Transmitter Outflow Research Articles

Adenosine and glutamate extracellular concentrations and mitogen-activated protein kinases in the striatum of Huntington transgenic mice. Selective antagonism of adenosine A 2A receptors reduces transmitter outflow

The basal ganglia and deep layers of cerebral cortex neurodegeneration typically characterize the postmortem brain of Huntington disease (HD) patients. In this study, we employed 10- to 11-week-old transgenic HD mice (R6/2 line), in which the striatal adenosine extracellular levels, measured using the microdialysis technique, are significantly increased in comparison to wild-type mice. An increase in striatal adenosine is probably a precocious index of mitochondrial dysfunction that is described in both the postmortem brain of HD patients and transgenic mice striatal cells. The adenosine increase is matched by activation of the p38 mitogen-activated protein kinase (MAPK) in the striatal neurons of R6/2 mouse but not in the cortex. This result indicates that p38 MAPK is a correlate of striatal damage and suggests a role for p38 in the striatal neuron suffering and apoptosis described in this disease. The selective adenosine A 2A receptor antagonist SCH 58261, administered through microdialysis fiber into the striatum, significantly decreases the outflow of glutamate in R6/2 mice. Antagonism of adenosine A 2A receptors might be regarded as potentially useful in the treatment of this disease to control striatal excitotoxicity.

The selective A 2A receptor antagonist SCH 58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat

Adenosine A 2A receptor antagonists have been proved protective in different ischemia models. In this study we verified if the protective effect of the selective A 2A antagonist, SCH 58261, could be attributed to the reduction of the excitatory amino acid outflow induced by cerebral focal ischemia. A vertical microdialysis probe was inserted into the striatum of male Wistar rats and, after 24 h, permanent right intraluminal middle cerebral artery occlusion (MCAo) was induced. Soon after waking, rats showed a definite contralateral turning behavior, which persisted up to 7 h after MCAo. During 4 h after MCAo, glutamate, aspartate, GABA, adenosine and taurine outflow increased. SCH 58261 (0.01 mg/kg, i.p.), administered 5 min after MCAo, suppressed turning behavior and significantly reduced the outflow of glutamate, aspartate, GABA and adenosine. At 24 h after MCAo, the rats showed severe sensorimotor deficit and damage in both the striatum and cortex. SCH 58261 significantly reduced cortical damage but did not protect against the sensorimotor deficit. The protective effect of SCH 58261 against turning behavior and increased outflow of excitatory amino acids in the first hours after MCAo suggests the potential utility of selective adenosine A 2A antagonists when administered in the first hours after ischemia. Furthermore, this study, for the first time, proposes that turning behavior after permanent intraluminal MCAo, be used as a precocious index of neurological deficit and neuronal damage.

Experimental uremia affects hypothalamic amino acid neurotransmitter milieu.

Chronic renal failure is associated with delayed puberty and hypogonadism. To investigate the mechanisms subserving the reported reduced pulsatile release of gonadotropin-releasing hormone (GnRH) in chronic renal failure, this study examined the amino acid neurotransmitter milieu in the medial preoptic area (MPOA), the hypothalamic region where the GnRH-secreting neurons reside, in 5/6-nephrectomized male rats and in ad libitum-fed or pair-fed controls. All rats were castrated and received either a testosterone or a vehicle implant to evaluate additional effects of the prevailing sex steroid milieu. Local excitatory (essential amino acids: aspartate, glutamate) and inhibitory (gamma-aminobutyric acid [GABA], taurine) amino acid transmitter outflow in the MPOA was measured by microdialysis via stereotactically implanted cannulae in the awake, freely moving rats. In addition to basal extracellular concentrations, the neurosecretory capacity was assessed by the addition of 100 mM KCl to the dialysis fluid. The mechanisms of neurosecretion were evaluated further by inhibition of vesicular release with the use of Ca(2+)-free, Mg(2+)-enriched dialysis fluid and by local perfusion with inhibitors of voltage-dependent synaptic release (1 microM tetrodotoxin) and of GABA reuptake (0.5 mM nipecotic acid). In the uremic rats, basal outflow of GABA, glutamate and aspartate, and K(+)-stimulated aspartate outflow were increased. K(+)-stimulated GABA and glutamate release was less sensitive to Ca(2+) depletion in the uremic than in the control rats. The elevated basal GABA and essential amino acid outflow in the uremic rats was due to a voltage- and Ca(2+)-independent mechanism. GABA reuptake was inhibited proportionately by nipecotic acid in uremic and pair-fed control rats. Testosterone supplementation had no independent effects on neurotransmitter outflow. In summary, the amino acid neurotransmitter milieu is altered in the MPOA of uremic rats by a nonsynaptic, nonvesicular mechanism. These abnormalities may contribute to the impaired function of the GnRH pulse generator.

