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M W McCulloch

Publications and source records attributed to M W McCulloch.

At least 19 recordsLinked to original sources
PubMed1985

Evidence for autoinhibition of stimulation-induced noradrenaline release from vasa deferentia of the guinea-pig and rat.

Both phenoxybenzamine and idazoxan increased the efflux of radioactivity elicited by a train of stimulation (4 pulses at 5 Hz) in vasa deferentia preincubated with [3H]-noradrenaline. Phenoxybenzamine increased the release of radioactivity from vasa stimulated with a single pulse, whereas idazoxan did not. The contractile response in both guinea-pig and rat vasa was biphasic: phenoxybenzamine enhanced the initial twitch component and reduced the second component in guinea-pig vasa stimulated with a single pulse or a train of pulses. Idazoxan enhanced both phases of the response of guinea-pig vasa stimulated with a train of pulses but did not affect the response to stimulation with a single pulse. The effect of phenoxybenzamine in increasing the efflux of radioactivity produced by a single pulse of stimulation was abolished by cocaine, indicating that the increase in efflux was due to blockade of noradrenaline uptake. Contractile responses of guinea-pig vasa stimulated with a single pulse in the presence of cocaine were unaltered by phenoxybenzamine, whereas with a train of stimulation the twitch component was enhanced and the second phase was reduced. The effects of phenoxybenzamine or idazoxan on the efflux of radioactivity from rat vasa portions were qualitatively the same as were observed in whole vasa. The contractile response of the prostatic portion consisted of a rapid twitch with a single pulse of stimulation, but was biphasic with a train of stimulation; the response of the epididymal portion was biphasic with either a single pulse or a train of pulses. These results suggest that there is no inhibitory feedback modulation of noradrenaline release with a single pulse of stimulation in guinea-pig and rat vasa deferentia whereas, with a train of stimulation, there is autoinhibition of noradrenaline release.

Adrenergic alpha-Antagonists↗
PubMed1984

The positive inotropic action of isoprenaline is associated with the release of noradrenaline from rabbit, guinea-pig and rat atria.

The actions of isoprenaline (1 microM) were investigated in spontaneously beating isolated paired atria from rabbits, guinea-pigs and rats and in paced left atria from rabbits and rats. Isoprenaline, when applied for a 10 min period to paired atrial from rabbits, guinea-pigs and rats, produced a short-lived release of noradrenaline which appeared to be associated with the positive inotropic actions, rather than with the positive chronotropic actions. Exposures of 3 min to isoprenaline in paired atria in the three species produced increases in force and release of noradrenaline (% of tissue content) in the order: rabbit greater than guinea-pig greater than rat. The increases in rate did not differ between species. Rat atria had the highest resting rates followed by guinea-pig and rabbit atria. In rabbit left atrial preparations which were electrically paced at resting rates of approximately 61, 158 and 334 beats per min there were progressive decreases in release of noradrenaline and positive inotropic actions produced by isoprenaline with increasing rates of pacing. In rat left atrial preparations which were electrically paced at a slower rate, which was similar to that of rabbit paired atria, a greater release of noradrenaline associated with a greater positive inotropic effect was induced by isoprenaline than in rat paired atria. In rabbit paced left atria, an increase in pacing frequency alone produced small increases in force and release of noradrenaline. Verapamil (1 microM) significantly reduced the positive inotropic effect and release of noradrenaline induced by isoprenaline without affecting the positive chronotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Release of noradrenaline from rabbit atria by isoprenaline and histamine.

The release of noradrenaline accompanying positive inotropic and chronotropic actions of isoprenaline and histamine was investigated in rabbit atria in which the transmitter stores were labelled with (2H)-noradrenaline. Propranolol (3 microM) significantly reduced the isoprenaline (1 microM)-induced release of radioactivity and positive inotropic and chronotropic actions. Cimetidine (30 microM) significantly reduced the histamine (25 microM)-induced release of radioactivity and positive inotropic and chronotropic actions. Tetrotoxin (0.9 microM) significantly reduced the release of radioactivity by both isoprenaline and histamine but did not affect the positive inotropic and chronotropic actions of these drugs. The results suggest that conducted action potentials are associated with isoprenaline- and histamine-induced release of noradrenaline and it is possible that the sympathetic nerves are ephaptically stimulated by increased myocardial activity.

