Physical training and baroreceptor control of sympathetic nerve activity in humans

In nine sedentary subjects (16.5 +/- 0.4 years, mean +/- SEM) we measured blood pressure (Finapres device), heart rate (electrocardiogram), and postganglionic muscle sympathetic nerve activity (microneurography from the peroneal nerve) at rest and during intravenous infusion of phenylephrine and nitroprusside. These measurements were performed before and after 10 weeks of endurance training (2 h/d, 5 d/wk) that increased maximum oxygen consumption from 34.8 +/- 2.1 to 40.4 +/- 1.8 mL/kg per minute (P < .02). Basal mean blood pressure and muscle sympathetic nerve activity were lower after than before endurance training (86.5 +/- 2.6 versus 97.5 +/- 1.8 mm Hg, P < .05, and 14.0 +/- 1.8 versus 21.2 +/- 2.3 bursts per minute, P < .02), and the changes in these variables were closely related (r = .95, P < .01). Similar mean blood pressure increases induced by phenylephrine caused greater reductions in heart rate and muscle sympathetic nerve activity after than before endurance training (-8.6 +/- 0.8 versus -6.1 +/- 1.1 beats per minute, P = NS, and -78.0 +/- 4.6% versus -53.6 +/- 4.8%, P < .05). Likewise, similar mean blood pressure reductions induced by nitroprusside caused greater increases in heart rate and muscle sympathetic nerve activity after than before endurance training (18.6 +/- 3.0 versus 12.4 +/- 2.4 beats per minute, P < .05, and 128.1 +/- 26% versus 63.2 +/- 11%, P < .02). No alteration in hemodynamics, oxygen consumption, muscle sympathetic nerve activity, and baroreceptor reflex sensitivity occurred in four other age-matched sedentary subjects studied before and after a 10-week observation period without endurance training.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma noradrenaline correlates to sympathetic muscle nerve activity in normotensive man

Recordings of multiunit sympathetic activity were made in muscle branches of the peroneal nerve in 22 healthy subjects at rest in recumbent position. Nerve activity was quantitated in terms of burst incidence (number of pulse synchronous sympathetic bursts per 100 heart beats or per min). In a separate session, 4-45 months later, blood was drawn from an antecubital vein for noradrenaline analysis. Both sympathetic activity and plasma concentrations of noradrenaline varied widely between subjects and both parameters increased with age. There was a significant positive correlation between a subject's level of sympathetic activity and his plasma concentration of noradrenaline. It is suggested that overflow of transmitter from sympathetic terminals in muscles contributes significantly to plasma levels of noradrenaline at rest.     

ORL1 receptor-mediated inhibition by nociceptin of noradrenaline release from perivascular sympathetic nerve endings of the rat tail artery

In the present study the effect of the opioid heptadecapeptide nociceptin, also termed orphanin FQ, an endogenous ligand for the orphan receptor named ORL1 (opioid receptor-like 1) receptor, was investigated on [3H]noradrenaline release induced by electrical field stimulation (24 pulses at 0.4 Hz, 200 mA, 0.3 ms duration) in the rat tail artery in the absence and presence of an alpha2-adrenoceptor antagonist, rauwolscine 3 microM. Nociceptin inhibited the electrically-evoked tritiated noradrenaline release in a concentration-dependent manner from rat tail arteries. This inhibitory effect of nociceptin was enhanced in the presence of the alpha2-adrenoceptor antagonist rauwolscine (maximum inhibition by 25% and 50% in the absence and presence of rauwolscine, respectively). At a supramaximal concentration (10 microM), the inhibitory action of DAGO, a selective micro-opioid receptor agonist, was less pronounced than that of nociceptin. The inhibitory effect of nociceptin was counteracted by naloxone benzoylhydrazone (3 microM) which by itself did not change the stimulation-evoked noradrenaline overflow. Naloxone (10 microM), a non-selective opioid receptor antagonist, did not affect the inhibitory effect of nociceptin whereas it abolished that of DAGO. In conclusion, these results suggest that nociceptin modulates noradrenergic neurotransmission by acting on prejunctional ORL1 receptors located on nerve terminals innervating the rat tail artery. They also demonstrate that prejunctional ORL1 receptors interact with prejunctional alpha2-adrenoceptors. The physiological significance of this phenomenon remains to be determined.     

