Liberation Of Noradrenaline Research Articles

Tumor Neurobiology and the War of Nerves in Cancer.

Nerves are emerging regulators of cancer progression. Cancer cells induce the outgrowth of nerves in the tumor microenvironment through the release of neurotrophic factors, and in return nerves liberate neurotransmitters that activate cancer growth and dissemination. Although sympathetic nerves drive tumor angiogenesis via the liberation of noradrenaline, sensory and parasympathetic nerves stimulate cancer stem cells. Interestingly, recent evidence indicates that parasympathetic nerves can eventually inhibit tumor progression, suggesting a yin-yang type of regulation of cancer by nerves. From a broader perspective, the question of a higher level of control of cancer development by the central nervous system should be raised. SIGNIFICANCE: Nerves are emerging regulators of cancer initiation, progression, and metastasis. Here, we review the evidence to date and explore the basic and clinical ramifications of these findings.

Beta-adrenoceptor activation plays a role in the reverse rate-dependency of effective refractory period lengthening by dofetilide in the guinea-pig atrium, in vitro.

1. Blockers of the rapid component of the delayed rectifier potassium current (I(Kr)) prolong cardiac action potential duration (APD) and effective refractory period (ERP) in a reverse rate-dependent manner. Since activation of beta-adrenoceptors attenuates prolongation of APD evoked by I(Kr) blockers, rate-dependent neuronal noradrenaline liberation in the myocardium may contribute to the reverse rate-dependent nature of the effects of I(Kr) blockers. In order to test this hypothesis, we studied the effects of dofetilide, a pure I(Kr) blocker, on ERP after activation or blockade of beta-adrenoceptors and after catecholamine depletion in guinea-pig left atrial myocardium paced at 3, 2 and 1 Hz, in vitro. 2. Dofetilide (100 nM) lengthened ERP in a reverse rate-dependent manner in the left atrial myocardium of guinea-pigs. Strong activation of beta-adrenoceptors using 10 nM isoproterenol abolished the dofetilide-induced lengthening of ERP at all pacing rates. 3. Blockade of the beta-adrenoceptors with metoprolol (1 micro M), atenolol (3 micro M) or propranolol (300 nM) increased the dofetilide-evoked prolongation of ERP at 3 and 2 Hz, but not at 1 Hz. As a consequence, metoprolol attenuated while propranolol and atenolol fully eliminated the reverse rate-dependent nature of the dofetilide-induced ERP lengthening. In catecholamine-depleted atrial preparations of the guinea-pig (24 h pretreatment with 5 mg kg(-1) reserpine i.p.), the effect of dofetilide on ERP was not frequency dependent, and propranolol did not alter the effects of dofetilide. 4. In contrast to results obtained in guinea-pig atrial preparations, propranolol failed to change the reverse rate-dependent effect of dofetilide on ERP in the right ventricular papillary muscles of rabbits and guinea-pigs. 5. As an indication of the functional consequences of rate-dependent noradrenaline liberation, propranolol decreased twitch tension at 3 and 2 Hz but not at 1 Hz in the atrial myocardium of control guinea-pigs, whereas no such effect was detected in catecholamine-depleted atrial preparations. Propranolol failed to change contractility of ventricular myocardium in guinea-pigs and rabbits. 6. It is concluded that rate-dependent noradrenaline release and the ensuing beta-adrenoceptor activation contributed to the reverse rate-dependent nature of ERP prolongation caused by I(Kr) blockers in isolated guinea-pig atrial myocardium.

