Peripheral Sympathetic Nerve Endings Research Articles

Role of autonomic system imbalance in neurogenic pulmonary oedema.

Neurogenic pulmonary oedema (NPE) is a life-threatening complication that develops rapidly and dramatically after an injury to the central nervous system (CNS). The autonomic system imbalance produced by severe brain damage may play an important role in the development of NPE. Activation of the sympathetic nervous system and inhibition of the vagus nerve system are essential prerequisites for autonomic system imbalance. The more severe the damage, the more pronounced the phenomenon. Sympathetic hyperactivity is associated with increased release of catecholamines from peripheral sympathetic nerve endings, which can cause dramatic changes in haemodynamics and cause pulmonary oedema. On the other hand, the abnormal inflammatory response caused by vagus nerve inhibition may also play an important role in the pathogenesis of NPE. The perspective of autonomic system imbalance seems to perfectly integrate the existing pathogenesis of NPE and can explain the entire development progression of NPE.

Comparative standardization study for determination of reserpine in Rauwolfia serpentina homoeopathic mother tinctures manufactured by different pharmaceutical industries using HPTLC as a check for quality control

Background: Rauwolfia serpentina (L.) Benth. ex Kurz (Apocynaceae) (Indian snakeroot), popularly known as Sarpagandha (Sanskrit), is used for the treatment of insanity, fever, snake bites, anxiety and in neuropsychiatric conditions. The antihypertensive actions of Reserpine are a result of its ability to deplete catecholamines (amongst other monoamine neurotransmitters) from peripheral sympathetic nerve endings which are normally involved in controlling heart rate, force of cardiac contraction and peripheral vascular resistance. Objective: Comparative study of Reserpine content in R. serpentina homoeopathic mother tinctures manufactured by different pharmaceutical industries and in-house mother tinctures applying high-performance thin-layer chromatography investigative techniques to facilitate the use of correct species. Materials and Methods: The authentic samples of roots of R. serpentina were supplied by Centre of Medicinal Plants Research in Homoeopathy, Emerald, Tamil Nadu, India. Authentic plant material was used to prepare the mother tincture (as per Homoeopathic Pharmacopoeia of India). Reserpine (C33H40N2O9,M.P. 360°C, purity >99% w/w by high-performance liquid chromatography [HPLC]) was purchased from Sigma-Aldrich as a standard reference. The solvents for the study, namely, ethanol, HPLC water, toluene, ethyl acetate, diethylamine and chloroform were of analytical grade purity (MERCK Ltd.,), used throughout. Results: Five samples of mother tinctures were used for the study, in-house mother tinctures (labelled: D and E) of R. serpentina shows a higher amount of Reserpine content than the marketed samples (labelled: A, B and C). Conclusion: It may be concluded that mother tinctures prepared by authentic plants showed the excess amount of Reserpine rather than that of mother tinctures procured from the market.

Silymarin Constituent 2,3-Dehydrosilybin Triggers Reserpine-Sensitive Positive Inotropic Effect in Perfused Rat Heart.

2,3-dehydrosilybin (DHS) is a minor flavonolignan component of Silybum marianum seed extract known for its hepatoprotective activity. Recently we identified DHS as a potentially cardioprotective substance during hypoxia/reoxygenation in isolated neonatal rat cardiomyocytes. This is the first report of positive inotropic effect of DHS on perfused adult rat heart. When applied to perfused adult rat heart, DHS caused a dose-dependent inotropic effect resembling that of catecholamines. The effect was apparent with DHS concentration as low as 10 nM. Suspecting direct interaction with β-adrenergic receptors, we tested whether DHS can trigger β agonist-dependent gene transcription in a model cell line. While DHS alone was unable to trigger β agonist-dependent gene transcription, it enhanced the effect of isoproterenol, a known unspecific β agonist. Further tests confirmed that DHS could not induce cAMP accumulation in isolated neonatal rat cardiomyocytes even though high concentrations (≥ 10 μM) of DHS were capable of decreasing phosphodiesterase activity. Pre-treatment of rats with reserpine, an indole alkaloid which depletes catecholamines from peripheral sympathetic nerve endings, abolished the DHS inotropic effect in perfused hearts. Our data suggest that DHS causes the inotropic effect without acting as a β agonist. Hence we identify DHS as a novel inotropic agent.