The co-existence of insulin-mediated decreased mean arterial pressure and increased sympathetic nerve activity is not mediated by the baroreceptor reflex and differentially by hypoglycemia

In this study we measured simultaneously and sequentially the lumbar sympathetic nerve activity (LSNA) or renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP), and heart rate (HR) in response to insulin with co-existing hypoglycemia or with glucose replacement in normal rats. Sinoaortic denervation (SAD) was used to evaluate the influence of the baroreflex. LSNA, RSNA, MAP and HR were determined using an acquisition processor and computer software. Bolus insulin infusion where the blood glucose was allowed to decrease resulted in an immediate decrease in MAP. The HR decreased for approximately 15 min and subsequently increased. The LSNA increased immediately after insulin infusion peaking at 25 minutes and then recovered toward baseline. Insulin infusion with glucose replacement resulted in a decrease in MAP and HR. The LSNA progressively increased and was maintained throughout the experimental period. Insulin infusion with hypoglycemia increased RSNA and when hypoglycemia was prevented the RSNA decreased. SAD attenuated the decrease in MAP and LSNA response to insulin. Thus, insulin acts to decrease MAP while simultaneously increasing HR, LSNA and RSNA when hypoglycemia is allowed to occur. However, insulin acts to decrease HR and RSNA when euglycemia is maintained. The insulin-induced increase in LSNA is modulated by the baroreflex mechanism. We conclude that insulin has independent direct and indirect effects on LSNA, RSNA, MAP and HR that are modulated by glycemia and the baroreflex.     

Propofol-induced increase in vascular capacitance is due to inhibition of sympathetic vasoconstrictive activity

BACKGROUND: Venodilation is thought to be one of the mechanisms underlying propofol-induced hypotension. The purpose of this study is to test two hypotheses: (1) propofol increases systemic vascular capacitance, and (2) the capacitance change produced by propofol is a result of an inhibition of sympathetic vasoconstrictor activity. METHODS: In 33 Wistar rats previously anesthetized with urethane and ketamine, vascular capacitance was examined before and after propofol infusion by measuring mean circulatory filling pressure (Pmcf). The Pmcf was measured during a brief period of circulatory arrest produced by inflating an indwelling balloon in the right atrium. Rats were assigned into four groups: an intact group, a sympathetic nervous system (SNS)-block group produced by hexamethonium infusion, a SNS-block + noradrenaline (NA) group, and a hypovolemic group. The Pmcf was measured at a control state and 2 min after a bolus administration of 2, 10, and 20 mg/kg of propofol. RESULTS: The mean arterial pressure (MAP) was decreased by propofol dose-dependently in intact, hypovolemic, and SNS-block groups, but the decrease in MAP was less in the SNS-block group (-25%) than in the intact (-50%) and hypovolemic (-61%) groups. In the SNS-block + NA group, MAP decreased only at 20 mg/kg of propofol (-18%). The Pmcf decreased in intact and hypovolemic groups in a dose-dependent fashion but was unchanged in the SNS-block and SNS-block + NA groups. CONCLUSIONS: The results have provided two principal findings: (1) propofol decreases Pmcf dose-dependently, and (2) the decrease in Pmcf by propofol is elicited only when the sympathetic nervous system is intact, suggesting that propofol increases systemic vascular capacitance as a result of an inhibition of sympathetic nervous system.     

