Stimulation Of Postganglionic Sympathetic Nerves Research Articles

Influence of the length of the stimulus period and frequency of sympathetic stimulation on the response of the guinea-pig isolated vas deferens to bretylium, guanethidine and amphetamine.

Abstract The height of contraction of guinea-pig isolated vas deferens preparations in response to pre- or postganglionic sympathetic nerve stimulation at various stimulus frequencies was shown to vary with varying length of stimulation period. Short stimulation periods, as used by some workers, produced suboptimal contractions especially at the lower frequencies. It is suggested that variations in the length of the stimulation period could account for some of the contradictory results reported by various workers using this preparation. Thus the effect of low concentrations of dexamphetamine was qualitatively changed as the length of the stimulation period was increased; with short stimulation periods dexamphetamine impaired the responses to sympathetic stimulation but enhanced them if stimulation was continued until contractions had reached the maximum height obtainable. Higher concentrations of dexamphetamine impaired the contractions, the effect being most marked against the higher stimulus frequencies. Using stimulation to maximal effect a qualitative difference in the blocking actions of bretylium and guanethidine was demonstrated. Bretylium reduced the responses to the higher stimulus frequencies to a greater extent than it reduced the responses to the lower frequencies. Guanethidine reduced the responses to all frequencies so that there was a parallel shift of the frequency/response curve to the right. The possible significance of these findings is discussed.

Impairment of sympathetic nerve responses by dopa, dopamine and their alpha-methyl analogues.

Abstract Dopa and dopamine reduced the response of the nictitating membrane to postganglionic sympathetic nerve stimulation in cats pretreated with the monoamine oxidase inhibitor pargyline. A similar reduction could be obtained with α-methyldopa and α-methyldopamine in untreated cats. The sensitivity of the membrane to injected noradrenaline, α-methylnoradrenaline or adrenaline was not reduced. The possible mechanism of the anti-hypertensive action of monoamine oxidase inhibitors and α-methyldopa is discussed in the light of these findings.

Sympathetic control of heart rate in nNOS knockout mice

Inhibition of neuronal nitric oxide synthase (nNOS) in cardiac postganglionic sympathetic neurons leads to enhanced cardiac sympathetic responsiveness in normal animals, as well as in animal models of cardiovascular diseases. We used isolated atria from mice with selective genetic disruption of nNOS (nNOS(-/-)) and their wild-type littermates (WT) to investigate whether sympathetic heart rate (HR) responses were dependent on nNOS. Immunohistochemistry was initially used to determine the presence of nNOS in sympathetic [tyrosine hydroxylase (TH) immunoreactive] nerve terminals in the mouse sinoatrial node (SAN). After this, the effects of postganglionic sympathetic nerve stimulation (1-10 Hz) and bath-applied norepinephrine (NE; 10(-8)-10(-4) mol/l) on HR were examined in atria from nNOS(-/-) and WT mice. In the SAN region of WT mice, TH and nNOS immunoreactivity was virtually never colocalized in nerve fibers. nNOS(-/-) atria showed significantly reduced HR responses to sympathetic nerve activation and NE (P < 0.05). Similarly, the positive chronotropic response to the adenylate cyclase activator forskolin (10(-7)-10(-5) mol/l) was attenuated in nNOS(-/-) atria (P < 0.05). Constitutive NOS inhibition with L-nitroarginine (0.1 mmol/l) did not affect the sympathetic HR responses in nNOS(-/-) and WT atria. The paucity of nNOS in the sympathetic innervation of the mouse SAN, in addition to the attenuated HR responses to neuronal and applied NE, indicates that presynaptic sympathetic neuronal NO does not modulate neuronal NE release and SAN pacemaking in this species. It appears that genetic deletion of nNOS results in the inhibition of adrenergic-adenylate cyclase signaling within SAN myocytes.

Cardiac sympathetic nerve stimulation does not attenuate dynamic vagal control of heart rate via alpha-adrenergic mechanism.

