Postganglionic Sympathetic Nerve Endings Research Articles

Reduced cardiac 123I-MIBG uptake is a robust biomarker of Lewy body disease in isolated rapid eye movement sleep behaviour disorder

Abstract Cardiac 123I-MIBG scintigraphy is used to assess the function of postganglionic presynaptic cardiac sympathetic nerve endings. 123I-MIBG cardiac uptake is markedly reduced in patients with isolated rapid eye movement sleep behaviour disorder, similar to Parkinson’s disease and dementia with Lewy bodies. As a result, it can be used as an early biomarker of isolated rapid eye movement sleep behaviour disorder. Most patients with isolated rapid eye movement sleep behaviour disorder develop synucleinopathies: Parkinson’s disease, dementia with Lewy bodies or multiple system atrophy. We aimed to investigate whether cardiac postganglionic denervation is present in patients with isolated rapid eye movement sleep behaviour disorder, as well as its possible usefulness as a marker for Lewy body disease status. This retrospective cohort study examined 306 patients (236 men and 70 women; mean age: 68.2 years; age range: 43–87 years) with polysomnography-confirmed isolated rapid eye movement sleep behaviour disorder who were followed for 1–3 months and underwent 123I-MIBG scintigraphy. We retrospectively analysed data from 306 patients with polysomnography-confirmed isolated rapid eye movement sleep behaviour disorder, and their longitudinal outcomes were documented at two centres. Among isolated rapid eye movement sleep behaviour disorder patients, reduced 123I-MIBG uptake was observed in the early and delayed images in 84.4 and 93.4% of patients, respectively, whereas 88.6% of the patients had a high washout rate. This large Japanese two-cohort study (n = 306) found that 91 patients (29.7%) developed an overt synucleinopathy (51 Parkinson’s disease, 35 dementia with Lewy bodies, 4 multiple system atrophy, and 1 cerebellar ataxia) during a mean follow-up duration of 4.72 ± 3.94 years, with a conversion risk of 14.5% at 3 years, 25.4% at 5 years, 41.4% at 8 years and 52.5% at 10 years. On the other hand, among patients with heart-to-mediastinum ratio < 2.2 in the delayed images (n = 286), 85 (29.7%) developed Parkinson’s disease or dementia with Lewy bodies during a mean follow-up duration of 4.71 ± 3.94 years, with a conversion risk of 14.5% at 3 years, 25.6% at 5 years, 42.0% at 8 years and 51.0% at 10 years. Among the 33 patients who underwent repeat 123I-MIBG scintigraphy, there was a progressive decline in uptake over the next 4.2 years, with patients exhibiting reduced uptake progressing to Parkinson’s disease or dementia with Lewy bodies. In contrast, patients without decreased 123I-MIBG uptake progressed to multiple system atrophy. Reduced cardiac 123I-MIBG uptake was detected in over 90% of isolated rapid eye movement sleep behaviour disorder patients, with progression to Parkinson’s disease or dementia with Lewy bodies, rather than multiple system atrophy, over time. Reduced 123I-MIBG uptake is a robust maker for Lewy body disease among isolated rapid eye movement sleep behaviour disorder patients.

2-1-05. PR interval of electrocardiography is significantly correlated with the findings of cardiac MIBG scintigraphy in Parkinson’s disease

Cardiac 123I-metaiodobenzylguanidine scintigraphy (MIBG) has been used to assess the postganglionic presynaptic cardiac sympathetic nerve endings and demonstrated an uptake reduction in patients with Parkinson’s disease (PD). On the other hand, epidemiologic research showed that electrocardiography (ECG) abnormalities occurred prior to motor signs in PD. In this study, we investigated whether the electrical conduction system of the heart was impaired in PD. Clinical features, ECG and MIBG parameters were analyzed in 191 patients with PD, 42 with multiple system atrophy (MSA) and 124 normal controls (NL). PR interval in ECG was significantly longer in patients with PD than in NL, and the PR interval negatively correlated with early and delayed heart-to-mediastinum ratios in MIBG scintigraphy in PD and MSA patients. No significant differences were detected in QTc between the three groups. This study is the first to demonstrate the prolongation of the PR interval in PD and its correlation with MIBG scintigraphy parameters. The PR prolongation must reflect some sympathetic system abnormality since it is mainly controlled by sympathetic nervous system. Repeated measures of PR interval might be one alternative tool to predict autonomic dysfunction in a part of PD patients.

