiently rose and then fell; NPY and CgA were unaltered. After the non-exocytotic adrenal medullary secretory stimulus glucagon, AD rose while NA, CgA and NPY did not change. After amantadine, an inhibitor of protein endocytosis, both CgA and fibrinogen rose, while NA and NPY remained unaltered. Neither CgA, NPY, nor catecholamines were altered by the catecholamine uptake and catabolism inhibitors desipramine, cortisol, and pargyline. 5 Human sympathetic nerve contained a far higher ratio of NPY to catecholamines than human adrenal medulla, while adrenal medulla contained far more CgA than sympathetic nerve. 6 It is concluded that peptides are differentially co-stored with catecholamines, with greater abundance of CgA in the adrenal medulla and NPY in sympathetic nerve. Activation of catecholamine release from either the adrenal medulla or sympathetic nerves, therefore, results in quite different changes in plasma concentrations of the catecholamine storage vesicle peptides CgA and NPY. Only profound, intense stimulation of chromaffin cells or sympathetic axons measurably perturbs plasma CgA or NPY concentration; lesser degrees of stimulation perturb plasma catecholamines only. Neither CgA nor NPY are released during non-exocytotic catecholamine secretion.     

Facilitation of noradrenaline release from sympathetic nerves in rat anococcygeus muscle by activation of prejunctional beta-adrenoceptors and angiotensin receptors.

1. Isolated preparations of rat anococcygeus muscle were incubated with [3H]-noradrenaline and the efflux of radioactivity induced by stimulation of intramural sympathetic nerves was used as a measure of release of transmitter noradrenaline. Isometric contractile responses were also measured. 2. Angiotensin I (0.03 microM) and angiotensin II (0.03 microM) produced non-sustained contractile responses and enhanced the stimulation-induced (S-I) effluxes of radioactivity as well as the contractile responses to electrical stimulation. These effects were blocked by the angiotensin II receptor antagonist saralasin (0.03 microM), and the effect of angiotensin I, but not angiotensin II, was blocked by the angiotensin converting enzyme inhibitor captopril (0.1 microm). 3. The findings indicate that there are both pre- and postjunctional receptors for angiotensin II and that angiotensin I is converted to angiotensin II in the anococcygeus muscle preparation. 4. Isoprenaline (0.1 microM) slightly enhanced the S-I efflux of radioactivity, and produced a greater enhancement after neuronal uptake blockade with desipramine (0.03 microm) and alpha-adrenoceptor blockade with phentolamine (1 microM). 5. The facilitatory effect of isoprenaline on S-I efflux of radioactivity was abolished by propranolol (0.3 microM), but was not affected by low concentrations of saralasin (0.03 microM) or captopril (0.1 microM) which abolished the effect of angiotensin I. The findings suggest that isoprenaline acts directly on prejunctional beta-adrenoceptors to enhance S-I noradrenaline release, rather than indirectly by releasing angiotensin II from within the tissue. Higher concentrations of saralasin (0.1 microM) or captopril (5 microM) did block the facilitatory effect of isoprenaline. The significance of this finding is not clear.     

Effects on renal sympathetic axons in dog of acute 6-hydroxydopamine treatment in combination with selective neuronal uptake inhibitors.

1. In anaesthetized dogs, we have investigated the effect on renal responses to sympathetic nerve stimulation of acute treatment with the catecholaminergic neurotoxin 6-hydroxydopamine (2 mg kg-1 i.v.), administered alone or after blockade of neuronal catecholamine uptake pathways for noradrenaline (NA) or dopamine with desmethylimipramine or benztropine, respectively. 2. Under control conditions, renal nerve stimulation caused renal vasoconstriction, reduced glomerular filtration and sodium and water excretion and caused net efflux of NA and dopamine into the renal venous plasma. Two h after administration of 6-hydroxydopamine alone, there was abolition of both functional responses and catecholamine efflux during nerve stimulation. 3. In animals pretreated with desmethylimipramine (1 mg kg-1), 6-hydroxydopamine had no significant effect on functional responses to renal nerve stimulation and nerve-evoked efflux of NA was only moderately reduced. Efflux of dopamine was still markedly reduced by 6-hydroxydopamine, but more variably than occurred without desmethylimipramine treatment. 4. In animals pretreated with benztropine (0.2 mg kg-1), nerve-evoked efflux of dopamine, but not that of NA, was protected against reduction by 6-hydroxydopamine. A higher dose of benztropine (1 mg kg-1) protected efflux of both NA and dopamine against 6-hydroxydopamine. 5. We conclude that acute treatment with a low dose of 6-hydroxydopamine is an effective method of inactivating peripheral sympathetic nerves. The differential effects of desmethylimipramine and benztropine in preserving nerve-evoked efflux of NA and dopamine after 6-hydroxydopamine support the view that these catecholamines originate predominantly from different intrarenal axons. However, neither uptake blocker appears to be completely specific in its actions.     

