Influence of impulse pattern on noradrenaline release from sympathetic nerves in cerebral and some peripheral vessels.

Earlier findings suggested that the physiological firing rate in sympathetic nerves did not exceed 10 Hz. Later recordings have revealed that this is a net value: impulses are usually not continuous but occur in bursts of high frequencies separated by quiet periods. The effects of continuous and burst-like neurogenic activation in various isolated blood vessels were compared. In the first part of the study changes in vascular tone were registered. Electrical field stimulatory parameters were chosen to give tetrodotoxin-blockable, neurogenic responses. From dose-response experiments in rat caudal artery a net frequency of 6 Hz was chosen, for bursts usually designed as 30 Hz during 0.2 s followed by a quiet period of 0.8 s. In the rabbit ear artery the neurogenic contraction was enhanced by a mean of near 50% during stimulation with bursts. Now appeared a minor phentolamine-resistant portion, which was not due to release of NPY, 5-HT, histamine or ATP. Also in the rat caudal artery and monkey pial artery a significant enhancement of contraction was seen during burst simulation, whereas in the rabbit facial vein no significant difference in dilatation through beta-receptor activation was obtained. In vessels that do not normally respond with purely neurogenic contractions/dilatations during continuous stimulation, like pial arteries from the rat and rabbit, not even bursts revealed a neurogenic response. In a second series of experiments the influence of continuous and burst-like nerve activation on the release of [14C]noradrenaline was studied in monkey, rabbit and rat pial arteries, rat caudal artery and rabbit central ear artery and facial vein.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of cerebrovascular sympathetic,parasympathetic, and sensory nerves on autoregulation and spontaneous vasomotion

The effect of removal of cerebrovascular sympathetic, parasympathetic or sensory nerve on brain cortical blood flow and spontaneous vasomotion during changes in systemic blood pressure was studied by laser-Doppler flowmetry in anaesthetized rats. Selective section of sympathetic fibres along the internal carotid artery markedly affected the ability to autoregulate, as measured in microvessels of the middle cerebral arterial territory. Removal of the parasympathetic nerves tended to reduce the ability to autoregulate, whereas no significant influence was found after sensory denervation. Following the denervations, spontaneous vasomotion was not significantly affected in frequency or amplitude.     

Electrical field stimulation of rat mesenteric small arteries: force and free cytosolic calcium during neurogenic contractions and mechanisms of non-neurogenic relaxations

The effect of transmural electrical field stimulation (TEFS) of rat mesenteric small arteries was studied. Stimulation parameters were selected to cause tetrodotoxin (TTX) sensitive contractions. In arteries precontracted with PGF_2α in the presence of phentolamine, TTX insensitive relaxation could be induced by TEFS. The relaxing effect of TEFS required higher stimulation amplitude and duration than the contractions. Thus, by appropriately choosing stimulation parameters, contractile responses could be elicited which were little affected by any relaxing effect, while contractions were abolished by TTX at any stimulation conditions in the present study. The contractions were abolished by cold storage and almost completely inhibited by phentolamine. Thus, contractions were neurogenic and primarily caused by noradrenaline. At low frequencies, TEFS caused phentolamine sensitive increases in free cytosolic calcium with no contractions. At higher frequencies, there was a further increase in free cytosolic calcium, associated with contraction. Only at high frequencies, noradrenaline from nerves caused sensitization of the contractile filaments to free cytosolic calcium as during stimulation with exogenous noradrenaline. The relaxations were associated with decreases in free cytosolic calcium and were probably non-neurogenic since they were resistant to TTX, cold storage, capsaicin, and repeated stimulation. Furthermore, relaxations were almost completely abolished by increasing extracellular potassium to 40 mM or by adding tetraethylammonium chloride or 4-aminopyridine. Relaxations were also reduced by ouabain and potassium free conditions.     