Cilnidipine Lowers Plasma Leptin of Patients with Obese Hypertension Associated with Cerebrovascular Disorder

Background: Since cilnidipine suppresses not only the L-type but also N-type calcium channels found on peripheral sympathetic nerve endings which control noradrenaline release, it is thought to be a Ca antagonist with low sympathetic nerve activation when lowering blood pressure (dual blocking action). As activation of sympathetic nervous system is suggested to contribute to hypertension in obesity, dual blocking action of cilnidipine may contribute to patients with obesity-hypertension. Methods: The effects of cilnidipine on plasma leptin levels and blood pressure were studied. Twenty three patients with obesity-hypertension associated with a past history of stroke or ischemic changes confirmed by brain magnetic resonance imaging were enrolled. Cilnidipine (10 mg/day) was administered orally once a day after breakfast. The duration of the study treatment was 12 weeks. Retroperitoneal adipose tissues around the kidney of both fat and lean cadaver and neuronal and non-neuronal tissues of rat were used for immunohistochemical examination. Result: The mean circulating leptin level decreased from 11.8 ng/ml to 10.8 ng/ml that reached statistical significance. Multiple regression analysis revealed no significant effects of covariates except for baseline leptin level. An immunohistochemical study revealed that N-type calcium channel protein was expressed on the cell membrane of adipocytes. We speculate that a blockade of calcium current through the N-type channel, instead of the L-type channel may suppress leptin secretion. Conclusion: The dual blocking action of cilnidipine may help control both arterial hypertension and leptininduced atherosclerosis in patients with obese hypertension associated with cerebrovascular disorder.

Low-frequency electroacupuncture suppresses carrageenan-induced paw inflammation in mice via sympathetic post-ganglionic neurons, while high-frequency EA suppression is mediated by the sympathoadrenal medullary axis

Although the frequency-dependent antinociceptive mechanisms of electroacupuncture (EA) have been well demonstrated, the anti-inflammatory mechanisms that underlie the suppressive effects induced by different frequencies of EA stimulation on peripheral inflammation are largely unknown. We have previously reported that EA stimulation can activate the sympathetic nervous system (SNS) and that this activation is responsible for the EA-induced suppression of zymosan-induced leukocyte migration. The present study was designed to evaluate the differential effect of low (1 Hz, LF EA) versus high (120 Hz, HF EA) frequency EA stimulation on SNS activation and ultimately on carrageenan-induced inflammation. Immediately after carrageenan injection, we applied either LF EA or HF EA bilaterally to the Zusanli (ST36) acupoints. To evaluate the anti-inflammatory effect of EA (EA-AI), paw volume and myeloperoxidase (MPO) activity, a marker of infiltrated leukocytes, were measured and the paw withdrawal latency to noxious heat stimulation was also assessed. Both LF EA and HF EA significantly suppressed the carrageenan-induced paw edema and MPO activity. Moreover, thermal hyperalgesia was strongly attenuated in both the LF EA and HF EA groups. Adrenalectomy significantly diminished HF EA-AI without affecting LF EA-AI. Pretreatment with the corticosterone receptor antagonist, RU-486 did not affect either LF EA- or HF EA-AI. On the other hand, administration of 6-hydroxydopamine (a neurotoxin for peripheral sympathetic nerve endings) selectively blocked LF EA-AI. Propranolol (a β-adrenoceptor antagonist) completely abolished both LF EA- and HF EA-AI. The results of this study suggest that the suppressive effects of LF EA on carrageenan-induced paw inflammation are mediated by sympathetic post-ganglionic neurons, while the suppressive effects of HF EA are mediated by the sympatho-adrenal medullary axis.

