Neuronal Blocker Research Articles

Substance P-immunoreactive nerve fibres in the anterior segment of the rabbit eye. Distribution and possible physiological significance.

Substance P-immunoreactive nerve terminals were found in several locations in the anterior segment of the rabbit eye. In the iris they occurred in the sphincter muscle and were randomly distributed in the iris stroma with some fibres running close to the dilator muscle. In the ciliary body these immunoreactive elements were few and occurred within bundles of nerve fibres. while in the ciliary processes they were more numerous with a predominantly subepithelial location. Blood vessels in the anterior uvea were often surrounded by substance P-immunoreactive fibres. No substance P-fibres were found in the cornea, while the sclera contained very few such elements. Using conventional in vitro techniques it was found that the sphincter pupillae muscle of the iris responded to electrical stimulation with a contraction that was resistant to cholinergic and adrenergic blockade, but was inhibited by the neuronal blocker tetrodotoxin. This indicates the existence of a non-cholinergic, non-adrenergic neuronal mediator of the contractile response. Exogenously applied substance P produced a long-lasting contraction of the spincter muscle, an observation compatible with the view that substance P is the noncholinergic, non-adrenergic neurotransmitter involved.

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.

Further evidence for norepinephrine as a neurotransmitter stimulating release of melanin-dispersing hormone in the fiddler crab, Uca pugilator: The changes in the melanophores of the crabs following reserpine, 6-hydroxydopamine and bretylium administration

1. 1. The effects on the melanophores of the fiddler crab, Uca pugilator, of the amine depletor reserpine, the catecholamine neurotoxin 6-hydroxydopamine and the noradrenergic neuron blocker bretylium were investigated. 2. 2. The most striking effect of these drugs was that they strongly reduced the amount of melanin dispersion that normally results on transferring the crabs from a white to a black background. The drugs had no effect on pigment migration in melanophores of isolated legs. These results are in accord with the hypothesis that norepinephrine serves as a neurotransmitter stimulating release of a melanin-dispersing hormone in Uca pugilator. 3. 3. Norepinephrine was found in the central nervous system of Uca pugilator.

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.

An electropharmacological analyses of the effects of some drugs on neuromuscular transmission in the vas deferens of the guinea-pig.

1 The effects of several drugs upon the excitatory junction potential (e.j.p.) in the guinea-pig vas deferens have been investigated. 2 Amiodarone, a noradrenergic neurone blocker which also blocks both alpha and beta-adrenoreceptors, did not reduce the e.j.p. 3 The alpha-adrenoreceptor antagonists, azapetine, piperoxan and prazosin, only enhanced the e.j.p. irrespective of their relative potencies at alpha 1 and alpha 2-adrenoreceptors. 4 Sotalol, a beta-adrenoreceptor antagonist, was without effect upon the e.j.p. 5 Clonidine and lysergic acid diethylamide, alpha-adrenoreceptor agonists, produced a dose dependent inhibition of the e.j.p. without apparently affecting the frequency or size of spontaneous junction potentials. 6 The effects of clonidine were antagonized by piperoxan in a competitive reversible manner. 7 It is argued that these results confirm the presence of alpha-adrenoreceptors prejunctionally upon the sympathetic excitatory innervation of the vas deferens but that although an endogenous alpha-adrenoreceptor agonist is released by nerve stimulation either the transmitter that is responsible for the e.j.p. is not noradrenaline or that the postjunctional receptors responsible for the generation of the e.j.p. are not adrenoreceptors.

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.

Minoxidil in the Management of Intractable Hypertension

Eighty-seven patients with intractable hypertension received minoxidil for a mean duration of 27 months (range three months to five years). A significant reduction in mean outpatient blood pressure from 206/129 to 158/98 mmHg (p less than 0.001 for both systolic and diastolic values) was recorded after one month's treatment. In 26 patients who received minoxidil for four or more years a further reduction in mean blood pressure to 147/89 mmHg was achieved. The mean daily dose of minoxidil was 23 mg (range 2.5 to 60 mg). In all patients a beta adrenergic neurone blocker and a diuretic were prescribed with minoxidil to counteract tachycardia and fluid retention. Thirteen patients required the addition of a fourth hypotensive agent. The use of minoxidil led to simpler drug regimens with the majority of patients well controlled on twice daily or once daily schedules. Most patients commented spontaneously on a feeling of improved wellbeing while taking minoxidil which also appeared to be relatively free from side effects commonly encountered with other hypotensive drugs, particularly drowsiness, dizziness and impotence. Fluid retention of 7 kg or more occurred in 18 patients, more commonly in those with renal impairment, but could be controlled by increasing the dose or potency of diuretics. Four patients with end stage renal failure and one patient with normal renal function developed pericardial effusions. Hirsutism was universal and limited the usefulness of the drug in women. We currently recommend minoxidil for hypertensive men who diastolic blood pressure remains greater than or equal to 110 mmHg despite an adequate trial of a beta adrenergic neurone blocker, diuretic and an additional drug, or for patients who find the side effects of such therapy intolerable.