Animals↗
PubMed1982

The operation of autoregulatory feedback loops in noradrenergic transmission to cardiovascular effector tissues.

The effects of alpha-adrenoceptor blocking drugs on circulating catecholamines or neurogenically released noradrenaline will depend on their relative selectivity for prejunctional or postjunctional alpha-adrenoceptors. Relatively selective prejunctional alpha-adrenoceptor antagonists will block the inhibitory feedback mechanism at sympathetic nerve terminals, thus increasing transmitter release, which will tend to overcome any postjunctional alpha-adrenoceptor blockade, and responses to sympathetic nerve stimulation will be resistant to blockade. They will have noradrenolytic activity in doses which are not sympatholytic; they may even enhance sympathetic nerve activity. In contrast, selective postjunctional alpha-adrenoceptor blocking drugs will be noradrenolytic and sympatholytic. Prazosin has weak prejunctional alpha-adrenoceptors blocking activity, but is relatively selective for postjunctional alpha-adrenoceptors. Yohimbine is relatively selective for prejunctional alpha-adrenoceptors, and phentolamine is not highly selective. Selectivity for postjunctional alpha-adrenoceptors appears to be a desirable action for an antihypertensive drug of this type.

Adrenergic alpha-Antagonists↗
PubMed1981

Prejunctional alpha-adrenoreceptors subserve a physiological role in cardiac noradrenergic transmission.

1 The question whether prejunctional alpha-adrenoreceptors subserve a physiological role in a noradrenaline-mediated autoinhibitory feedback loop has been studied in guinea-pig isolated atria by stimulating the accelerans nerve and measuring chronotropic responses and the release of radioactivity after labelling transmitter stores with 3H-noradrenaline. 2 Phentolamine (0.3 micrometer) significantly enhanced chronotropic responses when stimulation was with 0.5 Hz for 30 s, but the increase in the release of radioactivity was too small to be measured reliably. When the frequency of stimulation was increased to 4 Hz for 30 s, phentolamine significantly increased the release of radioactivity but the chronotropic response to stimulation was near maximal and phentolamine had no significant effect on it. 3 With prolonged stimulation (12 min) at the lower frequency (0.5 Hz), both the release of radioactivity and the chronotropic response to stimulation were significantly enhanced by phentolamine (3 micrometers). 4 The results support a physiological role for prejunctional alpha-adrenoreceptors in guinea-pig isolated atria.

Animals↗
PubMed1980

Adrenaline activation of prejunctional beta-adrenoceptors in guinea-pig atria.

1. Adrenaline in a concentration of 1.0 microM depressed the stimulation-induced efflux of tritium from the guinea-pig atria incubated with [3H]-noradrenaline, whereas adrenaline in a concentration of 0.5 nM significantly enhanced the stimulation-induced efflux of tritium. This enhancement was blocked by metoprolol (0.1 microM) and thus appears to be mediated by beta-adrenoceptors. 2. In guinea-pig atria incubated with unlabelled adrenaline and then with [3H]-noradrenaline, both catecholamines were released by field stimulation. In such atria metoprolol, practolol, oxprenolol or propranolol decreased the stimulation-induced efflux of tritium. These effects did not occur if the atria were incubated with unlabelled noradrenaline and then with [3H]-noradrenaline, suggesting that neuronally released adrenaline activates prejunctional beta-adrenoceptors. 3. The effect of oxprenolol in decreasing the release of tritium from guinea-pig atria, incubated with unlabelled adrenaline and then with [3H]-noradrenaline was greater in the presence of phentolamine. This may reflect the alpha-adrenoceptor blocking activity of oxprenolol.

Animals↗
PubMed1980

Facilitatory effect of nicotine on adrenergic neuroeffector transmission in the isolated ear artery of the rabbit.