Effects of cervical sympathetic stimulation on cerebral and ocular blood flows during hemorrhagic hypotension and moderate hypoxia

The effect of cervical sympathetic stimulation upon regional blood flows was investigated in albino rabbits during graded hemorrhagic hypotension and mild to moderate hypoxic hypoxia. Regional blood flows were determined using labelled microspheres. Cerebral blood flow (CBF) decreased in response to progressive hypotension and increased considerably during hypoxia (100–200%). Unilateral sympathetic stimulation did not change the ipsilateral cerebral flow responses under either condition. There was a greater tendency to autoregulate down to lower blood pressures in deep than in superficial cerebral structures. During hypoxia cortical gray matter blood flow increased relatively more than did white matter blood flow. Blood flow in different parts of the eye decreased during hypotension and tended to increase during hypoxia. Unilateral sympathetic stimulation reduced tlow rates on the stimulated side (10–50% of control side) under both conditions. The vasoconstrictory effect upon retinal blood flow tended. however, to be less during hypoxia. Dural blood flow showed a poor autoregulation and also no consistent vasodilatory response upon hypoxia. Sympathetic stimulation had a very marked effect. The results suggest that the cervical sympathetic nerves do not have any appreciable effect upon cerebral circulation during profound hypotensive and moderate hypoxic states. Dural and most ocular blood flows seem. however. to be clearly affected by sympathetic stimulation even under these extreme conditions.     

去心交感神经对QT离散度的影响

目的：采用动物实验方法，观察去心交感神经对QT离散度（QTd）的影响，并观察QT离散度的昼夜节律变化，以探讨QT离散度变化的电生理基础。 方法： 以新西兰兔作为实验对象，实验组手术去除心交感神经支配，对照组手术保留心交感神经支配。观察两组手术前后QTd变化及24 h内QTd的昼夜变化。 结果： 实验组在手术后QTd显著减小(P＜0.05)，对照组在手术前后QTd无显著变化（P＞0.05）；实验组在手术后24 h内QTd始终低于对应的对照组，且无明显节律变化，对照组在24 h内QTd呈现出显著的昼夜节律变化。 结论： 心交感神经活动可能是产生QTd的机制之一。     

Further studies on renal nerve stimulation induced release of noradrenaline and dopamine from the canine kidney in situ

The renal venous outflow of dopamine and noradrenaline were studied in the canine kidney in situ in connection with renal nerve stimulation (RNS). RNS (0.5-4 Hz) caused frequency-dependent increases in the outflow of both catecholamines, which could be detected already at 0.5 Hz. The ratio dopamine/noradrenaline in renal venous plasma (approximately 0.15) was not influenced by varying the RNS parameters but was significantly enhanced (to about 0.25) by pretreatment with guanethidine according to a procedure previously used to demonstrate renal dopaminergic vasodilatation. The unstimulated kidney removed conjugated dopamine (which represents 98–99% of the total dopamine in plasma). During RNS the conjugated dopamine outflow to renal venous blood increased, but measurements of conjugated dopamine were less reliable than measurements of free dopamine to assess dopamine release from the kidney. When studying the renal nerve contributions to the renal venous outflow of dopamine and noradrenaline more accurate estimates may be obtained by correcting for the removal of catecholamines delivered to the kidney in arterial plasma. Such corrections were performed with endogenous adrenaline or radiolabelled noradrenaline. The two methods of correction yielded similar results and showed that RNS reduced catecholamine extraction in the kidney. The high ratio of dopamine/noradrenaline in kidney tissue (with a preferential distribution of dopamine to the cortex) and the dopamine outflow to renal venous plasma during RNS support the existence of specific dopaminergic nerves in the dog kidney.     

Activation of sympathetic nerves exerts an inhibitory influence on afferent nerve-induced vasodilation unrelated to vasoconstriction in rat dental pulp

In order to elucidate a possible influence of the sympathetic nervous system on afferent nerve function, rat mandibular incisors were electrically stimulated and blood flow changes monitored in the incisor pulp of untreated and sympathectomized animals by a laser Doppler flowmeter. Monopolar electrical stimulation of the tooth (200 μA, 5 ms, 40 Hz, 1 s) in normal animals resulted in a transient reduction in pulpal blood flow (PBF) (16%, reduction, n= 10) followed by a small but long-lasting increase (11% increase). After administration of phenoxybenzamine or phentolamine (3 mg kg^-1, i.v.) the initial dip in PRF was reduced by 59% (P < 0.001) while the subsequent increase was enhanced by 185% (P < 0.001). Similarly, infusion of prazosin (50μg kg^-1, i.v.) and idazoxan (0.5 mg kg^-1 i.v.) significantly enhanced the increase in PBF by 118 and by 79%, respectively. In chronically sympathectomized animals the increase in PBF was 250% larger than that seen in untreated animals (P < 0.001). This increase in PBF was not further enhanced after α-adrenergic blockade. Acute resection of the superior cervical sympathetic ganglion, also resulted in some enhancement (by 56%) of the stimulation-induced increase in PBF (P < 0.01, n = 6). The increase in PBF was unaffected by infusion of timolol (150 μg kg^-1) and atropine (1 mg kg^-1) but was totally abolished by intravenous pre-treatment with capsaicin (1–3 mg kg^-1). The present results suggest that activation of sympathetic nerves exerts inhibitory effects on the afferent nerve-induced vasodilation in the rat incisor pulp unrelated to sympathetic vasoconstriction.     