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.

Long-term antihypertensive drug treatment and blood pressure control in three hospital hypertension clinics.

Prescribing patterns and blood pressure control have been studied in 1101 patients treated at three specialist hypertension clinics in Britain. Seventy-four per cent of the patients were already receiving treatment at the time they were referred by their general practitioners. Though the initial improvement in blood pressure control was satisfactory, there was often some deterioration of control over the long term. The pressure exceeded 140/90 mmHg in the majority of patients followed for a year or more. During 1971-5 diuretics remained first preference, with increasing use of beta-blockers and a distinct decline in the use of sympathetic neurone blockers both by hospital staff and referring practitioners. Multiple drug treatment was common, nearly half the patients requiring more than one antihypertensive drug. In newly treated patients the frequency of cessation of a particular class of drug because of side effects or lack of efficacy ranged from 6 per cent with diuretics to 57 per cent with adrenergic neurone blocking drugs. Long-term blood pressure control still presents many problems, and the results contrast with the more optimistic interpretations sometimes placed on short-term clinical trials of antihypertensive effect.

Delay by bretylium of adrenergic nerve degeneration after sympathectomy of the submaxillary gland

Administration of 24 μmol/kg of bretylium 10 h after ganglionectomy delayed the loss of endogenous norepinephrine and the impairment of neuronal uptake of 3H-metaraminol ( 3H-MA) that follow sympathetic denervation. This delay was evident 16 and 20 h after denervation. Twenty four h after ganglionectomy, when NE stores and uptake of 3H-MA were reduced to their lowest values in untreated rats, in bretylium-treated ones these values were approximately 40% of those in normal glands. The onset of degeneration secretion in treated rats was delayed by about 9 h. The development of prejunctional supersensitivity was also delayed. The subcellular distribution of NE in normal and 16 h denervated glands showed that denervation reduced the neurotransmitter to the same extent in the 3 fractions: coarse, supernatant and microsomal. Treatment with bretylium and pargyline prevented the loss of NE from the microsomal fraction. Previous administration of pargyline antagonized thep protection of 3H-MA uptake seen in 28 h denervated rats treated with bretylium. However, this drug combination induced a greater retention of endogenous NE 24 h after denervation. Bretylium inhibited intraneuronal MAO by 40%. It is concluded that bretylium treatment can delay the degeneration of adrenergic nerve terminals separated from the cell bodies by a phamacological effect probably not related to MAO inhibition or to its neurone blocking action.

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.

Inhibition of neuronal noradrenaline uptake by angiotensin II in the rat mesentery

In the isolated perfused rat mesentery, angiotensin II (3 × 10−9 M) in subpressor doses enhanced the vasoconstrictor responses to noradrenaline by 9.6 ± 1.4 mmHg. However, in mesenteries obtained from rats chemically sympathectomized with 6-hydroxydopamine, angiotensin II was without effect. Treatment of mesenteries with the noradrenaline neuronal uptake blockers desmethylimipramine (10−10 M), protriptyline (10−10 M), or cocaine (10−6 M) potentiated responses to noradrenaline by 3.8 ± 0.84, 3.7 ± 0.67, and 5.5 ± 0.26 mmHg, respectively. Angiotensin II alone or in combination with either desmethylimipramine, protriptyline, or cocaine potentiated the noradrenaline responses to a similar extent. On the other hand, corticosterone (1.5 × 10−6 M), an extraneuronal uptake blocker, enhanced noradrenaline responses by 4.3 ± 1.4 mmHg, and this enhancement was additive with the potentiation produced by cocaine and (or) angiotensin II. We conclude that angiotensin II in subpressor doses acts presynaptically to block selectively the neuronal uptake of noradrenaline without any appreciable effect on extraneuronal uptake.

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.