Complex sympathovagal interactions govern heart rate (HR). Activation of the postjunctional beta-adrenergic receptors on the sinus nodal cells augments the HR response to vagal stimulation, whereas exogenous activation of the presynaptic alpha-adrenergic receptors on the vagal nerve terminals attenuates vagal control of HR. Whether the alpha-adrenergic mechanism associated with cardiac postganglionic sympathetic nerve activation plays a significant role in modulation of the dynamic vagal control of HR remains unknown. The right vagal nerve was stimulated in seven anesthetized rabbits that had undergone sinoaortic denervation and vagotomy according to a binary white-noise signal (0-10 Hz) for 10 min; subsequently, the transfer function from vagal stimulation to HR was estimated. The effects of beta-adrenergic blockade with propranolol (1 mg/kg i.v.) and the combined effects of beta-adrenergic blockade and tonic cardiac sympathetic nerve stimulation at 5 Hz were examined. The transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with pure delay. beta-Adrenergic blockade decreased the dynamic gain from 6.0 +/- 0.4 to 3.7 +/- 0.6 beats x min(-1) x Hz(-1) (P < 0.01) with no alteration of the corner frequency or pure delay. Under beta-adrenergic blockade conditions, tonic sympathetic stimulation did not further change the dynamic gain (3.8 +/- 0.5 beats x min(-1) x Hz(-1)). In conclusion, cardiac postganglionic sympathetic nerve stimulation did not affect the dynamic HR response to vagal stimulation via the alpha-adrenergic mechanism.

The actions of bretylium: adrenergic neurone blocking and other effects. 1959.

Bretylium caused a specific and lasting depression of many excitatory and inhibitory responses evoked by electrical stimulation of the peripheral sympathetic nervous system, probably by impairing conduction of impulses in adrenergic neurones with consequent failure of noradrenaline and adrenaline release. This effect, which will be referred to as the adrenergic neurone blocking action, was preceded by weak sympathomimetic effects. In the presence of bretylium the effects of adrenaline and noradrenaline were increased, as after sympathectomy. Concentrations producing blocking of adrenergic neurones did not prevent the release of adrenaline and noradrenaline from the adrenal medulla by splanchnic nerve stimulation or by the injection of dimethylphenylpiperazinium iodide, nor did they cause antiparasympathetic or parasympathomimetic effects. No action on the central nervous system has been detected. Curare‐like neuromuscular block occurred with 10 to 30 times the amount required to block the response to adrenergic nerve stimulation alone and was accompanied by signs of temporary synaptic block in autonomic ganglia. A drenergic. nerve trunks and sensory nerves in the skin were readily blocked for long periods by topical application of bretylium, whereas the phrenic nerve of the rat was not. Bretylium had little effect on gastrointestinal propulsion or on the sensitivity of smooth muscle to acetylcholine, 5‐hydroxytryptamine, adrenaline, or noradrenaline, but moderate amounts depressed the peristaltic reflex and the sensitivity of the guinea‐pig ileum to histamine. Bretylium caused postural hypotension in the cat in doses which had little effect on the supine blood pressure. Experiments on the nictitating membrane indicated that compensation for the effects of bretylium on low rates of stimulation of postganglionic sympathetic nerves could be attained by a small increase in the rate of stimulation, whereas compensation for its effects on high rates required an increase in the rate of stimulation beyond physiological limits.

A novel electrophysiological approach to monitor pulse by pulse the concentration of released noradrenaline at the presynaptic alpha 2-adrenoceptors of sympathetic nerves in rat tail artery.