Striatal outflow of adenosine, excitatory amino acids, gamma-aminobutyric acid, and taurine in awake freely moving rats after middle cerebral artery occlusion: correlations with neurological deficit and histopathological damage.

While a number of studies have investigated transmitter outflow in anesthetized animals after middle cerebral artery occlusion (MCAO) performed by craniectomy, studies have never been performed after MCAO induced by intraluminal filament. In addition, it has been reported that after MCAO, infarct volume correlates with functional outcome and with transmitter outflow, although there are no studies that demonstrate a direct correlation between transmitter outflow and functional outcome. The purpose of the present study was to assess excitatory amino acids, gamma-aminobutyric acid, taurine, and adenosine outflow in awake rats after intraluminal MCAO and to determine whether, in the same animal, outflow was correlated with neurological outcome and histological damage. Vertical microdialysis probes were placed in the striatum of male Wistar rats. After 24 hours, permanent MCAO was induced by the intraluminal suture technique. The transmitter concentrations in the dialysate were determined by high-performance liquid chromatography. Twenty-four hours after MCAO, neurological deficit and histological outcome were evaluated. All transmitters significantly increased after MCAO. Twenty-four hours after MCAO, the rats showed a severe sensorimotor deficit and massive ischemic damage in the striatum and in the cortex (9+/-2% and 25+/-6% of hemispheric volume, respectively). Significant correlations were found between the efflux of all transmitters, neurological score, and striatal infarct volume. In this study, for the first time, amino acid and adenosine extracellular concentrations during MCAO by the intraluminal suture technique were determined in awake and freely moving rats, and a significant correlation was found between transmitter outflow and neurological deficit. The evaluation of neurological deficit, histological damage, and transmitter outflow in the same animal may represent a useful approach for studying neuroprotective properties of new drugs/agents against focal ischemia.

Mesoprefrontal dopaminergic neurons: Can tyrosine availability influence their functions?

The dopamine (DA) neurons projecting to the prefrontal cortex (PFC) are thought to be involved in working memory, stress response, and the pathogenesis of schizophrenia. In this commentary, we review the current evidence supporting a precursor tyrosine dependence of these mesoprefrondal DN neurons. Several studies in rats employing different experimental paradigms [i.e. experimental diabetes and early-treated phenylketonuria (PKU) model]have shown that reduced tyrosine levels in brain can affect markedly the physiology and functions of these DA neurons. However, supplemental tyrosine is effective in enhancing functional transmitter outflow from mesoprefrontal DA neurons only under conditions where their physiological activity is enhanced and DA synthesis and release are uncoupled from intrinsic regulatory controls. Recent studies in Humans have also suggested that variations in brain tyrosine levels can affect significantly higher cortical functions subserved by the PFC. In early-treated PKU patients with mildly reduced tyrosine levels, marked impairments in cognitive functions dependent on the dorsolateral PFC could be detected. In drugtreated schizophrenic patients, supplemental tyrosine was shown to have a disruptive effects on the smoothpursuit eye movement performance task. Furthermore, tyrosine administration was effective in restoring impaired working memory in humans following a cold stress paradigm, as assessed by a computer-based delayed matchingto-sample memory task. These human studies, together with the current evidence obtained from animal experiments, suggest that the functions of the mesoprefrontal DA neurons can, under certain circumstances, be readily influenced by the availability of the precursor tyrosine.

Mesocortical dopamine neurons: High basal firing frequency predicts tyrosine dependence of dopamine synthesis