Prueba farmacológica aguda con clonidina en el temblor de pacientes con enfermedad de Parkinson

Idiopathic Parkinson's disease has a prevalence of 1/1,000 and in 70-75% of these patients tremor is the commonest symptom. Of all the typical symptoms of this disease, the tremor is the most difficult to control. It is therefore necessary to seek drugs to solve this serious problem. To evaluate the usefulness of clonidine in the acute treatment of resting and postural tremor in patients with idiopathic Parkinson's disease. Acute pharmacological test (administration of 0.3 mg of clonidine chlorhydrate intramuscularly). The evaluation was done using a clinical protocol before administration and 30, 60, 120 and 240 minutes afterwards. Statistical comparison was done by variance analysis, taking a value of p < 0.0025 as significant. We included 28 patients (15 men and 13 women) of an average age of 66.9 years, and average duration of the disease of 5.53 years. Diagnosis followed the strict criteria of UKDDDSBB. There was no difference in the evaluations before and after the first dose of L-dopa. For both types of tremor, from 60 minutes onwards there were significant differences, with the maximum 120 minutes after administration (p < 0.0001). Clonidine is useful in the acute treatment of postural and intention tremor in patients with idiopathic Parkinson's disease. Its action is that of reducing the liberation of noradrenaline, synergically with the exciting dopaminergic system. It also seems to reduce the activity of spontaneous discharge at both thalamic and cortical levels.

Effects of acutely raising intracranial pressure on cardiac sympathetic efferent neuron function

To determine whether acutely raising intracranial pressure modifies the function of cardiac efferent autonomic neurons. The effects of suddenly raising intracranial pressure above systemic vascular pressure on heart rate, left atrial and left ventricular chamber pressures, as well as right and left ventricular intramyocardial pressures, were studied following removal of the adrenal glands from the circulation. Cardiac effects induced by systemic administration of nicotine, tyramine or isoproterenol were investigated before and after raising intracranial pressure: (1) in 9 dogs with neurally intact hearts in which cardiac release of catecholamines and intrinsic cardiac neuronal activity were studied; (2) in another 8 dogs in which intrathoracic autonomic neurons were disconnected from central neurons; (3) in another 8 dogs after decentralizing intrathoracic sympathetic but not parasympathetic neurons; (4) in 2 animals after decentralizing intrathoracic parasympathetic, not sympathetic neurons. Increasing intracranial pressure in neurally intact preparations induced ventricular augmentation followed by depression such that after 12 min of cerebral ischemia left ventricular systolic pressure was 62 +/- 5 mmHg. Isoproterenol and tyramine augmented right ventricular inotropism similarly before and after raising intracranial pressure, their effects on left ventricular systolic pressures being reduced secondary to the systemic vascular hypotension. Although nicotine excited intrinsic cardiac neurons similarly before and after raising intracranial pressure, it failed to enhance cardiac liberation of noradrenaline after compared to before raising intracranial pressure. Nicotine-induced ventricular augmentation was obtunded after brain death despite the fact that ventricular myocytes underwent no detectable histological changes. In contrast, nicotine induced similar cardiac augmentation before and after raising intracranial pressure when intrathoracic autonomic neurons or when intrathoracic sympathetic, not parasympathetic neurons, were decentralized. Cardiac sympathetic efferent neuronal function is obtained by acutely raising intracranial pressure.

Contrast Medium-Induced Vasoconstrictions

Angiographic contrast media (CM) may cause both vasodilatation and vasoconstriction. This study evaluates a contrast medium-induced vasoconstriction that occurs when isolated arteries are exposed directly to a CM. Segments of rabbit coronary arteries were mounted in tissue baths containing buffer solution. During the experiments the buffer solution was exchanged with iohexol iso-osmolar with plasma, which caused a temporary vasoconstriction of the vessel segments. The constriction did not depend on the degree of oxygenation of iohexol. The endothelium was not involved in the vasoconstriction. Prazosin slightly decreased the vasoconstriction and a small part of the constriction might thus depend on liberation of norepinephrine by iohexol. The constriction was totally inhibited by the calcium antagonist nifedipine, while it was augmented by addition of low concentrations of KCl to ihoexol. It is concluded that the otherwise safe CM iohexol causes vasoconstriction in vitro by depolarizing the smooth muscle cells and the nerve terminals in the vessel wall.

