Adrenergic Neurone Blocking Research Articles

Cardiac arrhythmic response evoked by stimulation of fastigial nuclei in the anesthetized cat

Using the Horsley-Clarke stereotaxic technique for positioning electrodes in the cerebellum of the cat, the present study has shown that electrical stimulation of the nucleus fastigius produces cardiac arrhythmia in addition to the already known pressor response. These arrhythmias ranged from sinus tachycardia to various kinds of ectopic beats, and the effects of the arrhythmias on cardiovascular haemodynamics are discussed. Administration of the beta-adrenergic-blocking drug (propranolol) and the adrenergic neuron-blocking drug (bretylium tosylate) showed that the cardiac arrhythmic responses were predominantly due to sympathetic activation. Bilateral cervical vagotomy facilitated the production of ectopic beats during fastigial stimulation, but either abolished those ectopic beats previously arising in the post-stimulation period or modified them to the extent that they characteristically became beats with short P-R intervals and wide QRS complexes. This evidence indicates a cerebellar control of autonomic system functions.

Mechanism of lithium action on the adrener GIC function

The intravenous injection of Lithium chloride (LiCl) in two dose levels (25 & 50 mg/kg) has led to a significant potentiation of the pressor response of rabbits to the i.v administration of both epinephrine and norepinephrine. The i.v injection of LiCl (50 mg/kg) resulted in a marked depression of the carotid occlusion reflex in rabbits. In vitro experiments revealed that LiCl (1.6 mcg/ml) and guanethidine (0.8 mcg/ml) exert the same action on the rabbit mesenteric nerve-intestine preparation and abolish the intestinal relaxation induced by electrical stimulation of the mesenteric nerve. Results confirm the assumption that Li might display a pre-synaptic, guanethidine-like, adrenergic neuronal blocking activity.

Direct evidence against a role of ATP as the nonadrenergic, noncholinergic inhibitory neurotransmitter in guinea pig tenia coli.

Electrical field stimulation of the isolated guinea pig tenia coli in the presence of a muscarinic receptor antagonist (atropine) and an adrenergic neuron blocker (guanethidine) produces relaxation. A large amount of indirect evidence has suggested that the neurotransmitter that is released from these nonadrenergic, noncholinergic inhibitory neurons is ATP or a related nucleotide, and the nerves have been termed "purinergic." A photoaffinity analog of ATP, arylazido aminopropionyl ATP, which produces a specific pharmacological antagonism of P2 purinergic receptors in isolated guinea pig vas deferens and urinary bladder, was utilized in the present study to evaluate directly whether ATP is the nonadrenergic, noncholinergic inhibitory neurotransmitter in tenia coli. By blocking postjunctional P2 receptors, arylazido aminopropionyl ATP produced a pronounced antagonism of relaxations induced by exogenously added ATP. Responses produced by ADP, AMP, and adenosine also were antagonized by arylazido aminopropionyl ATP, but to a lesser extent. Inhibitory responses to isoproterenol were not antagonized. Under these conditions of established, specific P2-receptor blockade of responses to exogenously added ATP, relaxations induced by field stimulation of intrinsic inhibitory nerves in the presence of atropine (1 microM) and guanethidine (1 microM) were not antagonized. Though these results provide no indication of the actual substance involved, they suggest strongly that the nonadrenergic, noncholinergic inhibitory neurotransmitter in the guinea pig tenia coli is not ATP.

Immunology of Cardiovascular Disease

This attractive book by contributors from both sides of the North Atlantic documents the important new diagnostic and therapeutic immunologic developments in cardiovascular research and practice that promote better understanding of transplantation of the heart, connective-tissue disorders, postcardiac injury disorders, infective and post-infective disorders, Chagas cardiomyopathy, vasculitis, platelets, drugs, atherosclerosis, and other autoimmune changes associated with or responsible for diseases of the cardiovascular system. Although the evidence linking immunologic reactions to the pathogenesis of degenerative diseases, such as hypertension, ischemic heart disease, and cardiomyopathy, commonly seen in cardiological practice remains incomplete, knowledge of the basic immunologic principles presented in this scholarly book will prove diagnostically and therapeutically helpful to the clinician in his practical management of patients with such cardiovascular disease. For example, drugs, particularly antibiotics, anti-inflammatory agents, adrenergic neuronalblocking drugs (like α-methyldopa), and vaccines may cause hypersensitivity reactions in the heart, leading to myocarditis or cardiomyopathy. Pro

Functions of adrenergic and cholinergic nerves in canine effectors of seminal emission.