The effects of nicotine were studied on perfusion pressure and vasoconstrictor responses to sympathetic nerve stimulation in the isolated ear artery of the rabbit. Infusions of nicotine (50 micro M) produced a transient increase in perfusion pressure and potentiated responses to nerve stimulation; these effects of nicotine were unaffected by atropine (0.3 micro M) and abolished or significantly reduced respectively by hexamethonium (300 micro M) or mecamylamine (1 micro M). In experiments with ear arteries previously labelled with [3H] noradrenaline an infusion of nicotine (50 micro M) produced a transient increase in tritium efflux and the potentiation of responses to nerve stimulation in the presence of nicotine was accompanied by a statistically significant increase in stimulation-induced tritium efflux; these effects of nicotine were abolished by hexamethonium (300 micro M) or mecamylamine (1 micro M).

Animals↗
PubMed1979

Modulation of sympathetic transmission by neuronally-released dopamine.

1 When rabbits were pretreated with Fla-63, there was a marked inhibition of dopamine-beta-hydroxylase such that, after incubation of the ear arteries with [3H]-dopamine 47.2% of the tritium in the tissue was retained as unchanged dopamine. 2 [3H]-dopamine was released by stimulation of the sympathetic nerves in ear arteries taken from rabbits pretreated with Fla-63 and incubated with [3H]-dopamine. 3 The dopamine antagonists metoclopramide (1.0 microM) and ergometrine (1.0 microM) enhanced the stimulation-induced efflux of tritium in ear arteries taken from rabbits pretreated with Fla-63 and incubated with [3H]-dopamine, but not when the arteries were incubated with [3H]-noradrenaline. 4. These results suggest that if dopamine is present in the transmitter stores, it can be released by stimulation of the sympathetic nerves, and if the amount is adequate, it can activate an inhibitory feedback loop where prejunctional dopamine receptors are present.

Animals↗
PubMed1979

Effects of the histamine H2-receptor blocking drugs burimamide and cimetidine on noradrenergic transmission in the isolated aorta of the rabbit and atria of the guinea-pig.

1 In rabbit aortic strips, concentration-response curves to noradrenaline (NA) were shifted to the right in a parallel and concentration-dependent manner by the alpha-adrenoceptor blocking drug, phentolamine and also by the histamine H(2)-receptor blocking drugs, burimamide and cimetidine. Responses to 5-hydroxytryptamine were not affected by these drugs.2 Burimamide had the properties of a competitive antagonist of noradrenaline, possessing about one-hundredth the potency of phentolamine. Cimetidine was weaker than burimamide and did not fulfil the requirements for competitive antagonism of noradrenaline.3 In guinea-pig isolated atria, in which noradrenergic transmitter stores were labelled with [(3)H]-noradrenaline, phentolamine (3 muM), burimamide (30 muM) and cimetidine (30 muM), in decreasing order of effectiveness, each enhanced stimulation-induced efflux of [(3)H]-noradrenaline, indicating that their blocking effects on prejunctional alpha-adrenoceptors in this tissue are in the same order of relative potency as on postjunctional alpha-adrenoceptors in rabbit aortic strips.4 In the concentrations used (30 muM), neither burimamide nor cimetidine interfered with the neuronal uptake of noradrenaline. Burimamide, and to a much lesser extent, cimetidine, increased the resting efflux of [(3)H]-noradrenaline from guinea-pig atria.5 The effect of clonidine, a partial agonist on prejunctional alpha-adrenoceptors in guinea-pig atria, in increasing stimulation-induced efflux of [(3)H]-noradrenaline when stimulated with 150 pulses at 5 Hz was blocked by cimetidine (30 muM) and reversed by phentolamine (3 muM) and burimamide (30 muM).

Animals↗
PubMed1979

Effects of clonidine, guanfacine and three imidazolidine derivatives related to clonidine on blood pressure, heart rate and gastric acid secretion in the anaesthetized rat.

The effects of histamine, guanfacine, clonidine (2,6-dichlorophenylimino-2-imidazolidine) and the 2,6-dibromo, 2,3- and 2,5-dichloroanalogues of clonidine were assessed on blood pressure, heart rate and gastric acid secretion in the anaesthetized rat, with lumen-perfused stomach. Histamine (100 microgram/kg to 1 mg/kg) and clonidine (250 microgram/kg to 1 mg/kg) each caused acute increases in acid secretion, the magnitude and duration of which were dose-dependent: the secretory effect of clonidine was blocked by cimetidine (2 mg/kg). Histamine produced a short-lasting hypotension with no effect on heart rate, whereas clonidine produced an initial transient rise followed by a prolonged fall in blood pressure accompanied by a marked bradycardia. Guanfacine and the three clonidine analogues all produced cardiovascular effects similar to those of clonidine; however, only the 2,6-dibromo analogue increased gastric acid secretion. These results confirm previous findings using guinea-pig atria that only imidazolidine derivatives with 2,6-substitution in the phenyl ring activate histamine H2-receptors mediating gastric acid secretion in the rat; this is not so for the hypotensive and bradycardic effects of the compounds.