Differences of the electrical and nicotinic receptor stimulation-evoked liberation of norepinephrine from chicken sympathetic neurons in culture: Possible involvement of different pools of the transmitter

We studied the release of [3H]norepinephrine from chicken sympathetic neurons in culture evoked by nicotinic and electrical stimulation with an intention to establish functional identity or nonidentity of the two stimuli in investigations of neurotransmitter release. Nicotinic stimulation evoked extracellular calcium dependent release of [3H]norepinephrine and the rise of intracellular calcium concentration. The release was completely blocked by nicotinic antagonists hexamethonium (100 mumol/l) and mecamylamine (10 mumol/l), and decreased by tetrodotoxin (0.3 mumol/l) and omega-conotoxin (0.1 mumol/l) to 17% and 27%, resp. The intracellular calcium response was decreased by nicotinic antagonists and tetrodotoxin, but not changed by omega-conotoxin. The electrical stimulation-evoked release was blocked by both tetrodotoxin and omega-conotoxin, and decreased by previous electrical, but not nicotinic, stimulation. The differential sensitivity to omega-conotoxin and tetrodotoxin,and the inability of nicotinic stimulation to decrease the liberation by following electrical stimulation may suggest the mobilization of different pools of the transmitter.

Contrast Medium-Induced Vasoconstrictions

Angiographic contrast media (CM) may cause both vasodilatation and vasoconstriction. This study evaluates a contrast medium-induced vasoconstriction that occurs when isolated arteries are exposed directly to a CM. Segments of rabbit coronary arteries were mounted in tissue baths containing buffer solution. During the experiments the buffer solution was exchanged with iohexol iso-osmolar with plasma, which caused a temporary vasoconstriction of the vessel segments. The constriction did not depend on the degree of oxygenation of iohexol. The endothelium was not involved in the vasoconstriction. Prazosin slightly decreased the vasoconstriction and a small part of the constriction might thus depend on liberation of norepinephrine by iohexol. The constriction was totally inhibited by the calcium antagonist nifedipine, while it was augmented by addition of low concentrations of KCl to ihoexol. It is concluded that the otherwise safe CM iohexol causes vasoconstriction in vitro by depolarizing the smooth muscle cells and the nerve terminals in the vessel wall.

Modulatory effects of noradrenaline on the spike activity of cat motor cortex neurons under conditions of skin electrostimulation and action of extra stimuli

Effects of iontophoretic application of ephedrine (an indirect adrenomimetic that evokes noradrenaline liberation) and obsidane (a blocker of β-adrenoreceptors) on extra stimulus-related modifications of evoked unit spike activity in cortical field 4 were studied in chronic experiments on cats. Neuronal responses were evoked by skin electrostimulation (SES) of extremities; a flow of air blowing on the muzzle 1.0 sec before SES was used as the extra stimulus. In most cases, the SES-evoked unit activity was depressed by ephedrine application, whereas obsidane enhanced it. Extra stimulus-related depression of the SES-evoked responses was removed by obsidane but it did not change or become even more pronounced during ephedrine applications. It is concluded that depressive effects caused by the extra stimulus on the SES-evoked responses of cortical neurons are essentially determined by noradrenergic mechanisms.

Protective effects of bradykinin on the ischaemic heart: implication of the B1 receptor.

