The effect of phenoxybenzamine and of tolazoline on the response to sympathetic stimulation

The effect of phenoxybenzamine has been determined on the physiological response to sympathetic stimulation in two preparations, the rabbit isolated ileum and the guinea-pig isolated vas deferens. In both preparations phenoxybenzamine increased the response to stimulation of low frequency, the response being inhibitory in the one and motor in the other. This increase was large. As the stimulus frequency was raised, phenoxybenzamine caused a progressively smaller increase in the response, and at high frequencies phenoxybenzamine decreased the response. These observations agree with those of earlier workers who showed that antiadrenaline substances have more than one property. They not only block the motor effects of adrenaline and noradrenaline, but at the same time they may increase the response to sympathetic stimulation. The observations which have been made are not consistent with the interpretation which has been placed by others on the effect of phenoxybenzamine on the amount of noradrenaline appearing in the splenic vein following sympathetic stimulation; this interpretation assumes that phenoxybenzamine will decrease the response to sympathetic stimulation at low frequency. The mode of action of phenoxybenzamine is discussed, and fresh evidence that it has an anticholinesterase action is given.     

The effects of cadmium ions on blood pressure, dopamine-beta-hydroxylase activity and on the responsiveness of in vivo preparations to sympathetic nerve stimulation, noradrenaline and tyramine

Changes in sympathetic nervous function of the rat caused by acute and chronic treatment with cadmium ((Cd2+) have been studied in vivo by measurement of changes in blood pressure and plasma dopamine-beta-hydroxylase (DBH) activity. In anaesthetized animals, acute injection of Cd2+ (0.1-1 microM) caused an initial fall followed by a rise in both diastolic and systolic blood pressure, plasma DBH activity increased in a dose-dependent manner. Animals subjected to repeated treatment with Cd2+ (0.5, 1 microM) daily for 12 days became markedly hypertensive, the increases in the systolic pressure being greater than those seen in the diastolic pressure. In pithed animals the blood pressure responses of the treated animals to electrical stimulation of the lower sympathetic outflow (T10-L1) and tyramine injection (35, 70, 140 nmol kg-1) were markedly decreased, whilst responses to low doses of noradrenaline (NA) (7, 15, 30 nmol kg-1) were potentiated compared with untreated animals. In addition, plasma DBH activities following sympathetic outflow stimulation and tyramine administration were markedly increased and decreased respectively compared with untreated controls. The data suggest that a correlation exists between changes in sympathetic nervous function and the induction of hypertension caused by Cd2+.     

The effect of angiotensin II on haemodynamic and plasma noradrenaline responses to tyramine infusion in man

Summary Six normal volunteers were studied on four separate occasions. On each occasion they received two concomitant infusions which were either placebo/placebo, placebo/tyramine, angiotensin II/placebo or angiotensin II/tyramine. Angiotensin II infusion was given at a constant rate of 2ng/kg/min whereas the tyramine infusion consisted of 10 min increments at 1.25, 2.5, 3.75, 5, 7.5 and 10 g·kg^–1·min^–1.Tyramine infusion caused a dose dependent increase in systolic blood pressure with increases in diastolic blood pressure and plasma noradrenaline only at the highest doses. These changes were not affected by concomitant angiotensin infusion.We have therefore found no evidence to support the enhancement of haemodynamic or plasma noradrenaline responses to tyramine infusion by low dose infusion of angiotensin II in man.     

Effect of noradrenaline, bretylium and cocaine on the blood pressure response to tyramine in the rat

Tyramine is mainly a pressor agent in the rat under urethane, although the hypertensive effect of tyramine in some experiments is followed by a prolonged increase or depression of blood pressure. Bretylium, in doses up to 10 mg/kg, prolonged the response to tyramine, whereas larger doses depressed or blocked its effect. When the hypertensive effect of tyramine was blocked by bretylium, both noradrenaline and dihydroxyphenylalanine, when slowly infused, were found to restore it. The well-known block by cocaine of the hypertensive response to tyramine could also be reversed by intravenous infusion of noradrenaline and dihydroxyphenylalanine. It is concluded that the infusion of noradrenaline and dihydroxyphenylalanine makes available noradrenaline in the postganglionic adrenergic nerves which is necessary for the action of tyramine.     

The effect of 1,1-dimethyl-4-phenyl-piperazinium on the response of mesenteric arteries to sympathetic nerve stimulation

The effect of 1,1-dimethyl-4-phenylpiperazinium (dmpp ) on the response to sympathetic nerve stimulation of rat mesenteric arteries perfused with Tyrode solution at a constant flow has been studied. dmpp (0·3 μg/ml) infused for 3 min enhanced the vasoconstriction caused by stimulation. Infusion of the same concentration for 16–40 min greatly reduced the response to nerve stimulation but did not affect the vasoconstrictor response to injected noradrenaline. The blockade of the response to nerve stimulation produced by dmpp was overcome either by adding (+)-amphetamine to the perfusion fluid or by raising the calcium concentration. Neither effect of dmpp was altered by the infusion of atropine. These effects of dmpp were similar to those seen when acetylcholine was added to the perfusion fluid except that the effects of acetylcholine were diminished or abolished by a concentration of atropine much higher than that of acetylcholine. It is concluded that the receptors at the adrenergic nerve terminals are partly muscarinic and partly nicotinic.     