Measurement of Catechol-O-methyltransferase Activity in the Brain of Dahl Salt-Sensitive Rats

Metabolism by catechol-O-methyltransferase (COMT) is one of the inactivation pathways of catecholamines (CAs), which are important hormones in regulating blood pressure both in central and in peripheral sympathetic nerve endings. We have reported the rapid determination method of COMT activity using high-performance liquid chromatography (HPLC)-fluorescence detection. In the present study, we applied the method to brain tissues, cerebral cortex, cerebellum, hypophysis and hypothalamus. COMT activities were assessed by measuring normetanephrine with the use of norepinephrine as an endogenous substrate. We examined the COMT activities in the brains of Dahl salt-sensitive (DS) rats given normal-salt or high-salt diet for 13 weeks, and found that membrane-bound COMT activities in the cerebral cortex were significantly reduced in high-salt loaded DS rats compared with normal-salt loaded DS rats.

Prolonged Activation of cAMP-response Element-binding Protein and ATF-2 Needed for Nicotine-triggered Elevation of Tyrosine Hydroxylase Gene Transcription in PC12 Cells

Phosphorylation (P-) of cAMP-response element-binding protein (CREB) by protein kinase A or mitogen-activated protein kinases was implicated in mediating the increased tyrosine hydroxylase (TH) gene expression after prolonged exposure to nicotine in vivo and in cell culture. We examined the time course and signaling pathways for phosphorylation of CREB and possible involvement of ATF-2. Treatment of PC12 cells with 200 microm nicotine triggered rapid but transient elevation of P-CREB followed by a second sustained rise after 2-5 h of continuous nicotine. In contrast, ERK1/2 was only phosphorylated with short term nicotine exposure. MEK inhibitor U0126 abolished nicotine-induced rise in P-ERK1/2, but not P-CREB, nor did it inhibit nicotine-evoked elevation in TH promoter activity, indicating that ERK1/2 was not needed for induction of TH gene expression by nicotine. In contrast, protein kinase A inhibitor H-89 or Ca(2+)/calmodulin-activated protein kinase inhibitor KN-93 reduced the nicotine-triggered rise in P-CREB and TH promoter activity. There was a delayed elevation of P-ATF-2 after 1 h of nicotine treatment, accompanied by increased ATF-2 protein. Upstream kinase JNK, but not p38, was phosphorylated especially after 5 min to 2 h of nicotine exposure. To examine the requirement for CREB and ATF-2, cells were transfected with dominant negative forms of ATF-2 or CREB. Both reduced the basal TH promoter activity and the response to nicotine. Knockdown of ATF-2 or CREB with siRNA did not alter basal TH promoter activity or mRNA but greatly attenuated the response to nicotine. The results suggest that both ATF-2 and CREB mediate activation of TH gene transcription by nicotine.

Low Catechol-O-methyltransferase Activity in the Brain and Blood Pressure Regulation

Catecholamines (CAs) are important hormones in regulating blood pressure both in centrally and peripheral sympathetic nerve endings. Production of CAs, release and inactivation are three components to regulate CAs level. We have reported that the inactivation of CAs by catechol-O-methyltransferase (COMT) in the liver is important in high blood pressure in spontaneously hypertensive rats (SHR). In the present study, we investigated central role of COMT in hypertension. We investigated COMT activities in cerebral cortex, cerebellum, hippocampus, brain stem, hypophysis, and hypothalamus of SHR and Wistar-Kyoto (WKY) rats. COMT activities were assessed by measuring normetanephrine with the use of norepinephrine as an endogenous substrate. Membrane-bound COMT activities in cerebral cortex were significantly reduced in SHR (19.1+/-1.8 pmol/min/mg protein) compared with WKY rats (25.0+/-3.3 pmol/min/mg protein). The ratio of concentrations of normetanephrine/norepinephrine in cerebral cortex was also lower in SHR than in WKY rats. Our results suggest that there is an association between MB-COMT in cerebral cortex and blood pressure regulation.