Modulation by presynaptic beta-adrenoceptors of noradrenaline release from sympathetic nerves in human dental pulp

BACKGROUND: Severe and therapy-resistant pruritus is the most prominent feature of macular (MA) and lichen (LA) amyloidosis that leads to further amyloid deposition by recurrent frictional trauma to the epidermis. Of the various therapeutic modalities with variable success, the most encouraging and beneficial effect has been observed with topical dimethyl sulfoxide (DMSO) therapy. In a previous study, we achieved marked clinical improvement in nine of 10 patients in a daily treatment regimen over 6-20 weeks, but relapses occurred in the post-treatment follow-up period. The aims of this study are to investigate whether the patients would benefit from intermittent therapy and to determine the optimal application interval of DMSO to maintain the relief of symptoms. METHODS: Thirteen patients with histopathologically verified cutaneous amyloidosis (five MA, two LA and six biphasic) were enrolled in the study. They were treated once daily with a 50 or 100% DMSO solution until pruritus disappeared. Then, DMSO was applied at increasing intervals until the widest effective application interval for maintenance of relief was reached. Patients were regularly followed-up by a scoring system for pruritus, papules, and pigmentation, control biopsies, photographs, blood biochemistry, and side-effects. RESULTS: The mean time required for the disappearance of pruritus was 4.1 weeks. Remarkable flattening of the papules was achieved after an average therapy period of 9 weeks. After a total therapy period of 6.5 months, a nearly 50% remission in pigmentation and >70% flattening of papules were achieved. The widest effective DMSO application interval was 8.6 days. The side-effects of therapy were contact urticaria, desquamation, burning sensation, and garlic-like breath odor, which were more prominent with the higher concentration of DMSO. In interval therapy, side-effects were tolerated more easily than in daily therapy. No reduction of amyloid deposits was revealed in control biopsies. CONCLUSIONS: Locally applied DMSO can break the vicious "pruritus-amyloid deposition-pruritus" cycle in patients with MA and LA. In addition to its daily use, interval therapy seems to maintain this effect and enables patients to tolerate side-effects more easily.     

Competitive and non-competitive re-innervation of mammalian sympathetic neurones by native and foreign fibres

The ability of native (sympathetic preganglionic) and foreign (vagal) nerve fibres to re-innervate neurones of the guinea-pig superior cervical ganglion, either alone or in competition with each other, has been studied by means of intracellular recording and electron microscopy. 1. Native fibres make synaptic contacts with nearly all ganglion cells within one month of cervical trunk section; within 6 months the degree of innervation, judged by measurement of excitatory post-synaptic potential (e.p.s.p.) amplitude and electron microscopical synapse counts, approaches normal. However, even after 15 months innervation was weaker than in normal control ganglia. 2. Vagal fibres are less successful during re-innervation. Although a similar number of foreign fibres grown into denervated ganglia and make contact with nearly all ganglion cells within a month, after 6-12 months e.p.s.p. amplitudes in response to foreign nerve stimulation remain relatively small, and counts of synapses are only about 60% as great as in ganglia re-innervated with the native nerve. 3. When both native and foreign fibres are allowed to re-innervate ganglion cells simultaneously, about half the neurones in the ganglion receive synapses from both sources after 1 month. The proportion of dually invervated cells remains roughly constant for at least 14 months. Neither set of preganglionic fibres dominates or displaces the other, although neurones generally are re-innervated more effectively by native than foreign fibres, as is true during non-competitive re-innervation. 4. Thus during re-innervation of mammalian sympathetic neurones native fibres are preferred to foreign ones only in the sense that roughly the same number of native fibres form many more synapses on ganglion cells than do vagal axons. A foreign synapse, once formed, is as stable as a native one, and shows no tendency to be replaced by native terminals. These findings are discussed in relation to other evidence which has suggested specificity and selectivity during re-innervation of mammalian autonomic neurones.     

Inhibition by ethanol of noradrenaline output from peripheral sympathetic nerves: possible interaction of ethanol with neuronal receptors

The sympathetic nerve terminals of the isolated rabbit heart perfused with Tyrode solution were used to study the action of ethanol on the noradrenaline uptake and release. The uptake of exogenous noradrenaline (10 ng/ml) into the sympathetic nerve endings, the noradrenaline output evoked by raising the concentration of potassium ions in the perfusion fluid, and the release in response to electrical stimulation of the nerve axons were inhibited only by lethal concentrations of the alcohol; the concentrations which caused 50% inhibition (IC50) amounted to 760 mM, 830mM, and 1150 mM respectively. However, ethanol at concentrations compatible with moderate intoxication reduced the noradrenaline release in response to activation of the nicotine receptors on the nerve terminals by dimethylphenylpiperazine; the threshold concentration was 36 mM and the IC50 was 129 mM. It is suggested that this effect is due to hydrophobic interaction of the alcohol with receptor proteins, thus inhibiting stimulus formation.     