Triphasic cardiovascular response to cannabinoids – Focus on underlying mechanisms

The endocannabinoid anandamide exerts complex effects on the cardiovascular system [Malinowska et al., Br J Pharmacol, 2011]. Thus, rapid intravenous injection of anandamide and its stable analogue methanandamide in anaesthetized rats and mice induces typical triphasic changes. Phase I, the so-called BezoldJarisch reflex, is characterized by a rapid bradycardia and hypotension associated with a decrease in cardiac contractility and an increase in total peripheral resistance. Phase II is a brief pressor response associated with an increase in cardiac contractility and blood flow in the mesenteric and renal arteries. Phase III comprises a prolonged (lasting up to 10 min) and marked decrease in blood pressure, mesenteric and renal blood flow, a marked decrease in cardiac contractility and a slight decrease in heart rate and total peripheral resistance. Phase I is mediated via vanilloid TRPV1 receptors since it was induced also by the TRPV1 receptor agonist capsaicin (but not by the CB1 receptor agonist CP55940), blocked by the TRPV1 receptor antagonists capsazepine and ruthenium red (but not by the CB1 receptor antagonist rimonabant) and absent in TRPV1 / mice. Phase II consists of a peripheral component that is most probably located in blood vessels, is sensitive to nifedipine, ruthenium red and pentobarbitone and, hence, probably represents a Ca-dependent mode of action and a central component. The paraventricular nucleus of the hypothalamus (PVN) may contribute to the latter since a pressor effect was obtained after injection of anandamide, methanandamide or CP55940 (intraventricularly or directly into the PVN). This effect only occurred when the peripheral CB1 receptors were blocked by administration of CB1 receptor antagonists, including AM6545 that does not reach the brain. It was sensitive to adrenalectomy and counteracted by antagonists of CB1, NMDA, thromboxane A2 and b2adrenergic receptors [AM251 (directly into the PVN), MK-801, SQ29548 and ICI118551, respectively] suggesting that the latter four receptors are involved in the events ultimately leading to the anandamide-induced adrenal secretion of catecholamines. Importantly, the hypotensive effect of intravenously administered CP55940 was reversed into a hypertensive one in the presence of AM6545 and both responses were abolished by chemical lesion of the PVN by kainic acid. Phase III is mediated mainly by presynaptic inhibitory CB1 receptors located on the postganglionic (although a preganglionic localization cannot be excluded) sympathetic nerve endings innervating resistance vessels and heart. The CB1 receptor antagonist-sensitive inhibitory effect of these receptors was detected after electrical stimulation of the preganglionic sympathetic nerve fibres in pithed rabbits or rats or following injection of nicotine but not phenylephrine/noradrenaline or isoprenaline (increasing blood pressure and heart rate, respectively). The prolonged hypotension might also be related to the activation of CB1 and/or vanilloid TRPV1 receptors in the spinal cord or to a direct vasodilatation via O-1918 sensitive receptors. In conscious rats anandamide and methanandamide induced a brief pressor (phase II) response connected with renal and mesenteric vasoconstriction and hindquarters vasodilatation. In addition, higher doses of anandamide elicited an initial bradycardia, hypotension and hindquarters vasoconstriction (phase I). However, unlike in anaesthetized rats, none of the cannabinoids led to a prolonged hypotension (phase III). Cardiovascular effects of anandamide are changed under pathophysiological conditions. Thus, in anaesthetized rats myocardial ischemia enhanced phase I and reduced phase III whereas hypertension enhanced phase III. Acknowledgement: B.M. and E.S. would like to express their gratitude to Professor Manfred Gothert for his continuous encouragement extending over a time period of decades.