1. We studied the role of bradykinin (BK) and its active metabolite Des-Arg9-BK on noradrenaline release in association with the incidence of ventricular arrhythmias at reperfusion of the ischaemic myocardium. 2. Experiments were performed in Langendorff perfused isolated hearts of rats subjected to 30 min no flow followed by 5 min reperfusion. The electrocardiogram was monitored continuously and noradrenaline was measured in the effluent as well as in the myocardial tissue. 3. In untreated hearts, cumulative noradrenaline overflow following global ischaemia reached 226 +/- 35 pmol g-1 of heart (n = 8, P < 0.05) during the 5 min of reperfusion along with ventricular tachycardia and/or fibrillation. A decrease in myocardial noradrenaline (-31%) was also observed. 4. Bradykinin perfused at concentrations between 0.01 and 1 microM, 10 min before flow was stopped and at reperfusion, inhibited noradrenaline overflow in a concentration-dependent manner. At a concentration of 1 microM, bradykinin completely abolished noradrenaline overflow. For the same concentration of bradykinin, myocardial noradrenaline contents were significantly higher (n = 5-8, P < 0.05). Ventricular fibrillation but not ventricular tachycardia was also prevented. 5. Des-Arg9-BK (0.1 microM) in the same experimental conditions had similar effects. While Hoe 140, a selective antagonist at B2 receptors, did not abolish the effects of bradykinin, Lys [Leu8] Des-Arg9-BK, an antagonist at B1 receptors, abolished the effects of both Des-Arg9-BK and bradykinin. 6. These results suggest that the cardioprotective action of bradykinin in the preparation may be mediated partially by an inhibitory effect on noradrenaline liberation which could be mediated by the activation of B1 receptors.

Beta 1- and beta 2-adrenoceptor subtypes in canine intrathoracic efferent sympathetic nervous system regulating the heart

The augmentation of cardiac inotropism induced by electrical stimulation of acutely decentralized efferent preganglionic sympathetic axons is reduced after the administration of timolol into the major ipsilateral intrathoracic ganglia. Thus it has been proposed that, in addition to nicotinic synapses, beta-adrenergic ones exist in intrathoracic ganglia that are involved in the efferent sympathetic regulation of the mammalian heart. Whether these are beta 1- as opposed to beta 2-adrenoceptor subtypes is unknown. In the present series of experiments, acutely decentralized canine efferent preganglionic sympathetic axons were stimulated before and after the administration of beta 1 (atenolol)- or beta 2 (ICI 118551)-selective adrenoceptor antagonists into the ipsilateral stellate and middle cervical ganglia to determine whether beta 1- or beta 2-adrenoceptors exist in intrathoracic ganglia that are involved in cardiac regulation. Augmentations of right and left ventricular inotropism induced by efferent preganglionic sympathetic axon stimulation were attenuated when either agent was administered into the major ipsilateral intrathoracic sympathetic ganglia. Myocardial liberation of norepinephrine evoked by these stimulations was also reduced after intraganglionic administration of either agent. These data indicate that canine intrathoracic neurons contain beta 1- and beta 2-adrenoceptors that are involved in the efferent sympathetic regulation of the heart.

Decreased Liberation of Noradrenaline from the Heart Following Cold Crystalloid Cardioplegia

Exogenous catecholamine support is often needed soon after termination of cardiopulmonary bypass even when appropriate cardioplegia has been used. To study the effect of hypothermic cardioplegic ischemia and reperfusion on the activity of the cardiac sympathetic nervous system, plasma noradrenaline concentration in the coronary sinus and general circulation was measured in six patients undergoing valve replacement for nonischemic mitral disease. Before cardiopulmonary bypass and cardioplegia the release of noradrenaline from the heart was greater than the mean systemic release. After ischemia, during reperfusion, the heart tended to extract noradrenaline, and 10 min after termination of bypass the plasma noradrenaline gradient over the heart remained less than pre-bypass. The results indicated decreased activity of the cardiac sympathetic nervous system, which may explain the frequent need for catecholamine support.

Neuronal sodium homoeostatis and axoplasmic amine concentration determine calcium-independent noradrenaline release in normoxic and ischemic rat heart.