Mechanism of the antagonism between guanethidine and dexamphetamine

1. The effects of dexamphetamine were studied on the responses of rabbit ileum, rabbit ear artery and sheep spleen to sympathetic nerve stimulation after exposure to guanethidine and in the absence of guanethidine.2. In the absence of guanethidine, dexamphetamine enhanced the responses to sympathetic stimulation and, in the spleen, this was shown to be due to an increase in noradrenaline output. However, the increase in these responses was much less than the increase obtained in preparations treated with guanethidine.3. Cocaine, in a concentration which produced the same effect on noradrenaline uptake as the concentration of dexamphetamine used, was also effective in reversing the adrenergic neurone blocking actions of guanethidine.4. It is suggested that the antagonism between dexamphetamine and guanethidine is due to a reduction in the uptake of guanethidine by the nerve endings rather than to interaction of the two drugs at the receptor site for the adrenergic neurone blocking action of guanethidine.     

Interactions between endothelin-1 and other chronotropic agents in rat isolated atria.

In isolated spontaneously beating right and left atria and in electrically driven left atrium from rat, endothelin-1 increased the rate and force of contraction, but significantly decreased the positive chronotropic and inotropic responses to sympathetic nerve stimulation. The decrease may be partly dependent on the positive cronotropic and inotropic effects of endothelin-1, since other agents with chronotropic activity (noradrenaline, isoprenaline, serotonin and Bay k 8644) also decreased stimulation-induced chronotropic responses. Endothelin-1 caused a significant rightward shift of the linear portion of the log concentration-response curve for the chronotropic actions of noradrenaline and isoprenaline. The changes in the log concentration-response curve were not a consequence of the direct chronotropic effect of endothelin-1, since they were still evident when the chronotropic action of endothelin-1 was offset by carbachol. Furthermore, the chronotropic agent, Bay k 8644, did not shift the linear portion of the log concentration-response curves for noradrenaline and isoprenaline. The mechanism of the effects of endothelin-1 in rat atria is not known, but they were not changed by blockade of alpha-adrenoceptors or of L-type voltage-sensitive Ca2+ channels.     

Influence of neuronal uptake on the contribution of smooth muscle α2-adrenoceptors to vasoconstrictor responses to noradrenaline in SHR and WKY isolated tail arteries

The effects of the selective alpha-adrenoceptor antagonists idazoxan (alpha 2) and prazosin (alpha 1) were examined on responses to exogenous noradrenaline and to sympathetic nerve stimulation in SHR and WKY rat isolated perfused proximal tail artery segments. The influence of inhibition of neuronal uptake with cocaine on the effects of these antagonists was also determined. The following results were obtained: Prazosin (10 nmol/l) was equieffective in antagonising responses to exogenous noradrenaline and sympathetic nerve stimulation in both SHR and WKY arteries and the degree of antagonism was similar in either the presence or the absence of neuronal uptake inhibition. In contrast to prazosin, the effects of idazoxan (100 nmol/l), on both exogenous noradrenaline and sympathetic nerve stimulation were dependent on the degree of inhibition of neuronal uptake. In SHR arteries, the degree of antagonism of responses to exogenous noradrenaline by idazoxan (100 nmol/l) decreased progressively as the concentration of cocaine was increased to 4 and 40 mumol/l; in WKY arteries, even in the absence of cocaine, idazoxan (100 nmol/l) did not antagonise responses to exogenous noradrenaline. In SHR arteries, the responses to sympathetic nerve stimulation were reduced to a lesser extent by idazoxan (100 nmol/l) when the concentration of cocaine was increased to 4 mumol/l than in the absence of cocaine. In WKY arteries, idazoxan (100 nmol/l) reduced the responses to sympathetic nerve stimulation in the absence of cocaine. However, this concentration of idazoxan increased the responses to nerve stimulation in the presence of cocaine. Our results indicate that smooth muscle alpha 2-adrenoceptors are present in SHR tail arteries, both intra- and extrajunctionally.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of adrenaline, noradrenaline and isoprenaline on inhibitory α- and β-adrenoceptors in the longitudinal muscle of the guinea-pig ileum