Spontaneous activity responses to acetylcholine (ACh), adrenaline (A), noradrenaline (NA) and barium chloride as well as the effects of various autonomic drugs on effects of field stimulation of nerves and muscle cells of isolated pieces or strips of cauda epididymidis, vas deferens, ampulla ductus deferentis and prostate of dog were studied. The main results and conclusions are: the muscles show little spontaneous activity but rhythmicity can easily be produced by e.g. stimulating agonists. The muscles are contracted by alpha-adrenoceptor stimulants. ACh has usually no or a very weak contractile effect in high concentrations. Muscles of young dogs are more sensitive to ACh. The excitatory innervation of the muscles is adrenergic and completely blocked by adrenergic neuron blockers as well as alpha-adrenoceptor blocking drugs. Stimulation of adrenergic nerves leads to maximum response already at low frequencies (4-6 Hz). This response is very similar to that provoked by a supramaximal dose of NA. Scopolamine enhances neurogenic contractile effects while physostigmine suppresses them. Hence cholinergic nerves may act by muscarinic prejunctional inhibition of the excitatory adrenergic neurotransmission rather than act directly upon the smooth muscle cells. Since secretory cells receive cholinergic innervation prejunctional inhibition of the adrenergic myomotor nerves may be of functional significance in at least the long copulatory events of the dog.

Mechanism of action of histamine in the estrogen-primed rat uterus

Histamine produced a dose-dependent relaxation of uterine strips obtained from the estrogen-primed rat uterus. The responses to histamine were blocked competitively by metiamide (10 −8 −10 −8M), a specific H 2-receptor antagonist. Propranolol, a selective β-receptor blocker also produced competitive antagonism of the responses to histamine in the same dose range (10 −8−10 −6 M). The pA 2 value obtained for metiamide (8.9) was not significantly different from that obtained for propranolol (8.6). Nialamide (2.2 × 10 −6 M), the monoamine oxidase inhibitor, and cocaine (4.3 × 10 −6 M), the selective noradrenaline uptake blocker, potentiated the responses to histamine. However bretylium (2.4 × 10 −5 M), an adrenergic neuron blocker inhibited the responses to histamine. The combined effect of tyramine and histamine was found to be additive. Our data suggest that the histamine-induced relaxation of rat uterus may be produced through the stimulation of presynaptic H 2-receptors which causes the release of noradrenaline. The released noradrenaline acts on the postsynaptic β-receptors and produces relaxation of the rat uterus.

Effects of Adrenergic Neuron Blocking Agent and Central Alpha-adrenergic Agonists on Urinary Catecholamine Excretion in Cold-stressed SHR

Ambulatory activity, water drinking, UV and UCA of SHR in the dark phase elevated significantly as compared with those in the light phase. UNE and UE of SHR were significantly increased by cold exposure in both light and dark phases. GUANE, which does not cross blood brain barrier, produced a significant decrease in UNE in cold-stressed SHR. CLO and GUANF did not influence in the UCA in cold-stressed SHR. These findings suggest that the increased peripheral sympathetic tone appear to be responsible for the increased UNE brought about by cold exposure in SHR.

Dual influence of hydralazine on constrictor response to noradrenaline in isolated arterial smooth muscle.

