Journal of the autonomic nervous system最新文献

Glucagon-like peptide-1 (7–36)amide (tGLP-1), a representative humoral incretin, released into the portal circulation in response to a meal ingestion, exerts insulinotropic action through binding to the tGLP-1 receptor known to be a single molecular form thus far. We previously reported that the hepatic vagal nerve is receptive to intraportal tGLP-1, but not to non-insulinotropic full-length GLP-1-(1–37), through a mechanism mediated by specific receptor to the hormone. In the present study, we aimed to examine how modification of the receptor function alters this neural reception of tGLP-1, by using the specific agonist, exendin-4, and the specific antagonist, exendin (9–39)amide, of the receptor at doses known to exert their effects on the insulinotropic action of tGLP-1. Intraportal injection of 0.2 or 4.0 pmol tGLP-1, a periphysiological and pharmacological dose, respectively, facilitated significantly the afferent impulse discharge rate of the hepatic vagus in anesthetized rats, as reported previously. However, unexpectedly, intraportal injection of exendin-4 at a dose of 0.2 or 4.0 pmol, or of even 40.0 pmol, did not facilitate the afferents at all. Moreover, intraportal injection of exendin (9–39)amide at 100 times or more molar dose to that of tGLP-1, either 5 min before or 10 min after injection of 0.2 or 4.0 pmol tGLP-1, failed to modify the tGLP-1-induced facilitation of the afferents. The present results suggest that the neural reception of tGLP-1 involves a receptor mechanism distinct from that in the well-known humoral insulinotropic action.

A 34-year-old male patient with familial amyloidotic polyneuropathy (FAP) amyloidogenic transthyretin (ATTR) Valine30Methionine (Val30Met), who underwent a liver transplantation in Sweden in 1994, was treated with sildenafil citrate (Viagra) to ameliorate his erectile dysfunction (ED). Some clinical symptoms and the examination data for autonomic functions were improved after liver transplantation, but ED was never improved after the operation. Five years after liver transplantation, he requested a sildenafil citrate therapy to enhance his erectile potential. One and a half hours after the administration of 25 mg of sildenafil citrate, the skin surface temperature around the pelvic area increased and the penis became erect, though the postdose hemodynamic parameters did not significantly change from the respective baseline or predose values. He was able to have sexual intercourse, though ejaculation did not occur. This case report appears to suggest that sildenafil citrate is an effective drug to treat ED in patients with an organic impairment of the autonomic nervous system without altering systemic circulation.

Dynamic arterial blood pressure (FINAPRES) response to active standing up, normally consisting of initial rise, fall and recovery above the baseline (overshoot), was compared with the early steady-state arterial blood pressure level to measure sympathetic vasomotor function in healthy subjects [group 1: n=50, 10 female subjects, age 51±2.5 years; weight 78±2.3 kg; height 174±1.4 cm (mean±standard error of the mean)] and in kidney transplant recipients under basal (group 2a: n=50, age 51.7±1.7 years; weight 77±2.1 kg; height 174±1.5 cm) and under high (group 2b: same subjects as in group 2a) ciclosporine A whole blood levels. Furthermore, baroreflex sensitivity and the activity of the generating compounds of the sympathetic nervous systems (Mayer waves) were measured. Systolic and diastolic overshoot values did not differ statistically significant in the present study. In the control subjects, a systolic overshoot of 15.4±2.7 mmHg and a diastolic overshoot of 15.2±2 mmHg was detected. The systolic overshoot disappeared in 57% of group 2a (−7.1±2.7 mmHg; P<0.001) and in 50% of group 2b recipients (−8.0±2.7 mmHg; P<0.001). Systolic early steady-state level was not lower in kidney transplant recipients before ciclosporine (baseline+2 mmHg) intake, but after ciclosporine administration (baseline−3 mmHg; controls: baseline+3 mmHg; P<0.05). There was a strong association between the overshoot and steady-state levels (P for χ²<0.001, n=150). Overshoot of group 1 levels (r=0.428; P<0.01) and group 2 levels (r=0.714; P<0.001) correlated to their respective steady-state blood pressure. Furthermore, recipients had reduced baroreceptor sensitivities estimated by sequence analysis as compared to controls (10±1 ms/mmHg vs. 7.5±1.4 ms/mmHg; P<0.05). Mayer waves amplitudes of the heart rate spectrum were elevated statistically significant in renal transplant recipients (44.4±0.2 vs. 43.8±2.2 A.U.). In conclusion, baroreceptor reflex-dependent overshoot of the arterial blood pressure after active standing up is diminished in kidney transplant recipients, whereas no association to the ciclosporine A whole blood level has been detected. The reduced overshoot may be due to the diminished baroreceptor sensitivity which could be shown in renal transplant recipients.