Differential inhibition of noradrenaline release mediated by inhibitory A1-adenosine receptors in the mesenteric vein and artery from normotensive and hypertensive rats

Mesenteric arteries and veins are densely innervated by sympathetic nerves and are crucial in the regulation of peripheral resistance and capacitance, respectively, thus, in the control of blood pressure. Presynaptic adenosine receptors are involved in vascular tonus regulation, by modulating noradrenaline release from vascular postganglionic sympathetic nerve endings. Some studies also suggest that adenosine receptors (AR) may have a role in hypertension. We aim at investigating the role of presynaptic adenosine receptors in mesenteric vessels and establish a relationship between their effects (in mesenteric vessels) and hypertension, using the spontaneously hypertensive rats (SHR) as a model of hypertension. Adenosine receptor-mediated modulation of noradrenaline release was investigated through the effects of selective agonists and antagonists on electrically-evoked [3H]-noradrenaline overflow. CPA (A1AR selective agonist: 1–100nM) inhibited tritium overflow, but the inhibition was lower in SHR mesenteric vessels. IB-MECA (A3AR selective agonist: 1–100nM) also inhibited tritium overflow but only in WKY mesenteric veins. CGS 21680 (A2AAR selective agonist: up to 100nM) failed to facilitate noradrenaline release in mesenteric veins, from both strains, but induced a similar facilitation in the mesenteric arteries. NECA (non-selective AR agonist: 1, 3 and 10μM), in the presence of A1 (DPCPX, 20nM) and A3 (MRS 1523, 1μM) AR selective antagonists, failed to change tritium overflow. In summary, the modulatory effects mediated by presynaptic adenosine receptors were characterized, for the first time, in mesenteric vessels: a major inhibition exerted by the A1 subtype in both vessels; a slight inhibition mediated by A3 receptors in mesenteric vein; a facilitation mediated by A2A receptors only in mesenteric artery (from both strains). The less efficient prejunctional adenosine receptor mediated inhibitory effects can contribute to an increase of noradrenaline in the synaptic cleft (both in arteries and veins), which might conduce to increased vascular reactivity.

S100+ cells: A new neuro-immune cross-talkers in lymph organs

Up to now, the ‘hardwired’ neural pathway of the neuro-immune regulation is not fully understood. Here we reported a new neural pathway which links sympathetic nerves with immune cells of the lymphoid tissues. Our results demonstrated that nerve fibers derived from superior cervical ganglion directly targeted only S100+ cells in the cervical lymph nodes. Moreover, we found co-expression of neurotransmitters such as norepinephrine, vasoactive intestinal polypeptide and neuropeptide Y in the postganglionic sympathetic nerve endings that innervate S100+ cells. Our findings suggested that S100+ cells serve as a neuro-immune cross-talker in lymph organs that may play a significant role in transmitting signals of nervous cells to targeted immune cells. The new findings provide better understanding of the cross-talk mechanism between the nervous system and the immune system.

Role of Dopaminergic Receptors in Glaucomatous Disease Modulation

Both studies on animals and humans suggest the presence of dopamine (DA) receptors in the anterior segment of the eye. Their role in the dynamics of intraocular pressure (IOP) is not yet clear. DA2 and DA3 receptors are mainly located on postganglionic sympathetic nerve endings. Their stimulation reduces the release of norepinephrine and suppresses the production of aqueous humor. DA1 receptors seem to be more expressed by the ciliary body and the outflow pathway of aqueous humor. The administration of DA1-selective agonists stimulates the production of aqueous humor, increasing IOP, whereas DA2- and DA3-selective agonists could reduce IOP and, therefore, the risk to develop a glaucoma (GL). GL is a broad spectrum of eye diseases which have in common the damage to the optic nerve and the progressive loss of the visual field. Further studies are desirable to clarify the role of the dopaminergic system and the usefulness of DA2 and DA3 agonists in reducing IOP.