Propranolol-induced seizures in mice: the role of noradrenaline

The effects of some noradrenergic agents, phenobarbitone, diazepam and phenytoin on seizures produced by propranolol were investigated in mice. Isoprenaline and DL-threo-3,4-dihydroxyphenylserine (DOPS) effectively antagonized the seizures elicited by propranolol. Pargyline and imipramine significantly attenuated propranolol-induced seizures and also significantly potentiated the protecting effect of DOPS against the seizures. alpha-Methyl-p-tyrosine, disulfiram and reserpine significantly potentiated propranolol-elicited seizures. However, DOPS significantly antagonized the seizure-potentiating effects of alpha-methyl-p-tyrosine, disulfiram and reserpine. Phenylephrine, clonidine, prazosin, idazoxan, phenobarbitone, diazepam and phenytoin did not significantly alter propranolol-induced seizures. These results suggest that propranolol-induced seizures in mice may involve a noradrenergic mechanism mediated via central beta-adrenoceptors.     

Cardiovascular care with the new T-type calcium channel antagonist: possible role of attendant sympathetic nervous system inhibition

DIFFERENCES AMONG TYPES OF CALCIUM ANTAGONISTS: Calcium antagonists lower blood pressure, relieve angina pectoris and improve chronic heart failure, primarily through peripheral and coronary vasodilation. The debate as to whether short-acting, long-lasting (L)-channel calcium influx antagonists of the 1,4-dihydropyridine type might be involved in excess cardiac mortality has raised new controversies with respect to the cardiac morbidity and mortality outcome for all calcium antagonists. Different pharmacodynamic effects (short-acting vasodilation inducing pulsatile sympathetic reflex stimulation) may explain differences in outcome with calcium antagonist therapies. Calcium antagonists also differ in their direct effects on the sympathetic nervous system, and on its long endocrine arm, the renin-angiotensin-aldosterone system. These differential effects relate to the cardiac conduction system and ventricular ectopic activity, to cardiac and vascular remodelling and hypertrophy, and perhaps also to the development of hypertension. L-CHANNEL CALCIUM ANTAGONISTS: Depending on their pharmacodynamic characteristics, L-channel calcium antagonists of the dihydropyridine, verapamil or diltiazem type reflexly activate the sympathetic nervous system and blunt beta-adrenoceptor-mediated calcium influx, thus eliciting negative inotropy and activation of the renin-angiotensin system. Both verapamil and diltiazem slow down pacemaker activity and atrioventricular conduction. MIBEFRADIL: The new-class T-channel blocker mibefradil exhibits vascular selectivity and induces peripheral and coronary vasodilation. There is no reflex sympathetic activation and no negative inotropic effect. It increases coronary blood flow without increasing oxygen consumption and causes a slight slowing of the heart rate, thereby inducing diastolic relaxation. The latter improves subendocardial and small artery perfusion. There is a sympatholytic effect, owing to T-channel expression in neurones, sinoatrial and atrioventricular nodes and Purkinje fibres. In experimental models, ventricular ectopic activity is reduced with mibefradil. The renin-angiotensin-aldosterone system and endothelin effects are blunted by T-channel inhibition. These and other factors reduce smooth muscle cell proliferation, hypertrophy and matrix deposition. T-type calcium channel inhibition, over and above its antihypertensive and anti-ischaemic effects, and afterload-reducing effects in chronic heart failure, offers the potential for a cardiovascular protective benefit, which may be critically related to interference with the sympathetic nervous system.     