Mesocortical dopamine (DA) neurons projecting to the prefrontal and cingulate cortices possess a faster basal firing rate and exhibit more bursting than other midbrain DA neurons. Thus, we examined whether tyrosine administration could preferentially affect DA synthesis in these DA neurons. Tyrosine administered at doses as low as 25 mg/kg significantly increased in vivo tyrosine hydroxylation in the prefrontal and cingulate cortices without affecting it in other mesocortical, mesolimbic, and nigrostriatal DA terminal fields examined. Further studies in the mesoprefrontal DA neurons showed that tyrosine administered at higher doses of 50 mg/kg initially enhanced tyrosine hydroxylation and elevated endogenous DA levels within 60 min. The resultant increases in DA levels appeared to feedback and normalize prefrontal tyrosine hydroxylase activity. The levels of DA metabolites in the prefrontal cortex were unaltered by doses of tyrosine from 25-200 mg/kg, suggesting that the functional transmitter outflow from these DA neurons is not normally affected by precursor administration under resting conditions. However, when these mesocortical DA neurons were pharmacologically activated following administration of the anxiogenic beta-carboline, FG7142, tyrosine administration (25 mg/kg) was effective in increasing DA metabolite levels in the prefrontal cortex. These results thus suggest that enhanced activity of the mesoprefrontal DA neurons renders these DA neurons much more dependent up on tyrosine availability for maintenance of transmitter output.

Effect of hypoxia on nerve-stimulation-induced release of noradrenaline from the rabbit heart.

The present study addressed the hypothesis that cardiac production of adenosine (ADO) and/or prostacyclin (PGI2) during hypoxia is augmented to a level sufficient to affect nerve-stimulation-induced release of noradrenaline (NA). Innervated rabbit hearts were perfused at high (95% O2) or low (8% O2) oxygen pressure. The effluxes of NA and purines from the heart were determined by HPLC and that of the PGI2 metabolite by radioimmunoassay. Five minutes of hypoxia elevated effluent purines (sum of ADO, inosine, and hypoxanthine) from 1.1 microM to 6.2 microM, but did not affect the outflow of NA. The ADO receptor antagonists THEO (100-200 microM) and 8PSOT (100 microM) given during hypoxia increased the evoked outflow of NA by 77% (P less than 0.01) and 37% (P less than 0.05), respectively. Indomethacin (30 microM, a prostaglandin synthesis inhibitor) reduced the efflux of PGI2 metabolite by 93% but did not per se affect NA outflow during simultaneous administration of THEO, either under normoxia or hypoxia. It is concluded that ADO, but not PGI2, plays a role in reducing transmitter release during hypoxia. In addition, hypoxia leads to an enhancement of transmitter release, probably unrelated to ADO or purines. The lack of effect of hypoxia alone on evoked outflow of transmitter seems to be the result of a combination of these two processes.

Influence of nootropic drugs on the stimulus‐release relationship of dopaminergic structures

AbstractBrain slices labelled with radioactive neurotransmitters are a well established system for the investigation of transmitter secretion. The basal outflow of transmitter in the absence of external stimuli is largely due to a passive diffusion from nerve endings. The potassiumstimulated overflow represents a quasiphysiological release with a well defined correlation between stimulus intensity and fractional efflux rate. Upon long‐term exposure of rats to mild hypobaric hypoxia (10 day, 20 hr daily) the stimulus‐release relationship shows a marked ascent in the gradient in comparison to naive animals. Twenty‐four hours after long‐term treatment with piracetam, pyritonol, meclofenoxate, or vinpocetine (twice a day for 3 weeks) only the pretreatment with piracetam (100 mg/kg, twice a day) leads to changes of the stimulus‐release relation comparable to that seen in rats that were exposed to a long‐term hypoxia. These effects continued until 10 days after the last injection of the drug or after cessation of hypoxia. Meclofenoxate, pyritinol, and vinpocetine were without marked effects on the stimulus‐release relation.

Noradrenergic rather than GABAergic processes as the common mediation of the antidepressant profile of GABA agonists and imipramine-like drugs in animals.

The present study was aimed at investigating in rats whether a common mechanism might underlie the reversal of depressive-like behaviors by classical antidepressants and by GABA agonists such as muscimol. Blockade of GABA transmission with picrotoxin (1 mg/kg IP) abolished the muscimol (0.5-1 mg/kg)-induced reduction of immobility in the swimming test and the reversal of escape failures in the learned helplessness paradigm. Conversely, picrotoxin was found not to reduce the efficacy of imipramine-like drugs in these same animal models. The combination of muscimol and tricyclics given at subeffective doses resulted in behavioral changes that can be accounted for by an additive interaction between these two classes of drugs. These data confirm the antidepressant-like profile of GABA agonists but suggest that it is unlikely that the primary antidepressant mechanism of conventional antidepressants involves GABA-A receptors. In the swimming test, prazosin (2 mg/kg), an alpha adrenoceptor blocker, antagonized the reduction of immobility produced by both muscimol and imipramine-like drugs. In the learned helplessness paradigm, penbutolol (0.25-0.5 mg/kg) and, though to a lesser extent prazosin, counter-acted the reversal of escape failures caused by muscimol and imipramine. On the basis of these data, it is tempting to speculate that increased transmitter outflow at noradrenergic receptors may be an essential component in the mechanism of action of imipramine-like drugs but also of GABA agonists.