The effects of hydralazine (Hyd) on vascular smooth muscle contractile response to alpha-receptor stimulation by exogeneous and endogenous noradrenaline (NA) in the absence and presence of Mg2+ (1.2 mM) were examined using a proximal segment of rabbit's ear artery. Intraluminal perfusion with Hyd (2 x 10(-4) M) in normal Krebs bicarbonate mediuim inhibited the NA-induced contraction only in the presence of Mg2+ (1.2 mM) in the medium. The extraluminal superfusion of the artery with Hyd (2 x 10(-4) M) enhanced the vasoconstriction to extraluminally superfused NA in either the presence or absence of Mg2+ in the medium. However, when the artery was preincubated with an adrenergic neuron blocker, guanethidine (3.2 x 10(-6) M), Hyd (2 x 10(-4) M) inhibited NA-induced vasoconstriction. Contrary to the effects of Hyd on intraluminal NA, Hyd potentiated the response of this superfused artery to electrical stimulation in the presence of Mg2+ (1.2 mM) whereas in the Mg2+-free medium, it inhibited the constriction. These findings suggest that Hyd may have dual effects on isolated vascular smooth muscle by directly inhibiting the contractile activation and indirectly by an interference at adrenergic nerves, which potentiates the effects of exogenous NA and(or) alters the release of endogenous NA.

Effects of adrenergic neuron and ganglion blockers on hemodynamics and plasma catecholamine levels after corticosteroids during hemorrhagic shock in the dog.

The involvement of adrenergic mechanisms in the ability of massive doses of methylprednisolone to potentiate the vasodilatory effects of phenoxybenzamine during controlled hemorrhagic shock was investigated. Dogs were subjected to ligation of the adrenals and, with the exception of the controls, were pretreated with either hexamethonium or bretylium. Despite careful surgery, the adrenal ligation, per se, failed to alter the concentration of plasma catecholamines. Hexamethonium and bretylium, on the other hand, both decreased the levels of plasma catecholamines: noradrenaline to a greater extent than adrenaline. Methylprednisolone was almost ineffective after ganglionic or adrenergic neuron blockade. Furthermore, the degree of vasodilation after methylprednisolone and phenoxybenzamine seemed to correlate better with plasma noradrenaline than with adrenaline. These findings indicate that the ability of methylprednisolone to induce vasodilation in the presence of adrenergic alpha-receptor blockade in hypovolemic shock in the dog relies on an intact release of noradrenaline from postganglionic adrenergic nerve terminals.

Cardiac arrhythmias induced by guanethidine in cats anesthetized with halothane

Rapid i.v. administration of guanethidine provokes severe and susteined ventricular arrhythmieas in cats anesthetized with halothane. The arrhythmias premature ventricular exciations, multifocal ventricular rhythm, bigeminy, trigeminy and ventricular tachycardia. They begin in about 20 sec and last from 4 to 19 min. By comparison, a standard dose of noradrenaline (10 ωg/kg) induces ventricular arrhythmias which develop in about 12 sec and continue for 1–2.5 min. Pretreatment with β-adrenoceptor blocking drugs prevents arrhythmias from both drugs, and pretreatment with imipramine or reserpine prevents arrhythmias from guanethidine but not noradrenaline. The adrenergic neuron blocking action of guanethidine does not alter the arrhytmogenic action of guanethidine since arrhythmias can still be produced after adrenergic neuron blockade. These results indicate that guanethidine causes arrhythmias by releasing noradrenaline from cardiac adrenergic neuron storage sites and, therefore, point out the vulnerability of the heart to arrhythmias when noradrenaline-releasing drugs interact with halogenated hydrocarbon anesthetics.

Recent studies of the actions of cholinomimetic drugs on adrenergic nerves and their implications for the cholinergic link hypothesis.

This review analyzes the results of recent studies of the actions of cholinomimetic drugs on adrenergic nerve terminals and their implications for the cholinergic link hypothesis. Thus far, evidence suggests that the only possible action of endogenous acetylcholine (ACh) present near noradrenaline (NA) stores is an inhibition of the release of NA from the adrenergic nerve terminals and that NA is released only when the action of acetylcholinesterase is inhibited. Nicotinic agents have been shown to act on adrenergic nerve terminal membranes, a finding that casts doubt on the proposed intraneuronal cholinergic sites for the action of endogenous ACh. Evidence also indicates that the mode of adrenergic neurone blocking action of bretylium and guanethidine is independent of the proposed cholinergic process in NA release. Current findings do not support the proposal that nicotinic agents in higher concentrations interfere with adrenergic neurotransmission. It is therefore concluded that nicotinic agents, in causing the release of NA from adrenergic nerve terminals, are merely exhibiting a pharmacological action and not mimicking the physiological function of ACh, as proposed by the cholinergic link hypothesis.