The Efficacy of Epidural Ketamine on Shivering during Transurethral Resection of the Prostate under Epidural Anesthesia

Ketamine may decrease core-to-peripheral redistribution of heat through direct central sympathetic stimulation and inhibition of norepinephrine uptake into postganglionic sympathetic nerve endings. The purpose of this study was to evaluate the efficacy of epidural ketamine in preventing shivering during transurethral resection of the prostate (TURP) under epidural anesthesia. Ninety-three male patients scheduled for TURP under epidural anesthesia were enrolled in this study. Patients were randomized into one of three groups. Group 1 consisted of 31 patients who received epidural 0.75% ropivacaine, group 2 consisted of 32 patients who received epidural ketamine (0.2 mg/kg) in addition to 0.75% ropivacaine, and group 3 consisted of 30 patients who received epidural ketamine (0.4 mg/kg) in addition to 0.75% ropivacaine. Shivering and side effects such as hypotension, bradycardia, nausea, and hallucination were recorded during the anesthesia and for 2 hours while in the postanesthetic recovery room. Shivering was statistically more frequent in group 1 than in the other groups. The incidence of sedation was significantly higher in group 3 than in the other groups. The incidences of side effects such as hypotension, bradycardia, and nausea were significantly higher in group 1 than in the other groups. In this study, epidural ketamine 0.2 mg/kg and 0.4 mg/kg was shown to have a lower incidence of shivering and other side effects except sedation. In patients who undergo TURP under epidural anesthesia, the prophylactic use of low-dose epidural ketamine would be helpful in preventing any adverse effects, including shivering.

The enhanced ciliospinal reflex in asymptomatic patients with cluster headache is due to preganglionic sympathetic mechanisms.

An amplified ciliospinal reflex response has been documented in patients with cluster headache, lacking a Horner-like syndrome. The mechanism is unknown. Tentatively, it may be due to an increased release of monoamines from post-ganglionic sympathetic nerve endings or an increased density of postsynaptic adrenergic receptors in the dilatator muscle of the iris. The instillation of a 1% phenylephrine solution into the conjunctival sac induces mydriasis by stimulating postsynaptic adrenergic receptors in the dilatator muscle of the iris, while the instillation of a 2% tyramine solution causes mydriasis by releasing noradrenaline from the presynaptic sympathetic nerve terminals in the iris. According to these premises, a positive correlation should be expected between the ciliospinal reflex response and the pupillary response to tyramine, if the enhanced ciliospinal reflex response was due to an increased presynaptic release of monoamines. No such correlation was found. Nor was there any positive correlation between the ciliospinal reflex response and the pupillary response to phenylephrine, contradicting an increased density of postsynaptic monoaminergic receptors in the dilatator muscle of the iris as the explanation. However, there was a significant positive correlation between the pupillary responses to phenylephrine and tyramine, ruling out any functionally caused "denervation" hypersensitivity in the dilatator muscle of the iris. It is concluded that the amplified ciliospinal reflex response in cluster headache patients (lacking a Horner-like syndrome) reflects compensatory pathophysiological mechanisms proximal to the third-order sympathetic neuron.

P2-receptor modulation of noradrenergic neurotransmission in rat kidney.

1. ATP has previously been shown to act as a sympathetic cotransmitter in the rat kidney. The present study analyses the question of whether postganglionic sympathetic nerve endings in the kidney possess P2-receptors which modulate noradrenaline release. Rat kidneys were perfused with Krebs-Henseleit solution containing the noradrenaline uptake blockers cocaine and corticosterone and the alpha2-adrenoceptor antagonist rauwolscine. The renal nerves were electrically stimulated, in most experiments by 30 pulses applied at 1 Hz. The outflow of endogenous noradrenaline (or, in some experiments, of ATP and lactate dehydrogenase) as well as the perfusion pressure were measured simultaneously. 2. The P2-receptor agonist adenosine-5'-O-(3-thiotriphosphate) (ATPgammaS, 3-30 microM) reduced the renal nerve stimulation (RNS)-induced outflow of noradrenaline (estimated EC50 =8 microM). The P2-receptor antagonist cibacron blue 3GA (30 microM) shifted the concentration-inhibition curve for ATPgammaS to the right (apparent pKB value 4.7). 3. Cibacron blue 3GA (3-30 microM) and its isomer reactive blue 2 (3-30 microM) significantly increased RNS-induced outflow of noradrenaline in the presence of the P1-receptor antagonist 8-(p-sulphophenyl)theophylline (8-SPT, 100 microM) by about 70% and 90%, respectively. The P2-receptor antagonist suramin (30-300 microM) only tended to enhance RNS-induced outflow of noradrenaline. When the nerves were stimulated by short pulse trains consisting of 6 pulses applied at 100 Hz (conditions under which autoinhibition is inoperative), reactive blue 2 did not affect the RNS-induced outflow of noradrenaline. 4. RNS (120 pulses applied at 4 Hz) induced the outflow of ATP but not of the cytoplasmatic enzyme lactate dehydrogenase. 5. ATPgammaS (3-30 microM) concentration-dependently reduced pressor responses to RNS at 1 Hz. Cibacron blue 3GA, reactive blue 2 as well as suramin also reduced pressor responses to RNS (maximally by 50 to 70%). 6. This study in rat isolated kidney, in which the release of endogenous noradrenaline was measured, demonstrates that renal sympathetic nerves possess prejunctional P2-receptors that mediate inhibition of transmitter release. These prejunctional P2-receptors are activated by endogenous ligands, most likely ATP, released upon nerve activity. Both, P2-receptor agonists and P2-receptor antagonists reduced pressor responses to RNS either by inhibiting transmitter release or by blocking postjunctional vasoconstrictor P2-receptors.