The effect of thyroid dysfunction on the chronotropic response to noradrenaline

Dose-response curves to noradrenaline in the presence and absence of beta-receptor antagonists were established with isolated atria from euthyroid, hypothyroid and hyperthyroid rats. Baseline atrial rate and Emax were significantly lower than normal in the hypothyroid group and significantly higher than normal in the hyperthyroid group. Differences between the groups were minimal for pD2 and range of response to noradrenaline. The response to beta-receptor antagonists was the same in all 3 groups with the exception of the hypothyroid group which showed an attenuated increase in baseline atrial rate with compounds possessing partial agonist activity. This was particularly marked for practolol. These results do not provide evidence for an altered responsiveness to catecholamines due to altered thyroid status but suggest that thyroid hormones have a direct action on cardiac tissue.     

The effects of cholinomimetic drugs on responses to sympathetic nerve stimulation and noradrenaline in the rabbit ear artery

1. The effects of infusions of the cholinomimetic drugs acetylcholine, methacholine, muscarine, carbachol, arecoline and pilocarpine were examined on vasoconstrictor responses of the perfused rabbit ear artery to sympathetic nerve stimulation and to injections of noradrenaline.2. The first effect of very low concentrations of acetylcholine or muscarine was a slight enhancement of responses to sympathetic nerve stimulation, but when higher concentrations of acetylcholine, methacholine, muscarine, carbachol and arecoline were infused, these vasoconstrictor responses were decreased. With still higher concentrations the responses tended to increase in size during the infusion. After stopping an infusion, the depressed vasoconstrictor responses rapidly recovered and became enhanced.3. Infusions of pilocarpine in a wide range of concentrations generally caused enhancement of responses.4. The depressant effects of cholinomimetic drugs on the responses to sympathetic nerve stimulation were antagonized by atropine. Larger concentrations of the drugs overcame the blockade by atropine.5. The effects of acetylcholine, methacholine and muscarine on the responses to sympathetic nerve stimulation were more pronounced at low than at high frequencies of stimulation.6. Vasoconstrictor responses to injected noradrenaline were enhanced by acetylcholine or methacholine, whereas responses to sympathetic nerve stimulation were decreased by the same concentrations of these choline esters.7. It is suggested that cholinomimetic drugs may act on receptor sites associated with the adrenergic terminal axon and that they may facilitate or impair the release of noradrenaline and impair noradrenaline uptake.     

Effect of neonatal 6-hydroxydopamine treatment on the blood pressure response to noradrenaline and tyramine in rats

Neonatal treatment of rats with 6-hydroxydopamine (6-OHDA) caused a permanent depletion of noradrenaline (NA) in the heart and the spleen, but not in the adrenals. In 10–12 week old animals, anesthetized with pentobarbital, sensitivity of the pressor response to various doses of i.v. administered NA increased 5-fold whereas the pressor response to i.v. administered tyramine was greatly diminished; the response to tyramine was further reduced after adrenalectomy, but not in controls. These results suggest that the pressor responses evoked by tyramine and NA can be used as a test for functional sympathetic denervation after 6-OHDA treatment.     

The effects of cadmium ions on blood pressure,dopamine-β-hydroxylase activity and on the responsiveness of in vivo preparations to sympathetic nerve stimulation,noradrenaline and tyramine

Changes in sympathetic nervous function of the rat caused by acute and chronic treatment with cadmium (Cd²⁺) have been studied in vivo by measurement of changes in blood pressure and plasma dopamine-β-hydroxylase (DBH) activity. In anaesthetized animals, acute injection of Cd²⁺ (0·1–1 μm) caused an initial fall followed by a rise in both diastolic and systolic blood pressure, plasma DBH activity increased in a dose-dependent manner. Animals subjected to repeated treatment with Cd²⁺ (0·5, 1 μm) daily for 12 days became markedly hypertensive, the increases in the systolic pressure being greater than those seen in the diastolic pressure. In pithed animals the blood pressure responses of the treated animals to electrical stimulation of the lower sympathetic outflow (T₁₀-L₁) and tyramine injection (35, 70, 140 nmol kg^?1) were markedly decreased, whilst responses to low doses of noradrenaline (NA) (7, 15, 30 nmol kg^?1) were potentiated compared with untreated animals. In addition, plasma DBH activities following sympathetic outflow stimulation and tyramine administration were markedly increased and decreased respectively compared with untreated controls. The data suggest that a correlation exists between changes in sympathetic nervous function and the induction of hypertension caused by Cd²⁺.     

The contributions of noradrenaline and ATP to the responses of the rabbit central ear artery to sympathetic nerve stimulation depend on the parameters of stimulation

The possibility that ATP and noradrenaline act as cotransmitters from sympathetic perivascular nerves was studied in the isolated rabbit central ear artery. Electrical stimulation of the perivascular nerves for either 1 s, or continuously until a maximum response was reached, produced frequency-dependent contractions that were sensitive to tetrodotoxin and guanethidine. Contractions to continuous stimulation were significantly greater than those to a 1 s train of stimulation. Prazosin (10(-6) M) significantly reduced, but did not abolish, all neurogenic contractions such that contractions to both a 1 s train and to continuous stimulation were now of a similar magnitude. A higher concentration of prazosin (10(-5) M) had no additional inhibitory effect on neurogenic contractions even though it further significantly inhibited contractions to exogenous noradrenaline. The greatest resistance to alpha-adrenoceptor blockade was seen at low frequencies. Desensitisation of the postjunctional P2-purinoceptor by repeated administration of alpha, beta-methylene ATP inhibited the non-adrenergic neurogenic contractions and contractions to exogenous ATP, but had no effect on contractions to exogenous noradrenaline. It is concluded that ATP and noradrenaline are excitatory cotransmitters from sympathetic perivascular nerves innervating the rabbit central ear artery. The relative contribution of each compound to neurogenic contractions of the ear artery is highly dependent on the parameters of stimulation used. Short pulse bursts (1 s) at low frequency (2-5 Hz) favour the prazosin-resistant (purinergic) component of the response.