The excitatory junction current (EJC) evoked by electrical stimulation of postganglionic sympathetic nerves of rat tail artery with 100 pulses at 2 Hz, at 1.3 mmol/l external Ca2+, was used as a measure of the per pulse release of ATP. In controls the EJCs were initially facilitated, then gradually depressed during the stimulus train. The first EJC was slightly depressed by the alpha 2-adrenoceptor antagonist yohimbine, but starting from the 4th pulse the EJCs were enhanced. Yohimbine increased the early facilitation without markedly modifying the subsequent depression. The yohimbine-induced enhancement of EJCs caused by pulses 11-100 was, thus, constant. The noradrenaline reuptake blocker cocaine depressed the EJCs, abolished the early facilitation and slightly enhanced the depression. These effects of cocaine were reversed by further addition of yohimbine. The alpha 2-adrenoceptor agonist xylazine (1 and 10 mumol/l) dose dependently depressed the EJCs starting from the first pulse. The inhibitory effect of 1 mumol/l xylazine, but not that of 10 mumol/l xylazine, declined with train length. The inhibition of individual EJCs caused by activation of presynaptic alpha 2-adrenoceptors was used to monitor the concentration of released noradrenaline at these receptors. The ratio of individual EJCs in the presence and absence of yohimbine was assumed to reflect, pulse by pulse, the relative concentration of released noradrenaline at the presynaptic alpha 2-adrenoceptors, and hence termed [NA]alpha 2. For comparison, the concentration of endogenous noradrenaline was monitored electrochemically by differential pulse amperometry with a carbon fibre microelectrode; this signal is termed [NA]CF. [NA]alpha 2 and [NA]CF grew during the first 7-10 or 14-16 pulses, respectively, and then remained relatively constant throughout the stimulus train. Cocaine caused [NA]alpha 2 and [NA]CF to continue to grow during the first 35 and 50 pulses, and enhanced their peak levels by 180% and 320%, respectively. For comparison with the effects on the EJCs mediated via presynaptic alpha 2-adrenoceptors, those caused by varying external Ca2+ level were examined. At 0.65 mmol/l Ca2+ the amplitude of the first EJC was smaller than that at 1.3 mmol/l Ca2+, but the facilitation of later EJCs was enhanced and the subsequent depression reduced. An increase in external Ca2+ to 2.6 mmol/l had the opposite effects. All effects on EJCs caused by changes in external Ca2+ were maximal for the first EJC and then declined with the train length.(ABSTRACT TRUNCATED AT 400 WORDS)

Muscarinic M 1- and M 2-receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens

Twitch contractions of the rabbit vas deferens elicited field stimulation were inhibited by tetrodotoxin, guanethidine, bretylium and α,ß-methylene-ATP but were unaffected by hexamethonium, physostigmine, 1,1-dimethyl-4-phenylpiperazinium and prazosin, suggesting that they resulted from ATP released following postganglionic sympathetic nerve stimulation. McN-A-343 inhibited but carbachol and several other muscarinic agonists potentiated the twitch contractions; these effects were not modified by hexamethonium or physostigmine. Muscarinic agonists had no effect on the tension in unstimulated organs whereas contractions elicited by ATP, noradrenaline and KC1 were potentiated by carbachol but remained unaffected by McN-A-343. The responses of the twitch contractions to McN-A-343 and carbachol were inhibited to different degrees by antimuscarinic drugs: the affinity (pA 2) of atropine, secoverine and himbacine against McN-A-343 and carbachol was similar. However, pirenzepine, telenzepine, trihexyphenidyl, dicyclomine and hexahydro-sila-difenidol displayed preferential antagonism of the responses to McN-A-343 whereas the converse was true for AF-DX 116 and gallamine. The highly significant correlation between the pA 2 values obtained for 10 antagonists against carbachol responses in rabbit vas deferens and rat left atrium suggests that the receptors may be similar. The data support the presence of a presynaptic M 1-receptor mediating inhibition and a postsynaptic, cardiac-like M 2-receptor responsible for enhancing neurogenic contractions in rabbit vas deferens.

Neuropeptide Y and non-adrenergic sympathetic vascular control of the cat nasal mucosa.