Nicotine and sympathetic neurotransmission.

Nicotine increases heart rate, myocardial contractility, and blood pressure. These nicotine-induced cardiovascular effects are mainly due to stimulation of sympathetic neurotransmission, as nicotine stimulates catecholamine release by an activation of nicotine acetylcholine receptors localized on peripheral postganglionic sympathetic nerve endings and the adrenal medulla. The nicotinic acetylcholine receptor is a ligand-gated cation channel with a pentameric structure and a central pore with a cation gate, which is essential for ion selectivity and permeability. Binding of nicotine to its extracellular binding site leads to a conformational change of the central pore, which results in the influx of sodium and calcium ions. The resulting depolarization of the sympathetic nerve ending stimulates calcium influx through voltage-dependent N-type calcium channels, which triggers the nicotine-evoked exocytotic catecholamine release. In the isolated perfused guinea-pig heart, cardiac energy depletion sensitizes cardiac sympathetic nerves to the norepinephrine-releasing effect of nicotine, as indicated by a leftward shift of the concentration-response curve, a potentiation of maximum transmitter release, and a delay of the tachyphylaxis of nicotine-evoked catecholamine release. This sensitization was also shown to occur in the human heart under in vitro conditions. Through the intracardiac release of norepinephrine, nicotine induces a beta-adrenoceptor-mediated increase in heart rate and contractility, and an alpha-adrenoceptor-mediated increase in coronary vasomotor tone. The resulting simultaneous increase in oxygen demand and coronary resistance has a detrimental effect on the oxygen balance of the heart, especially in patients with coronary artery disease. Sensitization of the ischemic heart to the norepinephrine-releasing effect of nicotine may be a trigger for acute cardiovascular events in humans, such as acute myocardial infarction and/or life-threatening ventricular tachyarrhythmias.

MK-801 enhances noradrenergic neurotransmission in rat vas deferens

The effect of MK-801 (dizocilpine) on the noradrenergic neurotransmission of the epididymal portion of rat vas deferens has been investigated. This drug potentiated the electrically induced responses (46.6% ± 5.09 at a concentration of 3.7 μM) and the contractile effect of exogenous noradrenaline with a concentration-dependent reduction of EC50 (from 0.99 ± 0.11 μM to 0.06 ± 0.01 μM). Moreover, MK-801 alone induced spontaneous contractile responses that were abolished by prazosin, not reversed by N-methyl-d-aspartate (NMDA) + glycine and that did not appear in organs obtained from reserpinized rats. In addition, MK-801 inhibited the [3H]noradrenaline uptake in slices from rat vas deferens (IC50 = 1.79 ± 0.06 μM). Since these effects took place in the presence of magnesium and were sodium-dependent, a direct participation of the NMDA receptor complex can be ruled out, pointing to the inhibition of the cathecolamine uptake systems in the postganglionic sympathetic nerve endings as the most feasible mechanism.