Magnesium and N-type calcium channel

Magnesium has been known to inhibit calcium influx via L-type calcium channel in vascular smooth muscle cells and thus cause vasodilation and hypotension. Moreover, it was reported that magnesium also modulates barofunction. Therefore we speculated that magnesium has inhibitory effect on sympathetic tone and we showed that magnesium inhibit norepinephrine release from peripheral sympathetic nerve endings. Also we showed that this effect was by inhibiting calcium influx from N-type calcium channel. These effect may explain organ protective effect of magnesium in acute myocardial infarction and also a new therapeutic target in treating hypertensives.

Magnesium inhibits norepinephrine release by blocking N-type calcium channels at peripheral sympathetic nerve endings.

Although Mg2+ contributes to blood pressure regulation partly in terms of vasodilator action, its sympatholytic effect may also play an important role to control blood pressure. Thus, in the present study, we investigated the effect of Mg2+ on sympathetic tone and blood pressure. We studied its actions on the blood pressure response to hydralazine, a direct vasodilator, in conscious spontaneously hypertensive rats (SHRs), and to electrical stimulation in the pithed Sprague-Dawley rat; catecholamine release by peripheral sympathetic nerve endings; and the N-type Ca2+ channels of cultured neural cells. Intravenous Mg2+ infusion (MgSO4: 3x10(-6) mol/kg body weight/min) induced the greater hypotensive response to hydralazine with attenuated reflex tachycardia in SHRs. In pithed rats, Mg2+ infusion significantly attenuated the blood pressure elevation (2+/-2 mm Hg versus 27+/-6 mm Hg, P<0.01) in response to spinal electrical stimulation. In the perfused mesenteric arteries system, norepinephrine release was significantly attenuated (51+/-2%, P<0.01) by high Mg2+ concentration solution (4.8 mmol/L) compared with normal Mg2+ solution (1.2 mmol/L). When we applied the perforated whole-cell patch clamp method to nerve growth factor-treated PC12 cells, Mg2+ blocked voltage-gated Ca2+ currents in a concentration-dependent manner. The majority of the voltage-gated Ca2+ currents were carried through N-type channels, followed by L-type channels. Mg2+ blocked both of these channels. These findings suggest that Mg2+ blocks mainly N-type Ca2+ channels at nerve endings, and thus inhibits norepinephrine release, which decreases blood pressure independent of its direct vasodilating action.

Elevation of sympathetic activity by eprosartan in young male subjects

Background Selective blockade of the type 1 angiotensin II receptors (AT1 receptors) reduced blood pressure (BP) elevation caused by sympathetic stimulation in the pithed rat model. This has been attributed to blockade of AT1 receptors located presynaptically on sympathetic nerve endings normally facilitating norepinephrine release. We examined the effects of AT1 receptor blockade on the sympathetic nervous system in humans. Methods Twenty-nine young white men with normal to mildly hypertensive BP values participated in a double-blind, placebo-controlled, randomized cross-over protocol receiving 600 mg/d of eprosartan or placebo for 1 week. At the last day of intake we measured hemodynamic parameters, muscle sympathetic nerve activity by microneurography, and plasma levels of norepinephrine, epinephrine, and angiotensin II during rest and cardiovascular stress. Results Eprosartan lowered resting mean arterial pressure (73.6 ± 11.0 v 78.0 ± 10.3 mm Hg, P < .05; Finapres, Ohmeda, Englewood, CO), and elevated heart rate (64.4 ± 7.6 v 61.1 ± 6.8 beats/min, P = .01), muscle sympathetic nerve activity (14.1 ± 10.4 v 9.8 ± 6.3 bursts/min, P < .05) and plasma angiotensin II (37.0 ± 33.7 v 6.9 ± 2.8 ng/L, P < .01), as well as norepinephrine levels (234.2 ± 87.6 v 187.8 ± 59.3 ng/L, P < .01). Eprosartan did not blunt sympathetic activation caused by lower body negative pressure or mental stress. Conclusions These results contrast with animal data showing antiadrenergic properties of this drug. If any, it appeared, that eprosartan causes augmented central neural vasoconstrictor outflow paralleled by increased plasma levels of norepinephrine, which casts doubt on its ability to dampen norepinephrine release from peripheral sympathetic nerve endings in humans. We hypothesize that eprosartan leads to a resetting of the baroreflex, presumably by the markedly elevated circulating angiotensin II.