Calcium-independent noradrenaline release was studied in the isolated perfused rat heart under conditions of normoxia, cyanide intoxication, and ischemia. The release of endogenous noradrenaline and dihydroxyphenylglycol were determined by high-performance liquid chromatography. The release of dihydroxyphenylglycol, the main neuronal noradrenaline metabolite, was used as an indicator of the free axoplasmic amine concentration. When storage function of neuronal vesicles was disturbed by Ro 4-1284 or trimethyltin, high dihydroxyphenylglycol release was observed without concomitant overflow of noradrenaline. If, however, these agents were combined with inhibition of Na+K+-ATPase or with veratridine-induced entry of sodium into the neuron, both dihydroxyphenylglycol and noradrenaline were released. Noradrenaline release was independent of extracellular calcium and was suppressed by blockade of neuronal catecholamine uptake (uptake1), indicating nonexocytotic noradrenaline liberation from the sympathetic nerve ending. This release critically depended on two conditions: 1) increased cytoplasmic concentrations of noradrenaline within the sympathetic neuron and 2) intraneuronal sodium accumulation. Both conditions together were required to induce noradrenaline efflux across the plasma membrane using the uptake1 carrier in reverse of its normal transport direction. A disturbed energy status of the sympathetic neuron, induced by cyanide intoxication or ischemia, likewise caused calcium-independent noradrenaline release by interfering with both vesicular storage function and neuronal sodium homoeostatis. Again, release was sensitive to uptake1 blockade. Since neuronal sodium accumulation was the rate-limiting step, release was further accelerated when residual Na+,K+-ATPase activity was inhibited. Na+-H+ exchange was identified as the predominant pathway of sodium entry into the sympathetic nerve ending in ischemia, and its inhibition by amiloride and ethylisopropylamiloride markedly suppressed ischemia-induced noradrenaline release.

Synergism between ouabain and monensin in neurogenic responses of guinea-pig vas deferens.

Interrelations between ouabain, a Na+-K+ ATPase inhibitor, and monensin, a Na+ ionophore, on noradrenaline liberation and contractile activity were evaluated in the guinea-pig vas deferens. Monensin (1 microM) per se elicited a small contraction of the tissue. However, amplitude and time to the peak of large and sustained contractions evoked by 10 microM ouabain were potentiated and markedly shortened, respectively, by monensin. Contractions elicited by ouabain with or without monensin were prevented by 3 microM phentolamine or by pretreatment with reserpine. Contractions evoked by K+-free solution were augmented by monensin. In an HPLC study, noradrenaline outflow from the vas deferens was moderately and considerably increased by monensin (10 microM) and ouabain (100 microM), respectively. The ouabain-evoked output of noradrenaline was enhanced in the presence of monensin and the time course for maximum noradrenaline release was shortened, as was the contractile activity. This enhanced outflow after ouabain plus monensin was reserpine sensitive but not tetrodotoxin sensitive. Furthermore, this noradrenaline outflow was roughly halved in Na+-deficient medium, but was unaltered in Ca2+-free medium. These findings suggest that the synergistic effect of ouabain and monensin on noradrenaline liberation from the guinea-pig vas deferens may be due to an elevation of cytoplasmic Ca2+ concentrations, presumably resulting from a stimulation of intracellular Na+-Ca2+ exchange system, but not enhanced Ca2+ entry.

Decreased basal cardiac interstitial norepinephrine release after neuronal uptake inhibition in dogs.

The effect of neuronal uptake inhibition on basal interstitial release of norepinephrine in the canine heart was examined by use of the multiple tracer dilution-bulk balance technique. A kinetic model incorporating the effects of flow, capillary permeability-surface product for norepinephrine, the interstitial uptake rate constant for neurotransmitter, and plasma norepinephrine input and output values was used to estimate rates of uptake from and release of norepinephrine into the interstitial space. The intravenous injection of the neuronal uptake inhibitor desipramine in anesthetized dogs under basal conditions reduced interstitial uptake of tracer norepinephrine in the heart, without significant changes in plasma concentration of norepinephrine in aorta and coronary sinus. The lack of change in the arteriovenous balance for norepinephrine across the heart, in the face of the lowered uptake for this amine, suggested that the liberation of norepinephrine by cardiac sympathetic fibers was reduced. Analysis of the data with the norepinephrine tracer kinetic-bulk model showed that, after desipramine, the interstitial release of norepinephrine was reduced to the same extent as uptake was diminished. As a result, the concentration of norepinephrine in the extracellular space of the heart did not increase significantly. The findings indicate the presence of a presynaptic neuronal feedback inhibition of release, which serves to fine tune the myocardial interstitial concentration of norepinephrine in the basal state; with this, after desipramine, both norepinephrine uptake and release are correspondingly diminished.