The influence of 5-hydroxytryptamine on the release of acetylcholine from guinea-pig brain EX vivo and in vitro

The effect of 5-hydroxytryptanune (5-HT) on the release of acetylcholine (ACh) from the brain of the guinea-pig was investigated in order to determine whether this amine plays a modulatory role on the cortical cholinergic projections. 5-Hydroxytryptamine (0.2–1 μmol), injected intracerebroventricularly (i.c.v.), caused mild excitation, stereotyped movements and ataxia. Simultaneously, it increased the output of ACh from the cortex in a dose-dependent manner. Methysergide (4.2 μmol Kg −1 i.p.) also increased the output of ACh by about 60–80%, but prevented the effect of 5-HT (1 μmol i.c.v.). Metitepine (1–4.2 μmol kg −1 i.p.) increased the output of ACh like methysergide but it changed the facilitation of the release of ACh by 5-HT into inhibition. At the same time the animals became hypothermic, sedated and their electroencephalogram (EEG) was synchronized. Pretreatment with 5,7-HT blocked the increase in release of ACh produced by 5-HT (1 μmol). d-Norfenfluramine (10.4 μmol kg −1) was ineffective alone but reduced the release of ACh in metitepine-pretreated animals. 5-Hydroxytryptamine (10–30μM) did not affect the efflux of [ 3H]choline from electrically-stimulated slices of cerebral cortex. The increase in the release of ACh caused by 5-HT, abolished by pretreatment with methysergide and 5,7-HT, may be explained by activation of 5-HT autoreceptors, while the increase of transmitter outflow induced by methysergide may be due to a blockade of 5-HT receptors present on the cholinergic neurones. Metitepine appeared to unmask the tryptaminergic inhibition caused by injection of 5-HT intraventricularly or by the 5-HT-releasing drug, d-norfenfluramine, possibly by acting on the autoreceptors and preventing auto-inhibition. These findings suggest that the influence of the tryptaminergic system on the release of ACh from the cortex is inhibitory. This effect seems to depend on the modulation of subcortical cholinergic structures and not on direct changes of neurosecretory processes for ACh in the cortex.

Muscle sympathetic activity and plasma noradrenaline in normotensive and hypertensive man.

Micro-electrode recordings of muscle sympathetic activity were made in the peroneal nerve of 20 normotensive subjects and 18 patients with essential hypertension resting in the recumbent posture. The level of sympathetic activity was quantitated as bursts/100 heart beats or bursts/min. On another occasion blood was sampled from an antecubital vein and analyzed for plasma noradrenaline using radioenzymatic technique. In both groups the level of sympathetic activity increased with age and taking age into account there was no significant difference in sympathetic activity between normotensive and hypertensive subjects. There was no significant difference in plasma levels of noradrenaline between the groups. Both for normotensive and for hypertensive subjects there was a positive correlation between a subject's level of sympathetic activity and his plasma concentration of noradrenaline, and the regression lines did not differ significantly between the groups. It is suggested (a) that outflow of transmitter from sympathetic terminals in muscles contributes significantly to plasma concentrations of noradrenaline at rest both in normotensive and hypertensive subjects: (b) that neither for muscle sympathetic activity nor for plasma noradrenaline do the resting levels differ between normotensive and hypertensive subjects.

Diazepam antagonizes GABA- and muscimol-induced changes of acetylcholine release in slices of guinea-pig cerebral cortex.