Neuropeptide Y (NPY) coexists with noradrenaline (NA) in a population of perivascular nerves in the cat nasal mucosa. In the present study, NPY was found to exert non-adrenergic nasal vasoconstrictor actions. Postganglionic sympathetic nerve stimulation induced a release of NPY-like immunoreactivity (LI) concomitant with vasoconstriction in the nasal mucosa. About 60 and 70% of the vasoconstrictor responses upon sympathetic stimulation at 2 and 10 Hz, respectively, remained after pretreatment with phenoxybenzamine and propranolol which abolished the effects of exogenous NA. Preganglionic denervation one week prior to the experiments did not change the vasoconstrictor response to sympathetic nerve stimulation or the NA or NPY contents of the nasal mucosa. The levels of NPY-LI in the superior cervical ganglion were however reduced. After reserpine treatment, which depleted the nasal NA content by almost 90% and the NPY content by 50%, a vasoconstrictor response to nerve stimulation was still present. After reserpine treatment combined with preganglionic denervation, nerve stimulation simultaneously induced an increased output of NPY-LI and a marked long-lasting vasoconstriction which was not influenced by phenoxybenzamine and propranolol. The reserpine-induced depletion of NA was not influenced by preganglionic denervation while the reduction in the nasal content of NPY-LI was prevented. In conclusion, NPY could be a non-adrenergic mediator of sympathetic vascular effects in cat nasal mucosa.

Identification of the neuroeffector transmitter in jejunal branches of the rabbit mesenteric artery.

Vasoconstriction or excitatory junction potentials (e.j.ps) evoked by nerve stimulation (15 field pulses at 2 Hz every 3 min) were recorded in rabbit isolated jejunal arteries. The resting diameter of the arteries and its decrease in response to stimulation was measured by a photoelectric method. Vasoconstriction was insensitive to prazosin 0.1 or 1 mumol/l. Yohimbine 1 mumol/l considerably enhanced, whereas alpha,beta-methylene ATP (alpha,beta-meATP) 1 mumol/l abolished the contractile response. In order to test the effect of exogenously applied transmitter candidates, noradrenaline (0.1-1 mumol/l) and ATP (10-30 mumol/l) were added in concentrations which evoked a vasoconstriction comparable to that induced by electrical stimulation. The action of noradrenaline was prevented by prazosin 0.1 mumol/l, but was unaffected by both yohimbine 1 mumol/l and alpha,beta-meATP 1 mumol/l. Alpha,beta-meATP 1 mumol/l depressed the effect of ATP. The e.j.ps evoked by a train of 15 pulses showed facilitation up to the third response and thereafter depression; a partial summation was also observed. Prazosin 0.1 mumol/l did not change the e.j.p. amplitudes. By contrast, when yohimbine 0.1 or 1 mumol/l was added to the prazosin-containing medium, both the late e.j.ps in the train and the summation were enhanced in a concentration-dependent manner. Alpha,beta-meATP 1 mumol/l almost abolished the e.j.ps. In conclusion, in rabbit jejunal arteries, stimulation of postganglionic sympathetic nerves may release noradrenaline together with ATP which is probably the sole neuroeffector transmitter under our conditions. Transmitter release seems to be modulated by the activation of presynaptic alpha 2-adrenoceptors. Under the stimulation conditions of the present experiments the released transmitter does not activate postsynaptic alpha 1-adrenoceptors.

Effects of chloride ion substitution on the frequency dependence and alpha-autoinhibition of [3H]noradrenaline secretion in guinea-pig vas deferens.

Guinea-pig isolated vas deferens, in which the stores of noradrenaline (NA) had been labelled by preincubation with [3H]NA, was used to study the effects of substitution of chloride with other anions, on transmitter secretion evoked by electrical stimulation of postganglionic sympathetic nerves. Chloride was omitted from the Tyrode's solution and substituted with acetate, nitrate, methylsulphate, sulphate or HEPES. All substituents increased both the spontaneous and the stimulus-evoked fractional secretion of [3H]NA under control conditions. The effect was essentially the same at all frequencies of stimulation (1-8 Hz). In the presence of the alpha-adrenoceptor blocker phentolamine, which enhanced the secretion of [3H]NA in all media, the secretion was not further enhanced by chloride substitution. Chloride substitution reduced the depressing effect of exogenous NA on the secretory response. In conclusion, chloride ions may be required for full expression of alpha-adrenoceptor-mediated inhibition of [3H]NA secretion, but do not markedly influence facilitation by increased frequency of stimulation.