The effects of 5-hydroxytryptamine (5-HT) and related drugs on colonic migrating motor complexes (CMMCs) were evaluated in isolated colons from the heterozygotes of pie-bald lethal mice. 5-HT produced a dose-related increase in the frequency of CMMCs without any change in the amplitude or duration of the CMMC contractions themselves. The 5-HT₂ agonist, α-methyl 5-HT, (100 nM–1 μM) increased the frequency of CMMCs whilst the 5-HT₃ agonist, 2-methyl 5-HT, did so at 10 μM. The 5-HT₄ agonist, 5-methoxy dimethyl tryptamine oxalate did not alter the frequency of CMMCs in the concentration range 1 nM–10 μM. The 5-HT₃ receptor antagonist, ondansetron, increased the interval between CMMCs in the concentration range 100 nM–1 μM, whilst the 5-HT₁ receptor antagonist, methiothepin, the 5-HT₂ receptor antagonist, cyproheptadine and the 5-HT₄ receptor antagonist, SDZ 205 557, had no significant effects on the interval between CMMCs in the concentration range 1 nM–10 μM. The effects of 5-HT did not appear to be altered by the presence of ondansetron (1 μM) or cyproheptadine (1 μM). However, in the presence of ondansetron (1 μM), the further addition of cyproheptadine (1 μM) effectively abolished CMMCs. Furthermore, in the combined presence of these antagonists the effects of 5-HT were severely diminished. It is suggested that the frequency of CMMCs may be under the influence of endogenously released 5-HT in this preparation

Physiological and histochemical studies have demonstrated the control and innervation of sympathetic nerves to the artery and vein vessels of splanchnic circulation. In our laboratory, we first used the technique of retrograde transport of horseradish peroxidase to identify the origin of sympathetic neurons innervating the mesenteric vein. In this study, double fluorescence staining technique was used for a simultaneous localization of the sympathetic postganglionic neurons supplying the mesenteric artery and vein in rats. First-order branches of mesenteric artery (A) and vein (V) in the vicinity of ileo-cecal junction were isolated for application of fluorescent dyes (Fast Blue, FB and Diamidino Yellow, DY). The application of FB and DY on A and V was alternated in the next animal to minimize the difference in dye uptake. The animal was allowed to recover for 6-7 days assuring a complete uptake of FB and DY into the cytoplasm and nucleus, respectively. The number of FB, DY and double staining neurons in the prevertebral and paravertebral ganglia were counted under a fluorescent microscope after animal fixation and serial frozen section (30 μm) of the sympathetic ganglia. Our study revealed the following findings: (1) Distribution of the fluorescence-staining neurons in the sympathetic ganglia was as follows: right celiac ganglion (39%), superior mesenteric ganglion (30%), left celiac ganglion (26%), inferior mesenteric ganglion (1%) and paravertebral ganglia (4%). (2) Double staining neurons that dually innervate A and V amounted to 54% of total staining neurons. There were 41% neurons singly innervating A and 5% innervating V. (3) The ratio of neurons supplying the A and V ranged from 1.41 to 1.75 (average 1.61). (4) There was no distinct topographical distribution with respect to the neuron location innervating A and V. The distribution of neurons appeared in a scattering pattern.

Systemic injection of sodium nitroprusside (30 μg/kg, i.v.) in the awake Bufo paracnemis toad induced a fall in arterial blood pressure and tachycardia. This tachycardia, but not the hypotension, was significantly reduced in toads with bilateral electrolytic lesion of the caudal and commissural regions of the solitary tract nucleus and in animals with transection of the spinal cord, 2 mm below the obex. This indicates that the tachycardia is reflex, depends on the integrity of the solitary tract nucleus and is due to descending spinal autonomic activation. Pretreatment with propranolol (4 mg/kg, i.v.) significantly reduced the tachycardia but did not block it completely, showing the importance of beta-adrenoceptors in its genesis. The reflex increase in heart rate induced by nitroprusside was not statistically significant in animals with bilateral section of the laryngeal nerve, whose baroreceptor fibers originate from the pulmocutaneous artery or in animals in which the bilateral section of the laryngeal nerve was performed together with section of the glossopharyngeal nerves, which incorporate fibers originating from the carotid labyrinth. The reduction of the reflex tachycardia was significant in toads with aortic arch denervation alone or combined with section of the laryngeal nerves or in animals with complete denervation of the three baroreceptors areas. These results suggest that the region of the aortic arch, when submitted to unloading, is the most important baroreceptor zone for cardiac compensation in toads.