Neural control of blood glucose level.

All of the experimental results described above can be categorized as follows: the relationship between glucose levels and pancreatic and adrenal nerve activities; innervations of the liver and their role in the regulation of blood glucose level; central integration of blood glucose level; glucose-sensitive afferent nerve fibers in the liver and regulation of blood glucose; oral and intestinal inputs involved in reflex control of blood glucose level. We showed that an increase in blood glucose content produced an increase in the activity of the pancreatic branch of the vagus nerve, whereas it induced a decrease in the activity of the adrenal nerve. It was also shown that a decrease in blood glucose activated the sympatho-adrenal system and suppressed the vago-pancreatic system. It seems rational that these responses are involved in the maintenance of blood glucose level. Studies on the innervation of the liver led us to a conclusion that sympathetic innervation of the liver might play a role in eliciting a prompt hyperglycemic response through liberation of norepinephrine from the nerve terminals, and that the vagal innervation synergically worked with the humoral factor (insulin) for glycogen synthesis in the hyperglycemic condition. The glucose-sensitive afferents from the liver seem to initiate a reflex control of blood glucose level. The gustatory information on EIR response, reported by STEFFENS, is supported by the electrophysiological observations. MEI's reports also indicated the importance of information from the intestinal glucoreceptors in the reflex control of insulin secretion. The role of integrative functions of the hypothalamus and brainstem through neuronal networks on neural control of blood glucose levels is also evident. A schematic diagram of the nervous networks involved in the regulation of the blood glucose levels is shown in Fig. 3.

Isolation and characterization of toxic proteins from the venom of the Brazilian scorpion Tityus serrulatus

Through gel filtration on Sephadex G-25 and chromatography on CM-cellulose-52 five toxic proteins, electrophoretically pure, were isolated from the venom of the Brazilian scorpion Tityus serrulatus and partially characterized, as follows: 1. 1. Toxin T 1 VIII, with 61 amino acid residues, mol. wt 6675 and amino terminal sequence Lys-Glx-Gly-Tyr-Leu-Met-Asx-His-Glx-Gly-Cys-Lys-; 2. 2. Toxin T 1V I, with 72 amino acid residues, mol. wt. 7549 and amino terminal sequence Gly-His-Phe-Gly-Lys; 3. 3. Toxin T 2III I, with 63 amino acid residues, mol. wt. 7216 and amino terminal sequence Lys-Lys-Asx-Gly-Tyr-Pro-Val-Cys-Cys-Ser-; 4. 4. Toxin T 2IV, which is apparently identical to toxin T 1VIII above, since it showed the same elution volume in chromatography on CM-cellulose-52, the same N-terminal Lys and the same electrophoretic mobility as T 1VIII; 5. 5. Toxin T 1IV, a not previously described toxin from the venom of T. serrulatus, with 45 amino acid residues, mol. wt. 5188 and amino terminal sequence Lys-Glx-Gly-Tyr-Leu-, identical to the first five residues of T 1VIII, although with a lower molecular weight. The pharmacological study of T 1VIII in guinea pig vas deferens showed a pre-junctional sensitizing action, evidenced by a decrease of the dose — response curves to adrenaline and acetylcholine, with no increase of the maximum. This effect may be due to the liberation of noradrenaline.

Effects of antidepressants of different chemical structure on uptake and liberation of noradrenalin by rat cortical slices