Pre- and postjunctional α-adrenoceptors at sympathetic neuroeffector junction in bovine mesenteric lymphatics

We studied isolated bovine mesenteric lymphatics to elucidate the pharmacological characteristics of pre- and postjunctional α-adrenoceptors at the sympathetic neuroeffector junction. Cylindrical strips were incubated with [ 3H]-noradrenaline and mounted for superfusion. Electrical stimulation (2 Hz, 0.5 msec, 50 V) augmented the fractional release of labeled noradrenaline. Exogenous noradrenaline and clonidine caused a depression of the evoked tracer release. Phenoxybenzamine and yohimbine markedly enhanced the evoked overflow of adrenergic transmitter. Rings of lympahatic vessels were mounted for isometric tension recording in organ chambers filled with Krebs-Ringer bicarbonate solution. The vessels contracted when exposed to phenylephrine and clonidine. The ED 50 of clonidine was significantly lower than that of phenylephrine. Prazosin caused a parallel shift to the right of the dose-response curve to phenylephrine. The antagonist, however, suppressed the magnitude of the maximum response to clonidine. Yohimbine caused parallel shift to the right of the dose-response curves to phenylephrine and clonidine, respectively. The Schild plots for yohimbine demonstrated that the drug was a competitive antagonist to phenylephrine and clonidine. The pA 2 value of yohimbine to clonidine (7.6 ± 0.4) was larger than that to phenylephrine (6.2 ± 0.4). The pA 2 value of prazosin to phenylephrine was 7.2 ± 0.3. These results suggest that prejunctional α-adrenoceptors are involved in the negative feedback mechanism for autoregulation of noradrenaline release during post-ganglionic sympathetic nerve stimulation, and that both α 1- and α 2-like adrenoceptors do exist on lymphatic smooth muscle cells.

Galanin potentiates electrical stimulation and exogenous norepinephrine-induced contractions in the rat vas deferens

In order to evaluate the mode of action of galanin (GAL) on the neuroeffector mechanism of peripheral sympathetic nerve fibers, the effects of this peptide were tested on the electrical stimulated and the unstimulated preparations of the isolated rat vas deferens in the presence of 10 −7 M atropine. The contractile responses, which were mediated predominantly by activation of postganglionic noradrenergic nerve fibers were dose-dependently potentiated by GAL in concentrations ranging from 1 to 50 nM. The facilitatory action induced by GAL in high concentrations (> 10 nM) usually returned to the control level at 2–3 min and were tachyphylactic. The potentiating action of GAL was not modified by pretreatment with 10 −7 M propranolol. Contractions produced by exogenous norepinephrine (NE) in the unstimulated preparations were not affected by pretreatment with low concentrations (< 5 nM) of GAL. On the other hand, the contractions were dose-dependently potentiated 1 min after pretreatment with higher concentrations (> 10 nM) of GAL, which recovered 15 min after constant flow washout. Contractions developed by exogenous 5-hydroxytryptamine were not affected, or slightly inhibited, by GAL (1–50 nM). In some preparations without electrical stimulation, high concentrations of GAL caused a slight contraction, which was not blocked by pretreatment with 10 −6 M phentolamine and 10 −6 M tetrodotoxin. These results suggest that GAL receptors exist presynaptically in the rat vas deferens and that stimulation of the receptors by GAL potentiates the release of NE from the nerve terminals during postganglionic sympathetic nerve stimulation. Other mechanisms for GAL action, such as influence on neuronal uptake and catecholamine metabolism, cannot be ruled out.

Calcium antagonism of the inhibitory effects of fentanyl on the contraction of the nictitating membrane in cats

The contractile responses elicited from the nictating membrane of cats by postganglionic sympathetic nerve stimulation were decreased by fentanyl (10–20 μg/kg injected in the lingual artery). The inhibitory effect of fentanyl was preferential on responses elicited bu low frequency stimulation. Fentanyl (10–25 μg/kg) did not change the contractile responses to noradrenaline and tyramine. The inhibitory effect of fentanyl was antagonized by naloxone. Increases in plasma calcium concentration did not alter the contractile responses to symphatetic nerve stimulation but antagonized the inhibitory effect of fentanyl in a dose-depedent manner suggesting a possible competitive antagonism.

Peripheral sympatholytic effects of 1-alpha-acetylmethadol.