The inhibitory innervation of the guinea-pig trachea: a study of its adrenergic and non-adrenergic components.

(1) Inhibitory responses to field stimulation have been determined in strip preparations from the thoracic, middle and cervical regions of the trachea and in the tracheal tube preparation. (2) The adrenergic neurone blocking drug guanethidine was found to cause a partial reduction of the amplitudes of the responses in all preparations. (3) The guanethidine-resistant inhibitory responses were resistant to pentolinium but were abolished by tetrodotoxin. The data favours the existence of non-adrenergic inhibitory intramural nerves in the guinea-pig trachea. (4) Inhibitory responses have been determined in the presence and absence of guanethidine at frequencies ranging from 2 to 60 Hz. This has enabled the combined responses to stimulation of both adrenergic and non-adrenergic nerves to be compared with the response to stimulation of non-adrenergic nerves alone at each frequency and in each preparation. (5) The contribution of each innervation to the combined inhibitory response was frequency dependent. The adrenergic innervation was more effective at lower frequencies and the non-adrenaration is discussed. Its origin is considered.

Isolation and Pharmacological Action of Epistephanine, an Alkaloid of Stephania hernandifolia

Alkaloids epistephanine, hernandifoline, aknadinine and magnoflorine have been isolated from the aerial parts of Stephania hernandifolia (Willd.) Walp. This is the first report of the occurrence of epistephanine in S. hernandifolia and it appears to be identical with aknadine, an uncharacterised alkaloid of this plant previously reported by an Indian worker. Epistephanine was found to possess significant adrenergic neurone blocking activity.

Increased levels of prostaglandin-like material in the canine blood during arterial hypotension produced by hydralazine, dihydralazine and minoxidil.

1. Indomethacin completely reversed within 15 min the hypotension produced by hydralazine or dihydralazine in anaesthetized dogs. Acetylsalicylic acid, diclofenac sodium and flufenamic acid inhibitors of prostaglandin synthesis structurally dissimilar to indomethacin — had the same effect. Pretreatment of anaesthetized dogs with indomethacin prevented in part the hypotension in response to a subsequent injection of hydralazine. 2. The development of hypotension in response to hydralazine or dihydralazine was paralleled by an increase in the concentration of prostaglandin-like (PG-like) material in the renal venous blood as determined with the blood bathed organ technique. PG-like material increased to a lesser extent, also in the femoral venous and in the aortic blood. Subsequent injection of indomethacin reduced PG-like material in the blood to levels no longer detectable by bioassay and reversed the hypotension produced by either of the two vaso-active antihypertensives. 3. Hydralazine and dihydralazine raised also the blood levels of angiotensin II. While there was no decrease in the elevated concentrations of PG-like material at 3 h after the injection of hydralazine, angiotensin II levels started to fall after 1 h and at 2 h an increase was no longer detected. 4. Pretreatment of the dogs with the betaadrenoceptor blocking agent propranolol had no major influence on the hydralazine-induced hypotension and on the induced appearance of PG-like material in the renal venous blood. 5. Although hydralazine raised the levels of PG-like material in the renal venous blood more than in femoral venous or aortic blood, exclusion of both kidneys from the circulation did not modify the hypotensive effect of the drug. 6. While the infusion of neither PGE2 nor PGI2 into the aorta was able to mimic the actions of hydralazine and dihydralazine on both blood pressure and the responses of the blood bathed assay organs, a combined infusion of PGE2 and PGI2 at a ratio of 4:1 was able to do so. 7. The hypotension in response to minoxidil —another vasoactive antihypertensive — was also accompagnied by the appearance of PG-like material in the renal venous blood. The increase in PG-like material was, however, smaller than that after hydralazine and dihydralazine in spite of a similar fall in blood pressure, and the hypotensive effect of minoxidil was only partially antagonized by indomethacin. The hypotension in response to the alpha-adrenoceptor blocking drug prazosin, to the adrenergic neurone blocking drug guanethidine, and to the centrally acting clonidine were neither accompagnied by the appearance of PG-like material in the renal venous blood nor influenced by indomethacin. 8. In the conscious dog and in the anaesthetized guinea pig indomethacin antagonized the hypotensive action of dihydralazine only partially and in other species such as the rat, the rabbit and the cat — all studied under anaesthesia — failed to affect the drug-induced hypotension. 9. The present results suggest that in the anaesthetized dog the hypotensive effects of hydralazine and dihydralazine — and in part of minoxidil — are mediated through vasodilator prostaglandins.