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RESPONSES OF ISOLATED DOG CORONARY ARTERIES TO TYRAMINE

In isolated dog coronary arteries contracted with prostaglandin F2α, tyramine in concentrations of 10-6 and 5 χ 10-6 M caused relaxations, but it produced contractions at 2×10-5 M or higher, The relaxant response to tyramine was attenuated, but the contractile response was enhanced at the second trial as compared with the responses at the first. Relaxations induced by low concentrations of tyramine were reversed to contractions by treatment with propranolol (10-6 M) or Sotalol (10-6 M), and were abolished by cocaine (3 × 10-6 M) or bretylium (2×10-5 M). In coronary arteries isolated from reserpine (0.5 mg/kg)-pretreated dogs, tyramine produced only a contraction. Under resting conditions, contractions induced by tyramine (5×10-6 to 2×10-3 M) were potentiated by cocaine and propranolol, and were inhibited by phentolamine. Norepinephrine produced a dose-dependent relaxation in the arteries contracted with prostaglandin F2α. In the presence of propranolol, the arteries under resting conditions were contracted by norepinephrine, the contraction being suppressed by treatment with phentolamine. It may be concluded that relaxations of dog coronary arteries induced by tyramine are mediated by liberation of norepinephrine from adrenergic nerves which stimulates beta-adrenoceptors in the smooth muscle. It seems likely that the tyramine (2×10-5 M or higher)-induced contraction is not mediated by norepinephrine released, but it is partly due to a direct action on alpha-adrenoceptors.

Responses of isolated dog coronary arteries to tyramine.

In isolated dog coronary arteries contracted with prostaglandin F2 alpha, tyramine in concentrations of 10(-6) and 5 x 10(-6) M caused relaxations, but it produced contractions at 2 x 10(-5) M or higher. The relaxant response to tyramine was attenuated, but the contractile response was enhanced at the second trial as compared with the responses at the first. Relaxations induced by low concentrations of tyramine were reversed to contractions by treatment with propranolol (10(-6) M) or sotalol (10(-5) M), and were abolished by cocaine (3 x 10(-6) M) or bretylium (2 x 10(-5) M). In coronary arteries isolated from reserpine (0.5 mg/kg)-pretreated dogs, tyramine produced only a contraction. Under resting conditions, contractions induced by tyramine (5 x 10(-6) to 2 x 10(-3) M) were potentiated by cocaine and propranolol, and were inhibited by phentolamine. Norepinephrine produced a dose-dependent relaxation in the arteries contracted with prostaglandin F2 alpha. In the presence of propranolol, the arteries under resting conditions were contracted by norepinephrine, the contraction being suppressed by treatment with phentolamine. It may be concluded that relaxations of dog coronary arteries induced by tyramine are mediated by liberation of norepinephrine from adrenergic nerves which stimulates beta-adrenoceptors in the smooth muscle. It seems likely that the tyramine (2 x 10(-5) M or higher)-induced contraction is not mediated by norepinephrine released, but it is partly due to a direct action on alpha-adrenoceptors.

Cholinergic inhibition of adrenergic neurotransmission in the canine gastric artery

Experiments were performed to examine the possible interaction between the cholinergic transmitter and the reactivity of gastric arteries to adrenergic activation. Helical strips of dogs' gastric arteries were mounted for isometric tension recording. The strips contracted on exposure to norepinephrine; these contractions were inhibited by phenoxybenzamine. Electrical stimulation caused an increase in tension, which was abolished by tetrodotoxin and phenoxybenzamine, indicating that electrical stimulation causes contraction by liberation of norepinephrine. Acetylcholine did not alter basal tension; it caused relaxation during responses to electrical simulation, but not during those to norepinephrine. The relaxation caused by acetylcholine was abolished by atropine. This indicates that acetylcholine inhibits adrenergic neurotransmission in the dog's gastric artery. When added during electrical stimulation, atropine caused an increase in tension. The same concentrations of atropine did not affect basal tension or the response to norepinephrine. Physostigmine depressed the response to electrical stimulation, but not that to norepinephrine. In the blood-perfused stomach of the intact dog, vagal stimulation depressed vasoconstrictions caused by sympathetic nerve stimulation more than comparable constrictor responses obtained with the infusion of norepinephrine. These experiments suggest that liberated acetylcholine can modulate adrenergic neurotransmission in the gastric blood vessels. The removal of cholinergic inhibition on the release of norepinephrine may help explain why vagotomy has a beneficial effect on gastric bleeding.