1-alpha-Acetylmethadol (LAAM), 1.4 mg/kg or greater, decreased the response of the cat nictitating membrane to pre- and postganglionic sympathetic nerve stimulation. LAAM had a greater effect on the low-frequency (0.5 Hz) than on the high-frequency (5-20 Hz) responses. No difference was observed between the effects of LAAM on the pre- as opposed to the postganglionic responses. The responses ot the nictitating membranes to intravenous epinephrine were not affected by LAAM. LAAM appears to act at the nerve terminal. The minimum dose of LAAM (1.4 mg/kg) which decreased the nictitating membrane responses also decreased blood pressure and heart rate. Naltrexone, 300 micrograms/kg, s.c., antagonized the effects of LAAM on the nictitating membrane responses and the cardiovascular actions of the drug. In anesthetized dogs, naltrexone completely blocked the blood pressure response to LAAM and partially blocked the effects of LAAM on heart rate and contractile force. The data suggest that LAAM may produce its cardiovascular effects, in part, by an action on the peripheral sympathetic nervous system which involves opiate binding sites. LAAM also appears to have direct actions on the heart to decrease heart rate and contractile force that do not involve opiate binding sites.

Regional sympathectomy induced by intra-arterial 6-hydroxy-dopamine

Single intra-carotid injections of 5–15 mg of 6-OH-DA HBr in adult cats reduced or abolished the responses of the ipsilateral nictitating membrane to electrical stimulation of post-ganglionic sympathetic nerves and intra-carotid injections of tyramine; the responses of the contralateral nictitating membrane to the same stimuli remained normal. One to five days after 6-OH-DA, the ipsilateral nictitating membranes, unresponsive to sympathetic stimulation, were hypersensitive to i.v. injections of adrenaline or noradrenaline. The advantages of regional over systemic chemical sympathectomy are discussed.

A NEW GUANIDINE DERIVATIVE: DISSOCIATION OF THE ADRENERGIC NEURON BLOCKING ACTIVITY FROM LOCAL ANESTHETIC ACTIVITY

AbstractEffects of 4-7-exo-methylene-hexahydroisoindoline-ethyl-guanidine hemi-sulfate (No. 865-123), a new guanidine derivative, on adrenergic neurons and its local anesthetic activity were investigated in comparison with guanethidine. Both derivatives produced in a dose-dependent manner a progressive irreversible reduction of positive chronotropic and contractile responses to postganglionic sympathetic nerve stimulation in isolated rabbit atria. The time course of the reduction by No. 865-123 was somewhat slower. In dogs administered both agents, the pressor response to carotid occlusion was reduced and that to exogenous noradrenaline was potentiated with a slight decrease in blood pressure. Noradrenaline stores in the heart and spleen of rats were also depleted to a similar extent. In the guinea pig weal method, guanethidine acted as a potent local anesthetic with a slow onset and a prolonged action as compared to procaine. No. 865-123 revealed no more anesthetic activity than did saline. It is unlikely that the local anesthetic activity of the guanidine derivatives contributes to the adrenergic neuron blocking activity.

Effect of nonachlazine on adrenergic neurotransmission in the rat vas deferens

The effect of a new antianginal preparation, nonachlazine, on adrenergic neurotransmission in the isolated rat vas deferens was studied by recording contractions of the duct in response to transmural stimulation of postganglionic sympathetic nerves by the electric current or by application of noradrenalin (NA) or BaCl2. The effect of nonachlazine on the NA content was studied spectrofluorometrically and the ability of the preparation to block the uptake of exogenous NA by the tissues also was investigated. Nonachlazine was found to have a moderate sympatholytic action, which was combined with its spasmolytic effect. Nonachlazine also has a well marked ability to block the reaccumulation of NA in the tissues.