Second messenger pathways in the modulation of neurotransmitter release.

Activation of receptors on postganglionic sympathetic nerve endings can alter the amount of noradrenaline release during a train of nerve impulses. These changes may be produced by the enzyme-linked synthesis of second messenger molecules within the nerve terminal. Cyclic AMP analogues enhance noradrenaline release and two hormones adrenaline and ACTH appear to enhance noradrenaline release through activation of adenylate cyclase. Activation of the phospholipase C/protein kinase C pathway also elevates stimulation-induced noradrenaline release and angiotensin enhancement of noradrenaline release appears to act through this pathway. On the other hand, receptors which inhibit noradrenaline release (alpha 2-adrenoceptors, muscarinic M2 receptors and neuropeptide Y receptors) do not act through either of these signal transduction pathways. Since these inhibitory systems are neurotransmitter activated and relay information on a nerve pulse to nerve pulse time scale back to the nerve ending a fast activation and deactivation rate of modulation is required. This may be better served by direct modulation of ion channels without a slow intervening enzyme step. Activation of protein kinase C by phorbol esters produces relatively large increases (two-threefold) in stimulation-induced noradrenaline release and this enzyme may also have a physiological role. Protein kinase C may be an appropriate target for drugs to manipulate transmitter release and development of selective activators and inhibitors of the many protein kinase C isoenzymes may prove clinically useful in diseases with inappropriate transmitter release profiles.

Modulation of Norepinephrine Release in Adriamycin-Induced Heart Failure in Rabbits

In congestive heart failure (CHF), sympathetic neurotransmitter release is enhanced. We investigated the possibility that this is due in part to alterations in activation of either release-inhibiting alpha 2-adrenoceptors or release-enhancing angiotensin II (AII) receptors at postganglionic sympathetic nerve endings. CHF was induced in rabbits by adriamycin [1 mg/kg intravenously (i.v.), twice weekly for 8 weeks] and was characterized by reduced cardiac output (CO) and enhanced norepinephrine (NE) release rate in pentobarbital-anesthetized rabbits. After pithing and stimulation of the spinal sympathetic outflow, there was no difference in NE release rate between the two groups, suggesting that the enhanced NE release rate observed in adriamycin-treated anesthetized rabbits was of central origin. The alpha 2-adrenoceptor-blocking drug yohimbine (1 mg/kg, i.v.) enhanced NE release rate, which is an indication of feedback inhibition of NE release through presynaptic alpha 2-adrenoceptors. In anesthetized rabbits, this effect of yohimbine was greater in adriamycin-treated than in vehicle-treated animals. However, in pithed rabbits with electrically stimulated sympathetic outflow, there was no difference in the facilitative effect of yohimbine between the two groups, suggesting that inhibitory presynaptic alpha 2-adrenoceptors are activated to a greater extent in heart failure due to the increased transmitter release. Removing inhibitory alpha 2-adrenoceptor input has a functional consequence in that yohimbine increased heart rate (HR) in adriamycin-treated but not in vehicle-treated anesthetized rabbits. Captopril (1 mg/kg, i.v.) decreased NE release rate in pithed rabbits with stimulated sympathetic outflow but had no effect on NE release rate in anesthetized rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Prejunctional inhibition of sympathetically evoked pupillary dilation in cats by activation of histamine H3 receptors.

Frequency-dependent pupillary dilations were evoked by electrical stimulation of the pre- or post-ganglionic cervical sympathetic nerve (sympatho-excitation) or the hypothalamus (parasympatho-inhibition) in sympathectomized anesthetized cats. Systemic administration of the selective histamine H3 receptor agonist (R)-alpha-methylhistamine (R alpha MeHA) produced a dose-dependent depression of mydriasis due to direct neural sympathetic activation but had no effect on responses elicited by parasympathetic withdrawal. The histamine H2 receptor agonist, dimaprit, was inactive. R alpha MeHA was much more effective in depressing sympathetic responses obtained at lower frequencies when compared to higher frequencies of stimulation. Responses evoked both pre- and postganglionically were inhibited by R alpha MeHA. This peripheral sympatho-inhibitory action of R alpha MeHA was antagonized by the histamine H3 receptor blocker thioperamide but not by intravenous pretreatment with the histamine H1 receptor antagonist chlorpheniramine. Histamine H2 receptor blockers cimetidine and ranitidine were also without effect. R alpha MeHA did not depress pupillary responses elicited by i.v. (-)-adrenaline. The results demonstrate that histamine H3 receptors modulate sympathetic activation of the iris at a site proximal to the iris dilator muscle. The predominant mechanism of action appears to the prejunctional inhibition of noradrenaline release from postganglionic sympathetic nerve endings. However, a concomitant ganglionic inhibitory action cannot be excluded.