Possible role of nerve impulse induced sodium ion flux in a proposed multivesicular fractional release of adrenaline and noradrenaline from the chromaffin cell

Based on own observations concerning a two-compartment storage of CA in the adrenal medulla and a cation exchange dependent release of CA from perfused chromaffin granules in vitro, and encouraged by recent reports from other laboratories about the importance of sodium ions for the CA release from the adrenal gland, we propose a modification of the current quantal theory of CA secretion. Instead of secretion of quanta, each quantum corresponding to the content of one vesicle, we envisage a concomitant fractional release of CA from multiple vesicles adjacent to the chromaffin cell membrane. The CA secretion should be the result of a cation exchange across the contact area between the plasma membrane and the granule membrane during the period of depolarization caused by the nerve impulse. The size of the released quanta should be determined by the nerve impulse induced sodium ion flux and the number of such ions which reach the CA binding ionic sites in the cation exchanger pool (the release pool) of the granules.     

The distribution pattern of the sympathetic nerve fibers to the cerebral arterial system in rat as revealed by anterograde labeling with WGA-HRP

Summary To clarify the projection route and the expansion of the terminal plexus of the sympathetic nerve fibers innervating the cerebral arterial system in rat, we labeled the postganglionic fibers originating in the superior cervical ganglion and traced their entire course by anterograde labeling with wheat germ agglutinin-horseradish peroxidase. Sympathetic innervation of the internal cerebral artery by labeled fibers actually began just at the portion where it enters the intradural space, and innervated it up to the small pial arteries located in the subarachnoid space, but not the intracerebral arterioles. On the main arteries in the circle of Willis, bundles of nerve fibers ran parallel to the long axis of the vessels and branched perpendicularly their terminal twigs with regular intervals to form a rib-structure pattern. On the arterial branches derived from the circle of Willis, a fine nerve bundle and delicate terminal axons formed a meshwork instead of a rib-structure pattern. These observations confirmed the existence of differences in the distribution pattern of the nerve plexus, which strongly affects the strength and quality of vasoconstriction by sympathetic activation in each level of the cerebral arterial system.     

Effects of sympathetic nerves on cerebral vessels in dog, cat, and monkey.

Cerebral vascular responses to sympathetic stimulation and denervation were examined in three species during acute severe hypertension as well as normal conditions. Cerebral blood flow (CBF) was measured with microspheres after the superior cervical sympathetic trunk was cut and during electrical stimulation of the superior cervical sympathetic ganglion. Sympathetic denervation did not increase CBF in anesthetized cats or monkeys. Under normal conditions, sympathetic stimulation decreased CBF significantly in monkeys (-26 +/- 3%) (mean +/- SE) but not in cats. During acute severe hypertension, decreases in CBF due to sympathetic stimulation were greatly augmented in cats (-29 +/- 7%, compared to -3 +/- 3%), only modestly augmented in dogs (-9 +/- 3%, compared to -1 +/- 2%), and not augmented in monkeys (-17 +/- 3%, compared to -23 +/- 4%). Disruption of the blood-brain barrier during hypertension was reduced by sympathetic stimulation. We conclude that 1) sympathetic tone to cerebral vessels is minimal because denervation does not increase CBF; 2) sympathetic stimulation decreases CBF under normal conditions in monkeys and during severe hypertension in cats, dogs, and monkeys, and it reduces disruption of the blood-brain barrier; and 3) there is an important species difference in responses to sympathetic stimulation under normal conditions and during acute hypertension.     