A newly identified peptide, proadrenomedullin N-terminal 20 peptide, induces hypotensive action via pertussis toxin-sensitive mechanisms.

Proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM) are novel hypotensive peptides. Although they are derived from the same gene product, proadrenomedullin, their hypotensive mechanisms are different; PAMP inhibits the release of norepinephrine from the peripheral sympathetic nerve endings, whereas AM fosters vasodilation by elevating intracellular cAMP, possibly via activation of cholera toxin-sensitive G proteins. In PC12 cells, PAMP inhibited N-type calcium channel via activation of pertussis toxin-sensitive mechanisms. To clarify the relationship between the hypotensive effect of PAMP and pertussis toxin-sensitive mechanisms, we administered pertussis vaccine intraperitoneally into rats for 3 consecutive days. By using mesenteric artery preparation, we showed that PAMP's ability to decrease norepinephrine overflow was significantly attenuated in pertussis toxin-treated rat (-18.5 +/- 6.9%; P<.05 versus control rats). In electrically stimulated pithed rat, PAMP (20 and 40 nmol/kg) showed a hypotensive effect (-13 +/- 5 and -18 +/- 7 mm Hg, respectively; P<.05, P<.01), whereas in pertussis vaccine-treated rat it did not (-2 +/- 3 and -8 +/- 9 mm Hg, respectively; P=NS). Also, in pithed rat, plasma norepinephrine level was significantly elevated by electrical stimulation in both control (0.323 +/- 0.035 ng/mL) and pertussis vaccine-treated groups (0.355 +/- 0.079 ng/mL). After injection of PAMP (40 nmol/kg), plasma norepinephrine level significantly decreased in the control group (0.225 +/- 0.044 ng/mL; P<.01) but not in the pertussis vaccine-treated group (0.392 +/- 0.021 ng/mL; P=NS). Moreover, in conscious rats, intravenous administration of PAMP (40 nmol/kg) did not evoke hypotension after pertussis vaccine treatment, although untreated controls had significantly decreased arterial pressure (-5 +/- 2 versus -20 +/- 3 mm Hg; P<.01). In contrast to PAMP, the administration of AM (1 nmol/kg) significantly reduced the blood pressure of pertussis vaccine-treated as well as control rats (-20 +/- 5 versus -18 +/- 7 mm Hg; P=NS). These results demonstrate that the ability of PAMP to inhibit norepinephrine release from peripheral sympathetic nerve endings and to decrease blood pressure is pertussis toxin sensitive. Our findings thus suggest that despite being derived from the same gene, PAMP and AM apparently produce hypotension by activating different signaling pathways.

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.

Effect of Insulin on Norepinephrine Overflow at Peripheral Sympathetic Nerve Endings in Young Spontaneously Hypertensive Rats