The non-adrenergic, inhibitory innervation of the guinea-pig gallbladder.

1. Stimulation in vivo of the cervical vagus nerve produces contraction of the gallbladder of the guinea-pig. Following block of this response by atropine, a relaxation is revealed which is not affected by the adrenergic neurone blocker guanethidine. The relaxation is blocked by hexamethonium, indicating that the non-adrenergic inhibitory neurones are in the bladder wall and are activated via nicotinic synapses. 2. Stimulation of the intramural nerves supplying the bladder in vitro confirms the existence of nonadrenergic inhibitory neurones: relaxations appearing in response to stimulation of intramural nerves in the presence of atropine are abolished by tetrodotoxin and xylocaine, and are unaffected by guanethidine, phentolamine and propranolol. 3. There is evidence to suggest that these inhibitory neurones are purinergic.

The vasodilator action of formaldehyde in dogs

The perfused hind legs of anesthetized dogs were used in investigations of the depressor effect of formaldehyde. An injection of formaldehyde into the right femoral vein caused a transient fall in systemic blood pressure and a one-step fall in perfusion pressure. The initial fall took place before the arrival of the drug in the perfused area. It was followed by a further decrease after the arrival of the drug in the area. Our study showed that dogs completely lack the pressor response to formaldehyde that rats have been reported to manifest. Though the initial fall in perfusion pressure was little affected by atropine or vagotomy, it was abolished by autonomic ganglion blocker, adrenergic neuron blocker, and a-adrenergic blocker. These results suggest that the initial decrease is caused by inhibition of the sympathetic nervous system. This in turn suggests that the depressor action of formaldehyde results from a combination of direct action on the cardiovascular system and inhibitory action on the sympathetic nervous system. The inhibition plays a smaller role in the depressor action than the vasodilator effect, because a-blockers in intact dogs augmented, rather than inhibited, the depressor effect.

Effect of prolonged treatment with adrenergic neuron blocking drugs on sympathoadrenal reactivity in rats

The effects of repeated high doses of the adrenergic neuron blocking drug guanethidine or a hexahydropyrazinoindole compound (2-guanyl-1,2,3,10,10,10a, hexahydro-1,2,a-pyrazinoindole, EMD 21192) (30 mg/kg i.p., 21.5 mg/kg i.p. respectively, equimolar doses) on sympathoadrenal activity were investigated in normotensive adult rats. During treatment for 5 weeks with either guanethidine or EMD 21192 the systemic blood pressure fell steadily. Noradrenaline content in the heart and vas deferens were decreased markedly by guanethidine and to a much less degree by EMD 21192. EMD 21192 markedly lowers the catecholamine content of the adrenal medulla, presumably as a result of inhibition of dopamine-β-hydrolase. The plasma catecholamine concentrations reflected the different sites of action of the drugs in the sympathoadrenal system, i.e. guanethidine mainly reduced circulating norepinephrine and dopamine-β-hydroxylase by more than 50%, whereas EMD 21192 decreased considerably by the total catecholamines (mainly epinephrine) without altering significantly in the plasma norepinephrine. Disappearance or reduction of fluorescent nerve endings in the iris and the heart and a decrease of the intensity of fluorescence in chromaffin cells of the adrenal gland caused by the drugs were consistent with the biochemical alteration. Whereas the repeated doses of guanethidine caused degeneration of sympathetic nerves, destruction of adrenergic neurons was not found after prolonged treatment with EMD 21192.

The uptake and overflow of radiolabelled beta-adrenoceptor blocking agents by the isolated vas deferens of the rat.