Animals↗
PubMed1978

Modulation of noradrenergic transmission in the rabbit ear artery by dopamine.

1. The effects of dopamine on vasoconstrictor responses to field stimulation of sympathetic nerves and to exogenous noradrenaline were studied in the isolated ear artery of the rabbit. Responses to noradrenaline were unchanged at the start of the dopamine infusions but were enhanced as the infusions continued and also after cessation of the infustion. 2 Dopamine (0.5 muM) reduced the stimulation-induced efflux of tritium from segments of ear artery labelled with [3H]-noradrenaline. The reduction persisted during 65 min of dopamine infusion, after which time the vasoconstrictor responses had generally recovered to 93% of control level. On ceasing the infusion, the stimulation-induced efflux and the vasoconstrictor responses were enhanced. 3 Metoclopramide, haloperidol and ergometrine, each in a concentration of 0.2 muM, prevented the inhibitory effect of 0.5 muM dopamine on the stimulation-induced tritium release, but not the inhibitory effect of 0.5 muM noradrenaline. Phenoxybenzamine (0.2 and 1 muM) and phentolamine (1 muM) prevented the inhibitory effects of both noradrenaline and dopamine on the stimulation-induced efflux, and phentolamine (0.2 muM) prevented the inhibition of the stimulation-induced release by noradrenaline but only partially prevented the inhibitory effect of dopamine on the stimulation-induced efflux. 4 A possible role for dopamine in the modulation of noradrenergic transmission is suggested.

Animals↗
PubMed1977

Effects of pimozide on noradrenergic transmission in rabbit isolated ear arteries.

In the rabbit ear artery both dopamine and noradrenaline inhibit stimulation-induced (S-I) transmitter noradrenaline efflux. Pimozide, which is reported to be a specific dopamine receptor antagonist, was used to further study the effects of dopamine on transmitter efflux. In a concentration of 0.2 micrometer pimozide blocked the inhibition of S-I efflux produced by 0.5 micrometer dopamine but not that produced by 0.5 micrometer noradrenaline. In a concentration of 10 nM, pimozide enhances transmitter release and vasoconstrictor responses to sympathetic nerve stimulation; this may be due to blockade of feedback inhibition of transmitter release by endogenous dopamine. In a concentration of 1 micrometer, pimozide reduced transmitter release and vasoconstrictor responses to sympathetic nerve stimulation. Vasoconstrictor responses to noradrenaline and histamine are antagonized by pimozide in a noncompetitive manner.

Animals↗
PubMed1976

Effects of beta-adrenoreceptor blocking drugs on adrenergic transmission.

The peripheral actions of beta-adrenoreceptor antagonists on adrenergic transmitter mechanisms have been reviewed. In addition to receptor blockade, beta-adrenoreceptor antagonists may in high concentrations inhibit neuronal uptake of noradrenaline; inhibit monoamine oxidase; inhibit the uptake of noradrenaline into transmitter storage vesicles and inhibit the extraneuronal uptake of noradrenaline. High concentrations of beta-adrenoreceptor antagonists (threshold about 30 muM) also release noradrenaline from intraneuronal stores; however, their intrinsic sympathomimetic activity is generally attributed to their partial agonist property. Beta-adrenoreceptor antagonists possess adrenergic neurone blocking activity and quinidine-like or local anaesthetic activity. The existance of a positive feedback mechanism involving prejunctional beta-adrenoreceptors is discussed. It is suggested that bradycardia produced by beta-adrenoreceptor antagonists is due to blockade of the action of circulating catecholamines or of transmitter noradrenaline at cardiac extrajunctional beta-adrenoreceptor sites.

Adrenergic beta-Antagonists↗