The action of extracellular cations on the release of the sympathetic transmitter from peripheral nerves

1. The noradrenaline stores in the sympathetic nerve endings of the cat colon were labelled in vivo with (+/-)-[7-(3)H]noradrenaline (500 muc, 11.3 mug) injected 3 hr before killing.2. The colon was removed and immersed in an organ bath containing Krebs solution. The vascular bed was perfused from the inferior mesenteric artery to the colic vein.3. The effects of Ca(2+), Ba(2+) and Mg(2+) on the output of [(3)H]noradrenaline and [(3)H]metabolites in the venous effluent were measured before and after electrical stimulation of the post-ganglionic inferior mesenteric nerves at 10 impulses/sec.4. Nerve stimulation increased the efflux of [(3)H]noradrenaline when the perfusion fluid contained Ca(2+). Variations in Ca(2+) concentration (1.5-10 mM) did not affect this response.5. Removal of Ca(2+) from the fluid passing through the vascular bed (and therefore from the region of the sympathetic nerve terminals), abolished the output of [(3)H]noradrenaline in response to nerve stimulation. There was no change when phenoxybenzamine was added to prevent the binding of transmitter on to post-synaptic receptors on the effector organ.6. The output of transmitter was not changed when Ca(2+) was present in the blood vessels of the colon even though it was removed from the solution in contact with the remainder of the tissue.7. Nerve stimulation released [(3)H]noradrenaline when Ba(2+) was used as a substitute for Ca(2+); Mg(2+) was not an effective substitute for Ca(2+) as then nerve stimulation did not increase the output of radioactive noradrenaline or metabolites.8. Ba(2+) also increased the resting output of [(3)H]noradrenaline in the absence of nerve stimulation. Addition of Ca(2+) or Mg(2+) did not change this spontaneous release but it was augmented by removal of Ca(2+).9. It is concluded that Ca(2+) is essential for release of the sympathetic transmitter by nerve stimulation but not for the spontaneous output that occurs in the absence of nervous activity. The site of action of Ca(2+) is considered to be the terminals of adrenergic fibres.     

Release of an insulin-like peptide from perfused extirpated cat legs in response to electrical stimulation of the sciatic and brachial nerves and to administration of ACh,bombesin, oxytocin and glibenclamide

The vascular system of extirpated cat legs was perfused with Tyrode's solution and insulin-like immunoreactivity (ILI) levels were determined in the perfusate with radioimmunoassay. During unstimulated conditions perfusate levels of ILI were almost undetectable. However, in response to electrical stimulation of the sciatic or brachial nerves (within a wide range of stimuli 5–40 V, 2–20 Hz and 0.2–40 ms) 1–20 ng of ILI was recorded in the perfusate. Blockers of cholinergic and adrenergic transmissions added to the perfusate did not influence the output of the ILI induced by nerve stimulation. Furthermore, after administration of acetylcholine (ACh) (0.1 and 10 μg kg^-1)t oxytocin (0.5 and 5 IU kg^-1)i glibenclamide (25 and 100 μg kg^-1) and bombesin (100 and 500 μg kg^-1) to the cat leg preparation, ILI appeared in the perfusate in amounts similar to those induced by electrical stimulation of the nerves. When subjected to high-performance liquid chromatography (HPLC) the insulin-like peptide detected in the cat leg perfusate following nervous stimulation, or administration of oxytocin and glibenclamide, co-eluted with a bovine insulin standard. We have previously shown that some peripheral nerves of the cat, such as the sciatic, brachial and vagal nerves, contain an insulin-like peptide with HPLC characteristics similar to the bovine insulin standard. It is therefore possible that the insulin-like peptide released from the isolated cat leg preparation by the above-mentioned stimuli derives from this nervous pool of insulin. Alternatively, the insulin-like peptide emanates from the striatal muscles innervated by the sciatic and brachial nerves, since also muscles have been shown to contain an insulinlike peptide.     

