The response to distension of the pulmonary vein-left atrial junctions in dogs with spinal section.
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1. A reflex increase in heart rate in response to pulmonary vein distension was observed in decerebrate dogs. This increase could not be totally abolished by treatment with both propranolol and bretylium tosylate. Only bilateral cervical vagotomy abolished the reflex increase in heart rate.2. A significant increase in heart rate occurred in a total of seventeen spinal dogs during pulmonary vein distension.3. In seven spinal animals in which blood pressure was maintained by the continuous infusion of noradrenaline, the increase in heart rate could be totally prevented by cervical vagotomy.4. The time course of the increase in heart rate observed in the spinal animals was rapid, reaching maximum expression within 10 sec of pulmonary vein distension. Such a time course is dissimilar from that associated with pulmonary vein distension in intact or decerebrate dogs in which maximum increases in heart rate take 1-3 min to develop.5. It is concluded that the reflex tachycardia resulting from pulmonary vein distension may be mediated by both an efferent sympathetic and an efferent vagal pathway, the relative significance of each component being dependent upon the prevailing autonomic drive existent in the animal at any specific time. (+info)
Significance of plasma dopamine beta-hydroxylase activity as an index of sympathetic neuronal function.
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Plasma norepinephrine and dopamine beta-hydroxylase (EC 1.14.17.1) activity were measured in rats. Adrenergic neuron blockade with bretylium for 4 hr and ganglion blockade with chlorisondamine for 72 hr lowered plasma norepinephrine. Neither treatment altered plasma dopamine beta-hydroxylase activity. Phenoxybenzamine for up to 48 hr markedly raised plasma norepinephrine and transiently lowered plasma dopamine beta-hydroxylase at 24 hr. Prolonged pharmacological modification of sympathetic nervous activity and plasma norepinephrine were not attended by parallel changes in circulating dopamine beta-hydroxylase activity. Plasma dopamine beta-hydroxylase activity does not appear to be a sensitive index of prolonged alterations in sympathetic neural activity. Norepinephrine in plasma, however, appears to reflect sensitively and accurately the rate of release of the neurotransmitter. (+info)
Effect of drugs on the synthesis of noradrenaline in guinea-pig vas deferens.
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1. Reserpine in vitro (10(-5)M) caused a profound inhibition (>85%) of the formation of both (14)C-catecholamine ((14)C-CA) and (14)C-dihydroxyphenylalanine ((14)C-DOPA) (in the presence of the amino acid decarboxylase inhibitor brocresine) from (14)C-tyrosine in guinea-pig vas deferens. The magnitude of the inhibition was similar for both (14)C-CA and (14)C-DOPA suggesting that the inhibition occurred primarily at the tyrosine hydroxylase step.2. One hour after in vivo treatment with reserpine (1 mg/kg) when tissue stores of noradrenaline (NA) were depleted by 50%, there was a significant inhibition of the formation of (14)C-DOPA. Twenty-four hours after such treatment, when endogenous NA could no longer be detected, synthesis of (14)C-DOPA was indistinguishable from untreated controls. However a 45% inhibition of (14)C-DOPA synthesis from (14)C-tyrosine could be produced in tissues which had been depleted of NA for 24 h or 48 h by the addition of reserpine, 10(-5)M, to the incubation medium.3. Addition of pteridine cofactor, 2-amino-6,7,-dimethyl-4-hydroxy-5,6,7,8-tetrahydropteridine, to the incubation medium in a concentration of 5 x 10(-3)M enhanced the formation of both (14)C-CA and (14)C-DOPA from (14)C-tyrosine in guinea-pig vas deferens. In 52 mM KCl Krebs-Henseleit medium (14)C-CA formation increased from 2.58+/-0.20 (nmol/g)/h to 6.35+/-0.47 (nmol/g)/h whilst (14)C-DOPA formation increased from 5.04+/-0.88 (nmol/g)/h to 11.29+/-0.59 (nmol/g)/h.4. Pteridine cofactor (5 x 10(-3)M) did not reverse the inhibition of (14)C-DOPA formation seen with reserpine (10(-5)M) in previously untreated tissues or in vasa deferentia from animals pretreated with reserpine 1 mg/kg for 24 hours. However, the inhibition did disappear in the presence of pteridine cofactor when treatment with reserpine was prolonged to 48 h and included two doses of reserpine of 2 mg/kg.5. Tyramine (5.8 x 10(-5)M) and bretylium (10(-5)M) in vitro inhibited the formation of (14)C-CA and (14)C-DOPA from (14)C-tyrosine to the same extent in guinea-pig vas deferens again indicating that their major site of action is on tyrosine hydroxylase. The inhibitory effects were reversed by pteridine cofactor.6. Synthesis of (14)C-NA from (14)C-tyrosine in calf splenic nerve was not increased by incubating the tissue in 52 mM KCl-Krebs-Henseleit solution. (+info)
The effect of cold storage on the adrenergic mechanisms of intestinal smooth muscle.