Modulation of noradrenaline release via activation of presynaptic beta-adrenoceptors in rabbits with adriamycin-induced cardiomyopathy.

We investigated the role of beta-adrenoceptors at postganglionic sympathetic nerve endings in noradrenaline release in rabbits with cardiomyopathic congestive heart failure produced by adriamycin (1 mg/kg, I.V., twice a week for 8 weeks). Plasma noradrenaline levels were measured before, 30 min after, and 60 min after the start of continuous intravenous administration of adrenaline (0.06 micrograms/kg/min) in adriamycin-treated and vehicle-treated rabbits in anesthetized condition and pithed condition with electrically stimulated sympathetic outflow (3 Hz, 1 ms square wave pulse, 90 V). In both the anesthetized and pithed conditions, adrenaline increased plasma noradrenaline levels in vehicle-treated rabbits. However, in the adriamycin-treated rabbits, adrenaline had no effect on the plasma noradrenaline level. Pretreatment with propranolol (0.2 mg/kg, bolus I.V. + 0.1 mg/kg/hr, continuous infusion) almost completely abolished the rise in plasma noradrenaline associated with adrenaline infusion in vehicle-treated rabbits. These results suggest that in rabbits with adriamycin-induced cardiomyopathy, the noradrenaline release from the sympathetic nerve endings via the activation of presynaptic beta-adrenoceptors is reduced. This might be due to down-regulation of presynaptic beta-adrenoceptors caused by the elevated plasma noradrenaline due to cardiac failure. However, other possibilities such as reduced affinity or impaired signal transduction cannot be excluded.

Enalapril decreases plasma noradrenaline levels during the cold pressor test in human hypertensives.

1. The effects of the angiotensin-converting enzyme (ACE) inhibitor enalapril on the responses of blood pressure and plasma catecholamine levels to the cold pressor test in human hypertensives were examined. 2. Systolic and diastolic blood pressure decreased significantly after treatment with enalapril (5 mg/day for 4 weeks) as did the resting level of plasma noradrenaline. 3. The cold pressor test induced a rise in blood pressure and plasma noradrenaline levels. After 2 and 4 weeks enalapril treatment, the rises in the plasma noradrenaline level and systolic and diastolic pressure due to cold pressor test were reduced significantly. 4. These results suggest that ACE inhibition has a sympatho-inhibitory effect. One possible explanation is that enalapril reduces angiotensin II formation thus decreasing the activation of release-enhancing angiotensin II receptors on postganglionic sympathetic nerve endings.

Prejunctional opioid mu-receptors and adenosine A1-receptors on the sympathetic nerve endings of the rat tail artery interact with the alpha 2-adrenoceptors.

Experiments were designed to study the interaction between prejunctional alpha 2-adrenoceptors and both adenosine and opioid receptors at the postganglionic sympathetic nerve endings innervating the tail artery of the rat. Segments of this vessel were preincubated with [3H]-noradrenaline and then perfused/superfused with [3H]-noradrenaline-free medium. Their perivascular nerves were field stimulated with standard stimulation parameters: 24 pulses at 0.4 Hz, 0.3 ms, 200 mA. In some experiments, the stimulation parameters were adjusted in order to obtain similar reference release values despite the presence of a first release-modulating drug. The adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA; 0.3-10 mumol/l) and [D-Ala2,MePhe4,Glyol5]enkephalin (DAGO; 0.3-10 mumol/l) depressed the stimulation-evoked overflow of tritium in a concentration dependent manner. The release-inhibiting effect of both NECA and DAGO was enhanced in the presence of the alpha 2-adrenoceptor antagonist rauwolscine (3 mumol/1) while it was attenuated in the presence of the alpha 2-adrenoceptor agonist 5-bromo-6-[2-imidazolin-2yl-amino]-quinoxaline (UK-14,304; 0.1 mumol/l). These changes occurred both at standard and adjusted stimulation parameters. These results demonstrate that the prejunctional adenosine A1- and opioid mu-receptors interact with the prejunctional alpha 2-adrenoceptors. The level at which these interactions take place (receptors themselves or transduction mechanisms) as well as the physiological significance of the phenomenon remain to be determined.