Facilitatory effect of adrenocorticotropic hormone and related peptides on ca2+-dependent noradrenaline release from sympathetic nerves

Strips of rabbit pulmonary artery and aorta were incubated with [ ³H]noradrenaline and subsequently superfused. Tritium overflow from strips superfused with physiological salt solution was stimulated either electrically (usually at a frequency of 2 Hz) or by tyramine 1 μmol/l and overflow from strips superfused with Ca²⁺-free solution containing K⁺ 54.7mmol/l was stimulated by introduction of Ca²⁺ 1.6mmol/l. In most of the experiments (stimulation by electrical impulses or CaCl²) neuronal and extraneuronal uptake and β-adrenoceptors were blocked by cocaine, corticosterone and propranolol, respectively. The electrically evoked overflow of ³H-labelled substances from pulmonary artery and aorta was increased by adrenocorticotropic hormone_1–24. In the pulmonary artery, the adrenocorticotropic hormone_1–24—induced increase in impulse—evoked overflow (and contraction) was the more pronounced, the lower the frequency of stimulation (6, 2 and 0.66 Hz: 360 impulses). The electrically evoked overflow of ³H-labelled substances was also increased by α-melanocyte-stimulating hormone and porcine adrenocorticotropic hormone, but was not affected by adrenocorticotropic hormone_4–10. Adrenocorticotropic hormone_1–24 also facilitated the Ca²⁺-evoked overflow of ³H-labelled substances promoted by high K⁺, but it did not affect the Ca²⁺-independent tyramine-evoked overflow. Adrenocorticotropic hormone_1–24 did not alter the percentages of [ ³H]noradrenaline and ³H-labelled metabolites contained in electrically or tyramine-evoked overflow of ³H-labelled substances.In conclusion, adrenocorticotropic hormone and fragments of adrenocorticotropic hormone cause an increase in stimulation-evoked, Ca²⁺-dependent noradrenaline release from postganglionic sympathetic nerve fibres, probably by activating presynaptic receptors for adrenocorticotropic hormone.     

Effect of methylapogalanthamine on tone of the cerebral,extracranial, and peripheral vessels

Acute resistographic experiments on anesthetized and unanesthetized cats showed that methylapogalanthamine lowers the general arterial pressure and the tone of the cerebral, extracranial, and femoral vessels. The effect on the femoral vessels is the strongest. A biphasic (dilator-constrictor) response was frequently observed. Methylapogalanthamine weakened the constrictor response of the intra- and extracranial vessels to stimulation of the cervical sympathetic nerve. Anesthesia potentiated, whereas rausedil weakened the vasodilator effect of methylapogalanthamine.Department of Pharmacology, Pyatigorsk Pharmaceutical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éxperimental'noi Biologii i Meditsiny, Vol. 86, No. 10, pp. 438–441, October, 1978.     

Patterns of reinnervation of denervated cerebral arteries by sympathetic nerve fibers after unilateral ganglionectomy in rats

Summary In order to clarify the manner in which previously denervated cerebral arteries become reinnervated after unilateral excision of the superior cervical ganglion (SCG), we observed directly the reinnervating sympathetic nerve fibers originating in the contralateral SCG by using anterograde labeling with wheat germ aggulutinin-horseradish peroxidase in rats. The nerve fibers sprouted from the nerve fibers in the contralateral anterior cerebral artery and reinnervated the arterial wall of the anterior cerebral artery of the denervated side as early as one week after ganglionectomy. In addition to this sprouting route, three other reinnervating nerve fiber routes were observed in the circle of Willis of the denervated side two weeks after ganglionectomy: the proximal portion of the internal carotid artery, the route passing between bilateral ethmodial arteries, and the posterior communicating artery. Eight weeks after ganglionectomy, these reinnervating nerve fibers formed a fairly dense plexus in a circular pattern in the circle of Willis. However, the reinnervation could not be observed in the arterial branches derived from the circle of Willis (middle cerebral artery and posterior cerebral artery) even 16 weeks after ganglionectomy. The present results clearly demonstrated the time course, distribution pattern and limitation of the reinnervation from the contralateral SCG following unilateral ganglionectomy. The fact that reinnervation could be observed only in the main cerebral arteries of the circle of Willis, in which the nerve plexus appeared to have a circular pattern, suggests a difference between the qualities of sympathetic innervation controlling the cerebral circulation in these arteries and the other arterial branches related to these differences in reinnervation capacity.     