To determine how the effect of insulin is related to the development of salt-induced hypertension, and whether a hyporesponse to insulin exists in the peripheral sympathetic nerves of a hypertensive model rat, we measured norepinephrine overflow from the periarterial nerve of isolated mesenteric arteries exposed to insulin in spontaneously hypertensive rats (SHR) as well as Wistar-Kyoto rats (WKY) fed diets that were high and low in salt. Salt loading (diet containing 8% salt for 4 weeks) accelerated the development of hypertension in young, spontaneously hypertensive rats (SHR) (157 +/- 5 mm Hg v 198 +/- 4 mm Hg, P < .01) but did not affect the blood pressure of Wistar-Kyoto rats (WKY) (102 +/- 7 mm Hg v 104 +/- 6 mm Hg, P = NS). Basal norepinephrine overflow did not differ in the SHR and WKY rats, but the overflow of norepinephrine after periarterial electrical stimulation (8 Hz 1 min.) was significantly greater in SHR (0.806 +/- 0.079 ng/g) than in WKY (0.723 +/- 0.022 ng/g; P < .01). Although insulin reduced the norepinephrine overflow by periarterial nerve stimulation in both WKY and SHR, the decrease with insulin was significantly greater in the SHR than in WKY (-18.4% +/- 4.0% v -32.0% +/- 4.6%, P < .05). The inhibitory effect of insulin on norepinephrine overflow was reduced by salt loading in SHR (-8.8% +/- 4.0%, P < .05), but not in WKY (-32.5% +/- 4.7%, P = NS). Cocaine and ouabain completely blocked the effect of insulin in all four groups. In contrast to insulin, direct stimulation of Na(+)-K+ ATPase with a high-potassium buffer (12 mmol/L) reduced NE overflow to the same extent among the four groups. These findings show that SHR have a blunted response to the suppression by insulin of norepinephrine overflow. Salt loading reduced the insulin response at peripheral sympathetic nerves of young SHR, but did not affect that of age-matched WKY. Thus, hyporeactivity to insulin may play a role in the development of salt-induced hypertension in young SHR, possibly through a reduced suppression of norepinephrine overflow from sympathetic nerve endings.

Insulin inhibits norepinephrine overflow from peripheral sympathetic nerve ending

The effects of insulin on peripheral nervous system are unknown. We therefore studied the effects of insulin on sympathetic nerve activity in isolated mesenteric arteries of Sprague-Dawley rats. The overflow of norepinephrine (NE) by electrical stimulation was used as the index of sympathetic nervous system activity. Insulin (0.5 to 1 U/I) decreased the NE release in a dose-dependent fashion. This inhibitory effect was, however, reversed by either 5×10 −5 M cocaine or 5×10 −4 M ouabain treatment. Thus, we postulate that insulin attenuates NE overflow from peripheral sympathetic nerve endings, probably due to enhanced NE reuptake.

Responsiveness of superficial hand veins to alpha-adrenoceptor agonists in insulin-dependent diabetic patients.

1. Diabetic autonomic neuropathy causes loss of sympathetic cardiovascular control and is associated with increased vascular sensitivity to catecholamines. Supersensitivity to catecholamines could be due to either a postsynaptic increase in vascular sensitivity or to decreased catecholamine uptake into peripheral sympathetic nerve endings. 2. To differentiate between these possible mechanisms we have measured the responsiveness in vivo to noradrenaline and phenylephrine with local infusions into peripheral veins of diabetic patients with and without symptomatic autonomic neuropathy and of healthy control subjects. The dorsal hand vein compliance technique was used. 3. Symptomatic diabetic patients required significantly lower doses of noradrenaline for half-maximal venoconstriction (ED50) (geometric mean 2.14 ng/min) than control subjects (geometric mean 6.61 ng/min, P = 0.032), but there was no difference in the results from the phenylephrine dose-response curves between the groups. There were no differences in venous responsiveness to noradrenaline or phenylephrine between the asymptomatic diabetic group and the control group. However, in the asymptomatic diabetic group, postural blood pressure change (an index of loss of sympathetic control) was correlated with the ED50 for noradrenaline (r = 0.74, P = 0.014), but not with the ED50 for phenylephrine. In the control group the ED50 values for noradrenaline and phenylephrine were correlated with each other (r = 0.81, P = 0.0005). 4. Both vasopressor drugs act on vascular alpha-adrenoceptors, but only noradrenaline is taken up into peripheral sympathetic nerve endings. Our results suggest that, in diabetic patients, vascular supersensitivity to catecholamines is primarily determined by decreased neuronal catecholamine uptake. A postsynaptic increase in vascular alpha-adrenoceptor stimulation does not appear to be prominent in diabetic autonomic neuropathy.