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1. In the guinea-pig taenia caecum, fluorescent adrenergic fibres terminate in both muscle layers. The density of these fibres is greater in the taenia than in the underlying circular muscle layer. The myenteric plexus and individual ganglion cells are also densely innervated by intensely fluorescent adrenergic nerve fibres.2. After three days of cold storage, the specific fluorescence disappeared from all tissue layers of the taenia caecum and smooth muscle fibres. In contrast, cholinesterase active substances were still demonstrable in all tissue layers even after seven days of cold storage but the density of these substances was decreased.3. Cold storage (3-7 days) decreased the tissue noradrenaline content and did not modify the cholinesterase enzyme activity (4 days).4. In cold stored strips, the inhibitory response to nicotine, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) or electrical transmural stimulation was abolished and enhancement of the contractile response occurred. Cold storage also inhibited the inhibitory action of tyramine. Similar results were observed after reserpine treatment.5. In fresh taenia, the relaxation produced by nicotine, DMPP and electrical transmural stimulation was inhibited by adrenoceptor blocking agents and bretylium. In cold storage preparations, contraction produced by these stimuli was blocked by parasympathetic blocking agents and potentiated by anti-cholinesterase. These results indicate that the inhibitory response to these stimulants is mediated by stimulation of the adrenergic nerve system more than by non-adrenergic nerves; the excitatory effect is probably due to stimulation of cholinergic nerves.6. These results suggest that the adrenergic mechanisms of the taenia caecum are more labile in cold storage than the cholinergic mechanisms. Thus, the inhibitory action of cold storage on the relaxation produced by nicotine, DMPP, and transmural stimulation is probably explained by selective physical degeneration of the adrenergic nerve terminal. Also, enhancement of the contractile response to these stimulants in cold stored preparations is explained by the lack of adrenergic inhibitory mechanisms. (+info)
Some observations on the intrinsic nervous mechanism in Hirschsprung's disease.
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Both at rest and during transmural stimulation acetylcholine output from isolated longitudinal and circular muscle strips is significantly higher in the spastic segment than in the proximal dilated bowel. No difference has been found in the tissue concentration of acetylcholine between ganglionic and aganglionic specimens. The pattern of response to transmural stimulation is also similar in the spastic and dilated bowel. However, after cholinergic and adrenergic blockade transmural stimulation fails to induce relaxation in aganglionic specimens, as it does in normal colon. The hypotheses are advanced that the increase in acetylcholine output may be partly dependent on a failure of the intrinsic modulating mechanisms and that an alteration of the non-adrenergic inhibitory neurons may be involved in the motor disturbances of the aganglionic tract. (+info)
Interaction of bretylium and guanethidine on the relaxations of the rat isolated fundal strip preparation, evoked by indirect stimulation.