Effects of pyroxamidine and guanethidine on contractile responses to field stimulation and to noradrenaline in the anococcygeus muscle and vas deferens of the rat

Abstract The effects of pyroxamidine (EMD 21192) and guanethidine on contractile responses were studied in the anococcygeus muscle and vas deferens of the rat. Pyroxamidine (10−6 and 10−5 M) and guanethidine (6 times 10−6 and 10−5 M) potentiated the responses to low concentrations of acetylcholine in the rat anococcygeus muscle. Following incubation of the muscle with 6-hydroxydopamine (10−3M for 3 h), pyroxamidine (10−5 M) and guanethidine (10−5 M) had no effect on responses to acetylcholine. This suggests that the potentiating effect of pyroxamidine and guanethidine on responses to acetylcholine is due to the release of subthreshold concentrations of noradrenaline. In the anococcygeus, pyroxamidine (10−6 and 10−5 M) and guanethidine (10−6 and 10−5 M) inhibited responses to field stimulation and potentiated responses to exogenously applied (−)-noradrenaline. The responses to field stimulation in the vas deferens were also inhibited by 10−5M pyroxamidine and by 10−5 M guanethidine. 10−6 M guanethidine, but not 10−5 M pyroxamidine, potentiated responses to (−)-noradrenaline in the vas deferens. In the presence of nortriptyline (10−6 M), a potent inhibitor of neuronal uptake, the inhibitory effects of pyroxamidine and guanethidine on responses to field stimulation were reduced or reversed and these drugs had no effect on responses to (−)-noradrenaline. This suggests that pyroxamidine is a noradrenergic neuron blocker and that its action is dependent on continued neuronal uptake. Following 6-hydroxydopamine incubation, 10−5 M pyroxamidine and 10−5 M guanethidine inhibited the responses to (−)-noradrenaline in the rat anococcygeus muscle. Thus it seems likely, at high concentrations, that these compounds have postsynaptic blocking activity.

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.

Reversible hyperphagia and obesity following intracerebral microinjections of colchicine into the ventromedial hypothalamus of the rat

Colchicine, a drug which produces a reversible inhibition of intraaxonal transport and synaptic transmission, was used as a reversible neural blocker to investigate the role of the ventromedial hypothalamus (VMH) in the control of ingestive behavior and body weight regulation. Male Sprague-Dawley rats received intracranial microinjections of colchicine into the VMH. Volume and concentration of the colchicine solution were varied to assess specificity of action and dose-response relationship. When colchicine (2 and 4 microgram) was microinjected bilaterally into the VMH, there was a dose-dependent increase in food and water intakes and body weight gain which lasted several days. The acute period of hyperphagia was followed by a marked depression in feeding which persisted until body weight was lowered to control levels. This suppression of feeding appeared to be a consequence of the preceding period of hyperphagia and obesity, since colchicine-treated rats which were pair-fed with controls to prevent obesity continued to maintain normal food intake and body weight gain when later fed ad libitum. The results of this study confirm the importance of the VMH in the long term regulation of feeding, and indicate that reversible neuronal blocking with colchicine is a useful technique for investigating the neural substrates of feeding and other behaviors.

STIMULATION OF PRESYNAPTIC β‐ADRENOCEPTORS ENHANCES [3H]‐N0RADRENALINE RELEASE DURING NERVE STIMULATION IN THE PERFUSED CAT SPLEEN

1 The effects of isoprenaline, propranolol and phosphodiesterase inhibitors on (3)H-transmitter overflow elicited by low frequency nerve stimulation were determined in the isolated perfused spleen of the cat.2 (-)-Isoprenaline (0.14, 1.4, and 14 nM) produced a concentration-dependent increase in [(3)H]-transmitter overflow evoked by nerve stimulation at 1 Hz and was more effective at 1 Hz than at 2 hertz.3 A concentration of propranolol (0.1 muM), devoid of neurone blocking activity, blocked this effect of (-)-isoprenaline. These results are compatible with the presence of beta-adrenoceptors in the noradrenergic nerve endings of the cat spleen.4 (+)-Isoprenaline (140 nM) failed to increase the release of radioactivity induced by nerve stimulation, indicating that the beta-adrenoceptor mediating the facilitation of transmitter release was stereospecific.5 The increase in (3)H-transmitter overflow induced by nerve stimulation during exposure to the phosphodiesterase inhibitor, papaverine (27 muM) was more pronounced than that obtained in the presence of 3-isobutyl-1-methyl xanthine (IBMX) 0.5 mM. The facilitation in transmitter release induced by papaverine was not correlated with the granular effect produced by this drug.6 In the presence of papaverine, the concentration-effect curve for (-)-isoprenaline on transmitter release was shifted to the left and its maximum was increased. In addition, propranolol significantly reduced the enhancement in noradrenaline release obtained by exposure to papaverine under conditions in which the granular effect produced by the phosphodiesterase inhibitor was even greater than in the absence of the beta-blocker.7 It is concluded that activation of presynaptic beta-adrenoceptors in the perfused cat spleen leads to an enhancement in transmitter release which appears to be linked to an increase in cyclic adenosine 3',5'-monophosphate levels in noradrenergic nerve endings.