The acetylcholine (ACh) release was studied in superfused, electrically-stimulated slices of guinea-pig cerebral cortex. Muscimol and 4,5,6,7-tetrahydroisoxazolo (5-4-c)-pyridin-3-ol (THIP), as well as exogenous GABA, reduced the electrically-evoked ACh release and enhanced its spontaneous outflow. Picrotoxin antagonized these effects. In addition, picrotoxin and ethanolamine-O-sulphate (EOS) caused opposite changes in transmitter outflow, suggesting the existence of an exogenous GABAergic control on the cholinergic nerve endings. Neither flurazepam 6.6 X 10(-6)--3.3 X10(-5) mol/l nor diazepam 3.3 X 10(-6)--3.3 X 10(-5) mol/l by themselves affected ACh release. Diazepam prevented GABA-, muscimol- and EOS-induced changes in spontaneous and 1 Hz-evoked outflow. Ro 15-1788 3.3 X 10(*-6) mol/l abolished diazepam antagonism vs exogenous GABA. The ineffectiveness of flurazepam and diazepam on normal release (i.e. the lack of potentiation vs the endogenous GABAergic control) supports the view that "synaptic" GABA receptors acting upon the cholinergic nerve endings are not coupled with Benzodiazepine receptors. The unexpected diazepam antagonism vs exogenous GABA and GABA-like compounds can be explained with an unusual Diazepam negative cooperation with "extrasynaptic" GABA receptors, possibly present on the cholinergic terminals. Thus, the rule of benzodiazepine-GABA synergism does not seem always tenable, at least at certain pre-synaptic sites.

Glycine-induced changes in acetylcholine release from guinea-pig brain slices.

The effect of glycine (Gly) on acetylcholine (ACh) release from superfused, resting or electrically-stimulated slices of guinea-pig caudate nucleus (CN), brain stem (BS) and cerebral cortex (CC) was studied. The amino acid 1 X 10(-4)-6 X 10(-3)mol 1(-1) reduced the electrically-induced release and increased the spontaneous and KCl-evoked transmitter outflow, mostly in CN but also in BS, whereas it was ineffective in CC. Taurine, chosen as a structurally related compound, moderately affected only the spontaneous release in CN. Strychnine 2 X 10(-7) mol 1(-1) was per se ineffective, but prevented most Gly effects. The Gly-induced increase of ACh outflow in resting CN slices, however, could be completely antagonized only by administering strychnine and picrotoxin together. These findings suggest that: (i) the overall pattern of Gly influence on cholinergic function is similar to that previously described for gamma-aminobutyric acid (GABA); (ii) specific receptors seem to be present in BS and, above all, in CN; (iii) a positive cooperation between endogenous GABA and Gly is evident in resting CN slices; (iv) the absence of any apparent endogenous glycinergic control on the cholinergic neurones casts doubt on but does not exclude the existence of glycinergic neurones in CN.

Facilitatory prejunctional β-adrenoceptors in human arteries and veins

The effects of β-adrenoceptor agonists and antagonists on both the transmitter outflow and the associated pressure response produced by perivascular nerve stimulation have been studied in human digital arteries and metatarsal veins, in which transmitter stores were labelled with [ 3H]noradrenaline. Both isoprenaline in arteries, and salbutamol in arteries and veins, at concentrations of 10 −8–10 −6 mol/l significantly enhanced stimulation-induced tritium outflow. These two agonists were approximately equipotent. Salbutamol also potentiated pressure responses to stimulation, and propranolol prevented the enhancement of stimulation-induced tritium outflow by salbutamol. Adrenaline, at a concentration of 10 −8 mol/l, but not lower concentrations, significantly enhanced stimulation-induced tritium outflow in arteries. Propranolol, however, had no effect on stimulation-induced transmitter outflow, even when the arteries were either perfused throughout the experiment with a low concentration of adrenaline, or when the arteries were preincubated in a high concentration of adrenaline as well as perfused throughout with a low concentration of adrenaline. It is concluded that facilitatory prejunctional β-adrenoceptors (probably of the β 2-subtype) are present in human arteries and veins, but that under the conditions of these experiments, neither transmitter noradrenaline, nor adrenaline that has been incorporated into transmitter stores with noradrenaline, activate these prejunctional β-adrenoceptors. They may, however, be activated under conditions of enhanced adrenomedullary secretion.

Local modulation of neurotransmitter release in bovine splenic vein.