Role of paraventriculo-spinal pathway in the inhibition of renal sympathetic nerve activity induced by blood volume expansion in rabbits

Bullous pemphigoid (BP) is an autoimmune blistering disease characterized in part by the presence of tissue-bound and circulating antibodies (mostly of IgG) to the basement membrane zone (BMZ). We previously reported that IgG subclasses of BP antibodies were IgG1, IgG2 and IgG4, and that only BP IgG1 fixed complements. In this study, we examined whether BP IgG sub-classes bound to the same epitope of BP antigen or a different epitope. In an inhibition immunofluorescence studies, the complement fixing capability of IgG1 was inhibited by the pretreatment with IgG4 and partially inhibited by IgG2. On immunoblot analysis, IgG1 and IgG4 were bound to the same MW of BP antigen. In enzyme-linked immunosorbent assay (ELISA), the binding capability of IgG subclass fractions from patients with BP to synthetic peptide P1-2, exceeding normal IgG subclass fractions was seen in five IgG1, one IgG2 and two IgG4, from eight BP patients. The binding capability of IgG subclass fractions from the patients with BP to P1-1, exceeding the normal IgG fractions was seen in two IgG1, three IgG2 and one IgG4 from ten BP patients. On inhibition ELISA, the binding activity to P1-2 of IgG4 was partially inhibited by the pretreatment of IgG1 and IgG2. These findings suggest that BP IgG1, IgG2 and IgG4 could bind to the same epitope though considerable variation occurred between patients.     

Stimulation of the sympathetic perimesenteric arterial nerves releases neuropeptide Y potentiating the vasomotor activity of noradrenaline: involvement of neuropeptide Y-Y1 receptors

Neuropeptide Y (NPY) appears to be involved in the sympathetic regulation of vascular tone. To assess the putative role of NPY in mesenteric circulation, the release and biological effect of NPY were examined after electrical stimulation of perimesenteric arterial nerves. Nerve stimulation with trains of 2-30 Hz increased the perfusion pressure of the arterially perfused rat mesenteric bed in a frequency- and time-dependent fashion. Trains of 15-30 Hz significantly displaced to the left, approximately threefold, the noradrenaline (NA)-induced pressor concentration-response curve, in addition to increasing significantly its efficacy. Perfusion with 10 nM exogenous NPY mimicked the electrical stimulation effect, causing a threefold leftward shift of the NA concentration-response curve and increasing the maximal NA response. These effects were antagonized by 100 nM BIBP 3226, indicating the activity of NPY-Y1 receptors. Electrical stimulation of the perimesenteric nerves released immunoreactive NPY (ir-NPY) in a frequency-dependent fashion; the ir-NPY coelutes with synthetic NPY as confirmed by HPLC. Both the electrically induced pressor response and the calcium-dependent release of NPY were obliterated in preparations perfused with 1 microM guanethidine or in rats pretreated intravenously for 48 h with 6-hydroxydopamine, thus revealing the sympathetic origin of these phenomena. Only a small proportion of the total NPY content in the perimesenteric arterial nerves is released after electrical stimulation. Chromatographic studies of the physiological sources of the ir-NPY support that NPY fragments are generated via peptidase degradation. The present findings demonstrate that NPY is released from the perimesenteric arterial sympathetic nerves and acts, via the activation of NPY-Y1 receptors, as the mediator responsible for the potentiation of NA's effect on perfusion pressure in the isolated rat mesenteric bed.     

Evidence for a role of inhibition of sympathetic neurotransmission in the cardiovascular effects of intravenously administered verapamil

The effects of intravenous administration of verapamil, nifedipine and diltiazem on sympathetic stimulation-induced increase in heart rate (HR) and blood pressure (BP) have been investigated in chloralose-anaesthetized and artificially-ventilated cats. Verapamil (300 micrograms kg(-1) i.v.) produced a significant inhibition of sympathetically-induced tachycardia and pressor responses. The same dose of verapamil did not significantly alter adrenaline (2 micrograms kg(-1) i.v.) induced increase in HR and BP. In contrast, neither the sympathetically-induced nor the adrenaline-induced pressor and tachycardiac responses were significantly affected by nifedipine or diltiazem. These results demonstrate that peripherally administered verapamil but not nifedipine and diltiazem can inhibit cardiovascular sympathetic neurotransmission and this can possibly contribute to its effects on HR and BP.     