Effect of ganglion blockade on cerebrospinal fluid norepinephrine.

The source of norepinephrine (NE) in CSF has been unclear. It has been suggested that CSF NE indicates central neural noradrenergic tone and is determined differently from plasma NE. If CSF NE depended specifically on NE release in the CNS, then interference with ganglionic neurotransmission would be expected to decrease plasma NE but not CSF NE. Hypotension caused by ganglionic blockade might be expected to increase CSF NE reflexively. We infused the ganglion blocker, trimethaphan, intravenously into anesthetized dogs and measured the effects on mean arterial blood pressure (MAP) and on cisterna magna CSF levels of NE. The results were compared with those obtained on administration of saline, clonidine (2 micrograms/kg), yohimbine (0.25 mg/kg), or nitroprusside and with those obtained when hypotension during ganglion blockade was prevented by concurrent treatment with phenylephrine. Trimethaphan decreased MAP by 40%, arterial NE by 64%, and CSF NE by 61%. Nitroprusside administered intravenously to produce the same 40% depressor response increased arterial NE by 612% and CSF NE by 155%. Prevention of ganglion blockade-induced hypotension using phenylephrine did not prevent the decrease in CSF NE caused by trimethaphan, and when phenylephrine was discontinued, the resulting hypotension was not associated with increases in CSF NE. The similar decreases in plasma NE and CSF NE during ganglionic blockade, and the abolition of reflexive increases in CSF NE during hypotension in ganglion-blocked subjects, cast doubt on the hypothesis that CSF NE indicates central noradrenergic tone and are consistent instead with at least partial derivation of CSF NE from postganglionic sympathetic nerve endings.

Evidence That Halothane Inhibits Norephinephrine Release from Sympathetic Nerve Endings in Dog Saphenous Vein by Stimulation of Presynaptic Inhibitory Muscarinic Receptors

Studies were done to determine the mechanism whereby halothane inhibits the release of norepinephrine from postganglionic sympathetic nerve endings. Helical strips of dog saphenous vein were mounted for superfusion and measurement of isometric contractile tension in the presence or absence of halothane (1.2 or 2.5%). Endogenous norepinephrine overflowing in response to electrical stimulation (10 V, 2 Hz for 15 min), and the content of norepinephrine remaining in the veins after stimulation, were measured by liquid chromatography with electrochemical detection. The data indicate that halothane decreased the stimulation-evoked release of norepinephrine by stimulation of prejunctional inhibitory muscarinic receptors. Evidence was also obtained that halothane may impair clearance of norepinephrine from the synaptic cleft.

Evidence that Halothane Inhibits Norepinephrine Release from Sympathetic Nerve Endings in Dog Saphenous Vein by Stimulation of Presynaptic Inhibitory Muscarinic Receptors

Studies were done to determine the mechanism whereby halothane inhibits the release of norepinephrine from postganglionic sympathetic nerve endings. Helical strips of dog saphenous vein were mounted for superfusion and measurement of isometric contractile tension in the presence or absence of halothane (1.2 or 2.5%). Endogenous norepinephrine overflowing in response to electrical stimulation (10 V, 2 Hz for 15 min), and the content of norepinephrine remaining in the veins after stimulation, were measured by liquid chromatography with electrochemical detection. The data indicate that halothane decreased the stimulation-evoked release of norepinephrine by stimulation of prejunctional inhibitory muscarinic receptors. Evidence was also obtained that halothane may impair clearance of norepinephrine from the synaptic cleft.