New role of nerve growth factor — an inhibitory neuromodulator of adrenergic transmission

In the present study, we investigated the effects of nerve growth factor (NGF) on norepinephrine (NE) release from peripheral sympathetic nerve endings of rat mesenteric artery. We made isolated mesenteric artery-intestinal loop preparations, by the modified method of Castelluci et al., from 4- and 8-week-old Wistar rats. NGF produced a dose-dependent inhibition of NE overflow from sympathetic nerve endings evoked by electrical nerve stimulation in the range of 0.1–10 ng/ml. Inhibition of NE overflow also occured in the presence of a neuronal uptake blocker, desipramine (5 × 10 −8M). NGF showed no effect on pressor response to exogenous NE (1 μg). These results suggest that NGF inhibits NE release from sympathetic nerve endings, in other words, NGF acts as an inhibitory neuromodulator of adrenergic transmission. This function of NGF might be considered as an inhibitory feedback mechanism against catecholamine-stimulated NGF synthesis.

Central and peripheral control of sympathoadrenal activity and energy metabolism in rats

The role of adrenoceptors in the hypothalamus and the peripheral sympathetic nervous system in the regulation of sympathoadrenal activity and glucose and FFA mobilization was investigated in exercising rats. Apparent close relations within the two parts of the sympathoadrenal system and between factors that regulate glucose and FFA mobilization during exercise were completely disrupted by local hypothalamic infusions of adrenoceptor antagonists or anesthetic drugs. The experiments actually identified specific areas in the hypothalamus that integrate the information regarding the substrate levels in the blood with the “central command” from higher centers in the brain. Furthermore, the results of experiments with exercising intact and adrenodemedullated (Adm) rats, with and without administration of selective adrenoceptor agonists and antagonists, suggest that the activity of the sympathetic nervous system is also regulated at the level of the peripheral sympathetic nerve endings. In particular, presynaptic adrenergic regulatory mechanisms can markedly influence the outflow of NE from the sympathetic nerve endings. In conclusion, the data show that an organ-specific organization of sympathetic output during exercise may take place at different levels within the sympathetic nervous system.

Contribution of Myosin Light Chain Kinase to Neurotransmitter Release from Peripheral Sympathetic Nerve Endings of Spontaneously Hypertensive Rats

Contribution of Myosin Light Chain Kinase to Neurotransmitter Release from Peripheral Sympathetic Nerve Endings of Spontaneously Hypertensive Rats

Sympathoadrenal influence on glucose, FFA, and insulin levels in exercising rats.

The effects of sympathoadrenal manipulations on the exercise-induced alterations in blood glucose, plasma free fatty acids (FFA), and insulin were investigated in intact and adrenodemedullated rats. Exercise consisted of strenuous swimming against a countercurrent for 15 min. Before, during, and after swimming, blood samples were taken through a permanent heart catheter. Adrenodemedullation (Adm) markedly reduced the exercise-induced increase in both glucose and FFA. This effect was counteracted by intravenous infusion of epinephrine (E, 20 ng/min). Intravenous infusion of 50 ng E/min into Adm rats caused an exaggerated increase in glucose. In two additional experiments 1) specific adrenoceptor agonists and antagonists were administered to exercising intact and Adm rats, and 2) E or norepinephrine (NE; 20 ng/min) was infused into intact resting rats. The results suggest that E from the adrenal medulla directly affects glucose and insulin but not FFA concentrations in the blood. NE released from peripheral sympathetic nerve endings probably acts in two different ways: as neurotransmitter on liver and pancreas and as a hormone on adipose tissue.