Hydralazine: effect on the outflow of noradrenaline and mechanical responses evoked by sympathetic nerve stimulation of the rat tail artery

1 The effects of hydralazine on the vasoconstrictor responses to field stimulation of sympathetic nerves were studied in the isolated proximal segments of the rat tail artery. Vasoconstrictor responses to transmural stimulation were depressed by superfusion of hydrazine (0.3, 3 and 30 muM) in a concentration-dependent manner. The inhibition appeared slowly and was not easily reversed by washing. 2 Hydralazine (30 nM, 0.3 and 3 muM) reduced the stimulation-induced overflow of tritium from proximal and distal segments of the tail artery labelled with [3H]-noradrenaline in a concentration-dependent manner. This phenomenon appeared rapidly and was easily reversed by washing. 3 Theophylline (0.5 mM) did not affect the inhibitory effect of hydralazine on the stimulation-induced tritium efflux from the distal segment of the rat tail artery. 4 The present results indicate that hydralazine has, in addition to its action on vascular smooth muscle, a very marked effect on sympathetic nerve terminals. The mechanism of this presynaptic inhibition appears to be different from the postsynaptic effect, in view of the much shorter delay, the shape of the dose-effect curve, and the lack of interaction with theophylline.     

Suppression of phospholipase C blocks Gi-mediated inhibition of adenylyl cyclase activity

The potential effect of inhibition of phospholipase C on the response of Gi-coupled receptors was investigated in neuroblastoma x glioma hybrid (NG108-15) cells. The phospholipase C specific inhibitor 1-[6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H -pyrrole-2,5-dione (U73122), which did not affect basal and forskolin-stimulated adenylyl cyclase activities, time- and dose-dependently blocked delta-opioid receptor-mediated inhibition of adenylyl cyclase activity, the EC50 (0.5 microM) of which was consistent with that for inhibition of bradykinin-dependent phospholipase C activation (EC50 = 1 microM). U73122 treatment also blocked functional responses of m4 muscarinic receptor and alpha2-adrenoceptor in NG108-15 cells and three opioid receptors (mu, delta and opioid receptor-like receptor (ORL1)) in human neuroblastoma SK-N-SH cells. 1-[6-((17Beta-3-Methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-2, 5-pyrrolidinedione (U73343), an inactive analog of U73122, did not show any effect, which suggests that the blockade by U73122 of Gi-coupled receptor-mediated signaling is probably mediated through inhibition of phospholipase C, although a possible direct modification of G proteins can not be excluded. Furthermore, treatment with U73122 but not U73343 blocked the GTP-induced inhibition of adenylyl cyclase, indicating blockade at the level of Gi proteins.     

Role of spinal alpha adrenoceptor in the inhibition of renal sympathetic nerve activity and natriuresis induced by blood volume expansion in rabbits

The effect of spinal alpha adrenoceptor blockage on the inhibition of renal sympathetic nerve activity (RSNA) and natriuresis induced by blood volume expansion was investigated in anesthetized and bilateral sinoaortic denervated rabbits. In the groups of rabbits with intrathecal injection of alpha-adrenoceptor blocker phentolamine or artificial cerebrospinal fluid the inhibition of RSNA induced by blood volume expansion were (-25.4 +/- 5.4)% and (-42.5 +/- 5.2)% respectively (P < 0.05). In the groups of rabbits with intrathecal injection of alpha 1 adtenoceptor blocker prazosin or artificial cerebrospinal fluid the inhibition of RSNA induced by blood volume expansion were (-29.3 +/- 6.1)% and (-42.5 +/- 5.2)% respectively (P < 0.05). These results suggested that both spinal alpha and alpha 1 adrenceptor blockage with attenuated the inhibition of RSNA induced by blood volume expansion. The spinal alpha 1 adrenceptor blockage with intrathecal injection of prazosin also attenuated signiticantly the natriuresis and diuresis induced by blood volume expansion (P < 0.05).     