1. A comparison of uptake into and overflow from the isolated vas deferens of the rat has been made between [3H]-noradrenaline ([3H]-NA), [14C]-D-sorbitol and three radio-labelled beta-adrenoceptor blocking agents, [14C]-practolol, [14C]-(+/-)-propranolol and [3H]-penbutolol. 2. The accumulation of [3H]-NA after 30 min incubation was reduced by desmethylimipramine (DMI) 1 X 10(-8)M and was also reduced in vasa from rats pretreated with 6-hydroxydopamine (6-OHDA). This was not so with [14C]-D-sorbitol. 3. 6-OHDA pretreatment of the rats reduced the uptake of [3H]-penbutolol after 30 min incubation but not that of [4C]-propranolol or [14C]-practolol. DMI 1 X 10(-8)M did not alter the tissue uptake of [14C]-propranolol, [14C]-practolol or [3H]-penbutolol. 4. Electrical stimulation of vasa preloaded with [3H]-NA caused a significantly greater increase in [3H]-NA overflow than during the resting, unstimulated periods. No such increase in overflow was observed with [14C]-sorbitol or any of the three beta-adrenoceptor blocking agents use. 5. The beta-adrenoceptor blocking agent penbutolol was shown to possess adrenergic neurone blocking activity in the isolated vas deferens of the rat. 6. It is concluded that any effect that practolol or (+/-)-propranolol have on noradrenergic neurones is brought about without the need for these drugs to gain access to the interior of the neurone.

INITIAL EXPERIENCE WITH PRAZOSIN IN NEW ZEALAND: A MULTICENTRE REPORT

Data are presented on 282 patients who began taking prazosin before March, 1975, and whose progress was followed until March, 1976. The following conclusions can be drawn. (i) Prazosin is an effective and useful antihypertensive agent, best used with a diuretic and a beta-blocker. (ii) For patients with suspected or definite coronary artery disease, prazosin should not be used without a beta-blocker. (iii) In patients suspected of having incipient heart failure, prazosin should not be used without a diuretic, and the latter should be given first. (iv) Many patients have little or no rise in heart rate with prazosin. However, patients with sinus tachycardia or a history of arrhythmias should preferably not be treated with prazosin. (v) The initial dose should be kept small (0·25 to 0·5 mg). Subsequent increments should also be small, not more than 2 mg/day. (vi) If prazosin is added to a regimen containing an adrenergic neurone-blocking drug, the dose of the latter should first be reduced. (vii) Prazosin should not, in the meantime, be used concomitantly with a phenothiazine, as the combination appears to be capable of causing agitation and confusion. (viii) There seems to be no long-term toxicity.

The mechanism of action of nicotine on vascular adrenergic neuroeffector transmission

The aim of this study was to determine the site and mechanism of action of nicotine on sympathetic neuroeffector transmission in the isolated pulmonary artery of the rabbit. Nicotine and cocaine potentiated the constrictor response elicited by electrical-field stimulation of postganglionic adrenergic neurones. The potentiation was reversible and in the case of nicotine, no tachyphylaxis developed. The nicotine-induced potentiation was characterized by a rapid onset and an initial, transitory peak, while the enhancement caused by cocaine progressed more slowly and was monophasic. Hexamethonium and (+)-tubocurarine prevented the potentiation caused by nicotine. Nicotine did not prevent the adrenergic neurone blocking effect of bretylium on the response to field stimulation. Nicotine increased the stimulation-induced outflow of tritium from pulmonary artery preloaded with 3H-(−)-noradrenaline. Contractions of the artery elicited by tyramine were enhanced by pargyline, unaltered by nicotine and blocked by cocaine. Nicotine did not alter the concentration-response curve of exogenous (−)-noradrenaline while cocaine moved it to the left. The accumulation of 3H-(−)-noradrenaline by rabbit isolated aorta was not altered by nicotine, hexamethonium and (+)-tubocurarine. The accumulation of 3H-nicotine by the aorta was much lower than that seen with 3H-(−)-noradrenaline. The disposition of the 3H-nicotine accumulation into adventitia and media was concentration-independent. These results suggest (1) that nicotine potentiates the neurogenic vasoconstriction response in part by increasing the stimulation-induced release of transmitter from adrenergic neurone terminals; (2)_that the site of the nicotinic receptors mediating this action is located on the outer surface of the neurones; and (3) that the potentiation is not due to blockade of noradrenaline re-uptake.