Effects of increasing arterial pressure on cerebral blood flow in the baboon: Influence of the sympathetic nervous system

The influence of stimulation of the cervical sympathetic chain on the response of cerebral blood flow to hypertension induced by the intravenous infusion of angiotensin was studied in anaesthetised baboons. Cerebral blood flow was measured by the intracarotid¹³³Xenon injection technique. Possible lesions of the blood-brain barrier were studied by injecting Evans blue towards the end of the experiment and ischaemic brain damage was assessed following perfusion fixation.In a control group of five baboons blood flow increased by 53±9% (mean ±S.E.) from the base line values in the arterial pressure range 130–159 mm Hg.In four baboons subjected to unilateral sympathetic stimulation flow increased by 16±4% in the same pressure range.In three babbons subjected to bilateral sympathetic stimulation there were not significant increases in flow until the arterial pressure had increased above 159 mm Hg.Disruption of the blood-brain barrier in the parietooccipital regions was only seen in the control animals but not in the stimulated baboons. Ischaemic brain damage was not observed with the exception of one small lesion in a single stimulated baboon.These findings provide strong support for the observations of Bill and Linder (1976) that activation of the cervical sympathetic can modify the level at which breakthrough of cerebral blood flow occurs in association with systemic hypertension.These investigations were supported by the Medical Research Council and Tenovus (Scotland)     

Influence of the sympathetic nervous system on renal function during hypothermia

Hypothermia increases preglomerular vasoconstriction leading to decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Since plasma catecholamine concentrations are increased during hypothermia, the present study was performed to determine the role of the renal sympathetic nervous system in the cold-induced renal vasoconstriction. In Inactin® anaesthetized rats, hypothermia at 28 °C decreased GFR by 50% but failed to alter efferent renal sympathetic nerve activity (ERSNA). Since hypothermia causes shivering which could have influenced the ERSNA recording, Inactin® anaesthetized rats were treated with pethidine or rats were anaesthetized with pentobarbital sodium or Saffan® to eliminate cold-induced shivering. In these non-shivering rats, hypothermia produced a reversible decrease in ERSNA in association with a fall in GFR that was of a similar magnitude as in shivering rats. Further studies in Inactin® anaesthetized rats showed that the fall in GFR was unaltered by renal denervation, bilateral adrenalectomy or intrarenal administration of the α₁-adrenoceptor antagonist prazosin. We conclude that cold-induced renal vasoconstriction is not due to an increase in ERSNA or adrenaline/noradrenaline-mediated activation of renal α₁-adrenoceptors.     

Development of the sympathetic innervation to the cerebral arterial system in neonatal rats as revealed by anterograde labeling with wheatgerm agglutinin-horseradish peroxidase

In order to clarify the developmental pattern in the sympathetic nerve fibers innervating the cerebral arterial system during the postnatal period in rats, we labeled the postganglionic nerve fibers originating in the superior cervical ganglion (SCG) and directly observed their extension and plexus formation by means of anterograde labeling with wheat germ agglutinin-horseradish peroxidase (WGA-HRP). The WGA-HRP solution was injected into the right SCG 1–7 days after birth. The rats were killed 48 h after trace injection, and the cerebral arteries were reacted with tetramethylbenzidine, then observed as a whole mount preparation. The labeled nerve fibers appeared as a few relatively straight bundles with branching fibers running longitudinally to the long axis of the artery in the ipsilateral right side of the circle of Willis and proximal portion of their main branching arteries at 3 days after birth. The nerve fibers started to form a circular pattern of nerve plexus only on the wall of the circle of Willis as early as 1 week after birth. At the beginning of postnatal week 2, labeled nerve fibers extended the collateral projections into the collateral side of the circle of Willis, and these expanding projections could not be observed at postnatal week 3. We observed a route of the sympathetic nerve fibers advancing into the cerebral arterial system which has not been described in previous studies; bundle of labeled nerve fibers entered into the wall of the middle portion of the basilar artery in half of the animals, in any postnatal period. We were able to confirm, by using an anterograde labeling technique with WGA-HRP, how the sympathetic nerve fibers advance into the cerebral arterial system, when they start to form nerve plexus during the postnatal period in rats, and clarified that the sympathetic nerve fibers showed overabundant collateral projection in the cerebral arterial system during the early postnatal period.