Bradykinin B2-receptor-mediated stimulation of exocytotic noradrenaline release from cardiac sympathetic neurons

Myocardial ischemia, as well as angiotensin-converting-enzyme-inhibitors, increase cardiac concentrations of the non-apeptide bradykinin. Cardiac effects of bradykinin are potentially mediated by modulation of sympathoadrenergic neurotransmission. Accordingly, the present study was designed to examine the influence of bradykinin on exocytotic noradrenaline release from rat isolated perfused heart. Exocytotic noradrenaline release was induced by electrical field stimulation (1 min, 5 V, 6 Hz) twice to compare the effect of intervention (S2) with respective control stimulation (S1). The overflow of endogenous noradrenaline was determined by high pressure liquid chromatography and electrochemical detection. The results are expressed as the mean S2/S1 ratio+/-S.E.M. Bradykinin (1 micromol/l) evoked a significant increase in noradrenaline release (S2/S1: 1.60+/-0.12; P<0.01), which was even more pronounced after inhibition of neuronal reuptake of noradrenaline by desipramine (0.1 micromol/l: S2/S1: 1.83+/-0.15; P<0.01) excluding interference of bradykinin with the noradrenaline uptake1 carrier. The concentration-response curve for bradykinin (0.1 nmol/l to 10 micromol/l) revealed a maximum effect at 1 micromol/l and an EC50-value of 7.5 nmol/l. The effect of bradykinin was unaltered by the B1-receptor antagonist des-Arg9 (Leu8)-bradykinin (1 micromol/l; S2/S1: 1.69+/-0.17), whereas it was reduced significantly by the B2-receptor antagonist Hoe 140 (1 micromol/l; S2/S1: 1.14+/-0.11; P<0.05). Des-Arg9-bradykinin (1 micromol/l), a specific B1-agonist, had no effect on stimulation-induced noradrenaline release (S2/S1: 0.94+/-0.08). Utilizing pharmacological interventions, we attempted to characterize the intraneuronal signal transduction pathway mediating the effect of bradykinin on exocytosis. Neither inhibition of cyclooxygenase nor blockade of nitric oxide synthesis affected bradykinin-induced stimulation of noradrenaline release. Likewise, inhibition of protein kinase C by bisindolylmaleimide (1 micromol/l) or tyrosine kinase by genistein (10 micromol/l) had no effect on the promoting action of bradykinin. In contrast, inhibition of cytosolic phospholipase A2 activity by the specific inhibitor AACOCF3 (1 micromol/l) prevented bradykinin-induced increase in noradrenaline release (S2/S1: 1.09+/-0.15; P<0.01). In conclusion, bradykinin increases exocytotic release of endogenous noradrenaline from cardiac sympathetic neurons via activation of presynaptic B2-receptors. Intraneuronal coupling of B2-receptors to phospholipase A2 appears to mediate the facilitatory effect of bradykinin on noradrenaline release in rat heart.     

Evaluation by microneurography of muscle sympathetic nerve activity in myelopathic patients

The purpose of this study was to observe the functional condition of the muscle sympathetic nerve activity (MSNA) in nine patients with mild myelopathy for which surgery was indicated [mean score 14/17 by Japanese Orthopaedic Association (JOA) cervical myelopathy and 7/11 for thoracic myelopathy]. The MSNA was obtained from the tibial nerve at the popliteal fossa by microneurography. The resting activities and the responses during handgripping were analyzed and compared with those of a control group of nine healthy volunteers and patients with disorders unrelated to myelopathy. The MSNA with the subjects supine was recorded first at rest for 5 min. (rest period), next during exertion of 20% of the maximum voluntary handgripping power for 5 min. (handgripping period), and last at rest for 5 min. (recovery period). The number of MSNA bursts per min. (burst rate) in the group with myelopathy was more than that in the control group (p < 0.05) in all three periods. The response by MSNA to handgripping in the group with myelopathy was higher than that in the control group at the start of handgripping (p < 0.01), and tended to be higher even 5 min. after handgripping ended. The results appeared to demonstrate that MSNA of patients with mild myelopathy for which surgery is indicated is increased in the lower extremities.