Bovine splenic vein has an abundant sympathetic innervation. Isolated strips were used to examine whether autoinhibition of norepinephrine release from the noradrenergic nerve terminals could be demonstrated under various experimental conditions and whether additional local regulatory modulators of transmitter release could also be implicated. In particular, the possibility of a histamine interaction with presynaptic inhibitory receptors was examined because ultrastructural evidence disclosed a close spatial relationship between mast cells and noradrenergic nerve terminals in the vessel wall. To investigate the presence of presynaptic alpha-receptors the competitive blocking agent phentolamine was included in the superfusion medium at concentrations ranging from 1 to 50 microM during electrical field stimulation at frequencies between 1 and 10 Hz. Transmitter outflow was measured as fractional tritium release. Low frequency stimulation (1 Hz) with 1 microM phentolamine resulted in the typical increase in norepinephrine release characteristics for presynaptic alpha-receptor inhibition. In contrast, high frequency (10 Hz) stimulation in the presence of 50 microM phentolamine caused an unexpected decrease in norepinephrine outflow. This unusual result can be explained by additional pharmacological actions of phentolamine unrelated to alpha-receptor blockade, e.g. histamine release from the mast cells which subsequently can act on presynaptic inhibitory histamine receptors. This effect, manifested at higher phentolamine concentrations, would overcome the alpha-receptor blockade. The presence of histamine receptors was supported by the results from electrical stimulation in the presence of exogenous histamine. Histamine decreased norepinephrine outflow while increasing basal tension and the contractile response of the vein strip. Unexpectedly, these effects appeared to be mediated by histamine receptors of the H1-type because they were reduced after pyrilamine but unaffected by agonists and antagonists to receptors of the H2-type. It is speculated that interactions between mast cells and noradrenergic nerve terminals may serve to maintain homeostasis in the bovine splenic vein.

Electrotonic depolarization of nerve terminals causes a normorphine-resistant release of transmitter

In the presence of tetrodotoxin (0.5 μM) electrical stimuli of high current strength and long impulse duration evoke the outflow of previously incorporated 3H-noradrenaline from the mouse vas deferens. The mechanism of action is probably an electrotonic depolarization of nerve terminals. The effect of normorphine, calcium and magnesium was compared on transmitter outflow evoked by conducted action potentials and electrotonic depolarization of nerve terminals. It is suggested that in the presence of tetrodotoxin electrical stimulation induces an asynchronous quantal release of transmitter.

Is There a Mast Cell-Noradrenergic Nerve Interaction in the Bovine Splenic Vein?

Release of neurotransmitter from noradrenergic nerve terminals can be modulated by a variety of endogenous and exogenous compounds which act as agonists or antagonists at receptors located on the presynaptic membrane of the terminal.For example, noradrenaline acts as an α-adrenoreceptor agonist to decrease further release. This effect can be reversed by drugs such as phentolamine which blocks the α-adrenoreceptor to increase the outflow of transmitter. Actually, the α-receptor mediated overflow after exposure to an antagonist is one of the most studied mechanisms in transmitter regulation. However, we have been confronted with an exception to the rule of noradrenaline overflow after phentolamine (Fig. 1). In this study isolated bovine splenic vein strips were preincubated in tritiated noradrenaline and mounted in a superfusion apparatus. Oxygenated Tyrodes medium (pH 7.4) containing 10-6M cocaine and 10-4M normetanephrine was used during superfusion.

Transmitter release and adrenergic mechanical responses in the heart: Effect of papaverine and imidazole

Chronotropic and inotropic responses were elicited in isolated rabbit hearts by stimulation of the sympathetic nerves or by infusion of noradrenaline or adrenaline and the effects of papaverine and imidazole (10 −7−10 −6 M) on these responses were studied. The outflow of noradrenaline induced by sympathetic nerve stimulation was assayed in the absence and in the presence of papaverine and imidazole (10 −7−5×10 −7 M). Papaverine increased the outflow of transmitter during nerve stimulation by 45% and potentiated both the chronotropic and inotropic responses induced by nerve stimulation and those induced by infusion of catecholamines. Imidazole inhibited the outflow of transmitter during nerve stimulation by 33%. The data indicate that the “second messenger” cyclic AMP is active in more than one step in adrenergic neurotransmission and receptor activation in the heart. Furthermore, tissue cyclic AMP seems to be involved not only in the inotropy induced by circulating catecholamines but also in the more “physiological” inotropy elicited by sympathetic nerve stimulation.

Interactions of angiotensin, phenoxybenzamine and propranolol on noradrenaline release during sympathetic nerve stimulation

In isolated rabbit hearts, angiotensin, phenoxybenzamine, cocaine and propranolol increased the overflow of noradrenaline caused by sympathetic nerve stimulation. After the outflow of transmitter had been raised by propranolol, angiotensin caused a further increase indistinguishable from that observed in non-pretreated hearts. The potentiation of overflow by cocaine was prevented in propranolol-treated hearts. After the outflow of noradrenaline had been augmented by phenoxybenzamine, addition of angiotensin did not result in a further increase. It is proposed that phenoxybenzamine and angiotensin share a common mechanism of action, i.e. an increase of the amount of the adrenergic transmitter liberated per stimulus from the nerve terminals.