The unique contractile profiles of bronchial smooth muscle (Kondo et al., 1995) and its neural control were investigated by comparing responses of the bronchus and trachea to acute hypercapnia, stimulation of vagus efferent fibers before and after intravenous atropine, and intravenous acetylcholine in decerebrated and paralyzed dogs. During acute hypercapnia, airway resistance represented by peak airway pressure (Pedley et al., 1970) significantly increased as well as tracheal tension (Ttr). During electric stimulation of the vagal efferent fibers, Ttr increased and was sustained throughout the simulation period while the peak airway pressure was not maintained at the peak level. The peak Ttr and the airway resistance (Raw) calculated from ventilatory flow and airway pressure increased with increases in intensity of electric stimulation. Ttr reached its maximal level at an intensity 16 times of the threshold (T), while Raw became maximal at 4T. Although both the Ttr-stimulus intensity and Raw-intensity curves were shifted to the right by administration of intravenous atropine, the Raw curve shifted more to the right than the Ttr curve with the same dose of atropine. When muscular muscarinic receptors were directly stimulated by intravenous acetylcholine, Ttr once increased and then decreased promptly while peak airway pressure remained at a high level for a few minutes. These findings suggested that the bronchus is more sensitive to vagal efferent stimulation and susceptible to competitive antagonist of actylcholine than the trachea. In conclusion, the contractile profiles of the fifth-order bronchus we have reported (Kondo et al., 1995) were reflected in airway resistance, and the neuromuscular junction may be the site of adaptation of bronchoconstrictor response to motor nerve adaptation.

Noradrenaline (NA) kinetics represent an effective tool for evaluating the activity of the sympathetic system: thus plasma NA concentration, spillover rate (SOR) and metabolic clearance rate (MC) were measured in the rat. The dilution technique was adapted and validated: pithing that caused mechanical destruction of the spinal cord was shown to reduce drastically NA-SOR and plasma NA concentration with no effect on NA-MC. NA-SOR and plasma NA concentration were restored within their normal limits when 2.5 Hz electrical stimulation of the sympathetic roots was superimposed. Normal values of NA kinetics in non-anaesthetised normotensive 12-week-old rats are reported: NA-SOR=196.1±26.4 ng/kg/min, NA-MC=413.9±38.8 ml/kg/min and plasma NA=486±52 pg/ml. NA kinetic was investigated in response to anaesthesia, known to depress excitable tissues of the central nervous system and expected to depress the activity of the sympathetic system. When NA-SOR was significantly reduced during anaesthesia with either sodium pentobarbital or chloralose, plasma NA concentration was not changed because NA-MC was also reduced. Thus, plasma NA concentration can be a misleading marker of the sympathetic activity. The response of the sympathetic activity to four different anaesthetic agents is shown to be heterogeneous, ranging from inhibition to stimulation. Sodium pentobarbital anaesthesia was associated with a statistically significant reduction of both NA-SOR (105.6±14.1 ng/kg/min, P<0.01) and NA-MC (239.3±18.7 ml/kg/min, P<0.001) while plasma NA was not changed (438±47 pg/ml). Chloralose reduced NA-SOR (101.6±20.1 ng/kg/min, P<0.05) while ketamine did not (150.6±35.5 ng/kg/min, n.s.): both compounds reduced NA-MC (257.9±27.8 ml/kg/min, P<0.01 and 265.8±34.3 ml/kg/min, P<0.05, respectively). Diethyl ether was shown to increase both NA-SOR (472.2±111 ng/kg/min, P<0.05) and plasma NA concentration (1589±436 pg/ml, P<0.01), while NA-MC remained unchanged. Thus, any investigation of the activity of the sympathetic system in the anaesthetised rat has to take into account the specific effects related to the anaesthetic agent used.

In an attempt to determine the effect of hyperinsulinemia on sympathetic function, release of norepinephrine (NE) from isolated aorta by insulin was measured in Wistar rats with insulin resistance. Insulin resistance was produced when the hypoglycemic action of glibenclamide at a dose of 10 mg/kg was almost abolished in rats that received daily injections of long-acting insulin for 15 days. Moreover, the stimulatory effect of insulin on glucose uptake was markedly reduced in both skeletal muscle strips and white adipocytes obtained from these rats with insulin resistance. However, the stimulatory effects of insulin at concentrations from 5 to 15 U/l on the release of NE from the aortic strip of insulin-resistant rats were not modified in the same manner but only slightly reduced compared with that of normal rats. These results suggest that insulin desensitization was produced later in sympathetic nerve terminals than in other organs in insulin-resistant rats and this may be helpful to explain the sympathetic hyperactivity associated with diabetes in clinics.