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1. Isolated rat stomach fundal strip bathed in Krebs solution containing atropine (1 mug/ml), responded to indirect stimulation by a relaxation which was frequency dependent. These responses were blocked by phenoxybenzamine (6 mug/ml) or phentolamine (8 mug/ml).2. Strips obtained from rats previously treated with reserpine did not show relaxation to indirect stimulation. These responses were therefore adrenergic in nature.3. Bretylium (0.1-100 mug/ml) failed to block the relaxations produced by indirect stimulation, in fact relaxations were potentiated by the drug.4. Guanethidine (10 mug/ml) blocked the relaxations induced by indirect stimulation.5. Guanethidine may be taken up by adrenergic nerves actively since its action is not seen at 12 degrees C.6. Bretylium (10 mug/ml) prevented the actions of guanethidine at 37 degrees C. (+info)
Mechanisms regulating the cardiac output response to cyanide infusion, a model of hypoxia.
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When tissue metabolic changes like those of hypoxia were induced by intra-aortic infusion of cyanide in dogs, cardiac output began to increase after 3 to 5 min, reached a peak (220% of the control value) at 15 min, and returned to control in 40 min. This pattern of cardiac output rise was not altered by vagotomy with or without atropine pretreatment. However, this cardiac output response could be differentiated into three phases by pretreating the animals with agents that block specific activities of the sympatho-adrenal system. First, ganglionic blockade produced by mecamylamine or sympathetic nerve blockade by bretylium abolished the middle phase of the cardiac output seen in the untreated animal, but early and late phases still could be discerned. Second, beta-adrenergic receptor blockade produced by propranolol shortened the total duration of the cardiac output rise by abolishing the late phase. Third, when given together, propranolol and mecamylamine (or bretylium) prevented most of the cardiac output rise that follows the early phase. When cyanide was given to splenectomized dogs, the duration of the cardiac output response was not shortened, but the response became biphasic, resembling that seen after chemical sympathectomy. A similar biphasic response of the cardiac output also resulted from splenic denervation; sham operation or nephrectomy had no effect on the monophasic pattern of the normal response. Splenic venous blood obtained from cyanide-treated dogs, when infused intraportally, caused an increase in cardiac output in recipient dogs; similar infusion of arterial blood had no effects. THESE RESULTS SUGGEST THAT THE CARDIAC OUTPUT RESPONSE TO CYANIDE INFUSION CONSISTS OF THREE COMPONENTS: an early phase, related neither to the autonomic nervous system nor to circulating catecholamines; a middle phase, caused by a nonadrenergic humoral substance released from the spleen by sympathetic stimulation; and a late phase, dependent upon adrenergic receptors but not upon sympathetic transmission. (+info)
The effects of bretylium on the subcellular distribution of noradrenaline and on adrenergic nerve function in rat heart.
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1. The effects of bretylium were investigated on the content and subcellular distribution of noradrenaline in the rat heart and on the response to stimulation of the sympathetic nerves supplying the heart.2. In most experiments bretylium produced no change in the total noradrenaline content of the heart but significant changes were produced in the subcellular distribution of noradrenaline.3. Treatment with amphetamine both prevented and antagonized the bretylium-induced adrenergic neurone blockade and most of the accompanying changes in the subcellular distribution of noradrenaline.4. There was a temporal correlation between the bretylium-induced depletion of noradrenaline from the microsomal (P(2)) fraction and adrenergic neurone blockade.5. The onset of adrenergic neurone blockade was also accompanied by an elevation of the noradrenaline content in the low-speed coarse (P(1A)) fraction and in the mitochondrial (P(1B)) fraction; this elevation was prevented by pretreatment with alpha-methyl-p-tyrosine.6. It is concluded that although the elevation of the noradrenaline content of the P(1A) and P(1B) fractions and a depletion of amine from the P(2) fraction are associated with the onset of adrenergic neurone blockade only the depletion from the P(2) fraction is required for its maintenance. This conclusion supports the hypothesis that only a small portion of the noradrenaline content of an adrenergically-innervated organ is associated with the release of transmitter, for when this small ;store' is depleted, by agents like bretylium, the nerves fail to function. (+info)