Effect of digitalis on response of the ventricular pacemaker to sympathetic neural stimulation and to isoproterenol

It is established that digitalis antagonizes the chronotropic effect of adrenergic stimulation of the heart, and this finding suggests that the sympathetic nervous system does not play a significant role in ventricular arrhythmias produced by digitalis. However, this antagonism has been established by testing the response of the sinus nodal pacemaker to digitalis and adrenergic stimulation. Since clinically significant digitalis-induced arrhythmias are ventricular in origin, the response of the ventricular pacemaker seems the more critical variable. To test this hypothesis, we applied two types of adrenergic stimulation before and after ouabain administration to anesthetized dogs with complete atrio-ventricular block. Ouabain in a dose of 40 μg/kg caused no significant change in the increase in heart rate produced either by electrical stimulation of postganglionic sympathetic nerves or by isoproterenol administration. In 6 of the 12 dogs ventricular tachycardia developed after digitalis administration at levels of adrenergic stimulation that did not cause arrhythmia before the drug was given. These results indicate that digitalis does not affect the chronotropic response to adrenergic stimulation of ventricular pacemakers. Moreover, the heart exposed to digitalis appears to be sensitized to the arrhythmogenic effects of adrenergic stimuli.

A muscarinic inhibition of the noradrenaline release evoked by postganglionic sympathetic nerve stimulation

1 The noradrenaline output from isolated rabbit hearts perfused with Tyrode solution was estimated fluorimetrically. The postganglionic sympathetic nerves of the heart were stimulated (10 shocks/sec; 1 msec) for three 1 min periods with intervals of 10 min. 2 The noradrenaline output evoked by 3 consecutive stimulation periods decreased exponentially. 3 Acetylcholine (10−9—10−6 g/ml) administered continuously one min before to one min after the second stimulation caused a dose-dependent reduction of the noradrenaline output evoked by the second stimulation to as low as 19% of the normal value. Acetylcholine in the concentrations applied did not cause a noradrenaline output by itself. 4 The inhibitory action of acetylcholine 10−6 g/ml was fully antagonized by atropine 10−6 g/ml, whereas hexamethonium 3×10−6 g/ml had no significant antagonistic effect. 5 The noradrenaline output caused by nerve stimulation was not decreased in the presence of DMPP 10−6 g/ml. DMPP 10−5 g/ml applied 3 min before electrical nerve stimulation caused an output of noradrenaline for 2 min but did not inhibit the noradrenaline release by nerve stimulation. 6 Tyramine 5 × 10−6 g/ml was administered to the rabbit heart for two 6 min periods at an interval of 15 min. Methacholine 7.4 × 10−5 g/ml or atropine 10−6 g/ml if present during the second tyramine infusion did not alter the noradrenaline output produced by tyramine. 7 It is concluded that low concentrations of acetylcholine by stimulating muscarinic inhibitory receptors interfere with the noradrenaline release from the postganglionic sympathetic nerve fibres evoked by electrical nerve stimulation. The possibility of a peripheral direct interaction of the cholinergic with the adre-nergic nervous system is discussed.

Influence of sodium ions on the membrane potential of the sino-atrial node in response to sympathetic nerve stimulation.

1. Sympathetic nerve-atrial preparations isolated from rabbits were used in the present study. Transmembrane potentials were recorded from sino-atrial (S-A) nodal pace-maker fibres.2. A reduction of [Na(+)](o) (extracellular concentration of sodium ions) decreased the maximal diastolic potential, reduced the size of the overshoot, prolonged the depolarization time, increased the rate of early repolarization and decreased the rate of late repolarization.3. A Na(+)-deficiency markedly augmented the positive chronotropic effect of stimulation of post-ganglionic sympathetic nerves at a frequency of 5/sec but slightly augmented the effect of stimulation at 1 and 20/sec.4. The marked membrane effect of sympathetic nerve stimulation at low [Na(+)](o) was an increase in the slope of slow depolarization during diastole. Corresponding to an induced acceleration of S-A nodal rate, the 90% duration of the action potential was decreased but the other action potential parameters measured were not influenced.5. A reduction of [Na(+)](o) to 51.7 mM produced in the pace-maker membrane, subthreshold oscillations the rate and the amplitude of which were increased by sympathetic nerve stimulation until conducted potentials were generated.6. It is presumed that cardiac noradrenaline elicits an increase in the slope of slow depolarization during late diastole which is due to an increase in Na(+) permeability, a decrease in K(+) permeability or a non-selective increase in ion permeability, but that it does not influence the pace-maker membrane during systole.