1. Two preparations, a segment of the ileum and the myenteric plexuslongitudinal muscle preparation, have been used for an analysis of the inhibitory effects of adrenaline, noradrenaline and isoprenaline on the contractor responses of the longitudinal muscle to acetylcholine or to electrical, coaxial or field, stimulation.2. Since the inhibitory effects of adrenaline, noradrenaline and isoprenaline on the acetylcholine-induced contractions were not affected by phenoxybenzamine but were antagonized by propranolol, it is concluded that beta-adrenoceptors are present on the muscle cells.3. The responses to electrical stimulation were suppressed by adrenaline or noradrenaline but only partly inhibited by isoprenaline. Propranolol antagonized the effect of isoprenaline and, to some extent, that of noradrenaline, but scarcely affected the action of adrenaline. Phenoxybenzamine, on the other hand, antagonized most of the effect of adrenaline and, to some extent, that of noradrenaline; it usually potentiated the effect of isoprenaline.4. The output of acetylcholine evoked by electrical stimulation was diminished by adrenaline or noradrenaline but was not affected by isoprenaline. The depressant effect on acetylcholine release was antagonized by phenoxybenzamine but not affected by propranolol; therefore these effects of adrenaline and noradrenaline are mediated by alpha-adrenoceptors.5. It may be assumed that alpha-adrenoceptors in situ are stimulated mainly by circulating adrenaline and possibly noradrenaline and thus cause a prejunctional inhibition at the nerve-smooth muscle junction.     

The effects of acute reserpine administration on the sensitivity of the isolated pacemaker from rat heart to isoprenaline and noradrenaline

The effects of reserpine on the sensitivity of the isolated pacemaker from rat heart to the chronotropic effect of isoprenaline and noradrenaline were studied. A single large dose of reserpine (2m?5 mg kg^?1) administered to rats 24 h before killing induces supersensitivity of the isolated pacemaker to isoprenaline, leaving unaltered the responsiveness of the pacemaker to noradrenaline. Reserpine at the dose of 1m?0 mg kg^?1 did not alter the sensitivity of the pacemaker to the catecholamines. Only the larger dose of reserpine raised the corticosterone plasma level. It is possible that a corticosterone-mediated inhibition of the extraneuronal uptake process is responsible for the supersensitivity to isoprenaline. Large doses of reserpine should not be used in experiments aimed to study cardiac sensitivity to isoprenaline or extraneuronal uptake and metabolism of the catecholamine.     

Alpha- and beta-adrenoceptor-mediated responses of the guinea-pig ileum and the effects of neuronal uptake inhibition

Summary The effects of noradrenaline and isoprenaline were examined on preparations of guinea-pig ileum, in which contractions were induced by three different methods; by transmural electrical stimulation, by exogenous carbachol and by potassium depolarization. Alpha- or beta-adrenoceptor-mediated responses were examined by construction of cumulative concentration-response curves in the presence of propranolol (10^–6 M) and phentolamine (5×10^–6 M) respectively. Stimulation of alpha-adrenoceptors by noradrenaline virtually abolished the twitches from transmural stimulation, but only partially inhibited the carbachol- and potassium-induced contractions. The effects on the last two preparations were attributed to a postsynaptic inhibition at alpha-adrenoceptors on the longitudinal smooth muscle. In the transmurally-stimulated preparation there was an additional pre-synaptic alpha-adrenoceptor-mediated inhibition of cholinergic transmission. The maximum beta-adrenoceptor-mediated inhibition of all three preparations to noradrenaline and isoprenaline was of the same magnitude and attributed only to a post-synaptic action on longitudinal smooth muscle.The predominant post-synaptic beta-adrenoceptor-mediated (carbachol-contracted ileum) and pre-synaptic alpha-adrenoceptor-mediated (transmurally-stimulated ileum) relaxations were significantly (P<0.05) potentiated by the neuronal uptake inhibitor desmethylimipramine. These receptors may therefore be considered to be closely associated with the sympathetic innervation. The effect on the post-synaptic alpha-adrenoceptor-mediated relaxation was equivocal. Additional minor excitatory responses were identified as a direct alpha-adrenoceptor-mediated contractile response to noradrenaline and as a beta-adrenoceptor-mediated potentiation of transmural stimulation by isoprenaline, possibly due to facilitation of cholinergic transmitter release.