Autonomic modification of the atrioventricular node during atrial fibrillation: role in the slowing of ventricular rate. (1/66)

BACKGROUND: Postganglionic vagal stimulation (PGVS) by short bursts of subthreshold current evokes release of acetylcholine from myocardial nerve terminals. PGVS applied to the atrioventricular node (AVN) slows nodal conduction. However, little is known about the ability of PGVS to control ventricular rate (VR) during atrial fibrillation (AF). METHODS AND RESULTS: To quantify the effects and establish the mechanism of PGVS on the AVN, AF was simulated by random high right atrial pacing in 11 atrial-AVN rabbit heart preparations. Microelectrode recordings of cellular action potentials (APs) were obtained from different AVN regions. Five intensities and 5 modes of PGVS delivery were evaluated. PGVS resulted in cellular hyperpolarization, along with depressed and highly heterogeneous intranodal conduction. Compact nodal AP exhibited decremental amplitude and dV/dt and multiple-hump components, and at high PGVS intensities, a high degree of concealed conduction resulted in a dramatic slowing of the VR. Progressive increase of PGVS intensity and/or rate of delivery showed a significant logarithmic correlation with a decrease in VR (P<0.001). Strong PGVS reduced the mean VR from 234 to 92 bpm (P<0.001). The PGVS effects on the cellular responses and VR during AF were fully reproduced in a model of direct acetylcholine injection into the compact AVN via micropipette. CONCLUSIONS: These studies confirmed that PGVS applied during AF could produce substantial VR slowing because of acetylcholine-induced depression of conduction in the AVN.  (+info)

Characterization of non-adrenergic, non-cholinergic inhibitory responses of the isolated guinea-pig trachea: differences between pre- and post-ganglionic nerve stimulation. (2/66)

1 Differences in the mechanism of non-adrenergic, non-cholinergic (NANC) inhibitory responses to preganglionic- and post-ganglionic nerve stimulation were investigated in the guinea-pig isolated trachea. 2 Stimulation of the vagus nerve at frequencies above 4 Hz elicited NANC relaxation of the trachealis muscle. Responses to low frequencies of stimulation (4-8 Hz) were abolished by the nitric oxide (NO) synthase inhibitor L-NOARG (10 microM), while a L-NOARG resistant component was observed at higher stimulus frequencies. The L-NOARG-resistant component of NANC inhibitory responses to higher frequencies of vagus nerve stimulation were significantly attenuated by the proteinase alpha-chymotrypsin (2 U/ml), suggesting that a neuropeptide such as VIP may contribute to NANC responses. 3 When postganglionic nerves were stimulated by electrical field stimulation (EFS), responses were readily elicited at frequencies below 4 Hz. Like responses to vagus nerve stimulation, responses to low frequency (<4 Hz) EFS were abolished by L-NOARG while a L-NOARG-resistant component was apparent at higher stimulus frequencies. 4 The L-NOARG-resistant component of NANC inhibitory responses to EFS was sensitive to alpha-chymotrypsin only if stimuli were delivered in either long trains at a low frequency (4 Hz for 10-30 s) or short trains of high frequency (16 Hz for 2.5-7.5 s). 5 Responses to preganglionic nerve stimulation were approximately 35% of the amplitude of responses to EFS in the same preparations. 6 In conclusion, responses to preganglionic and postganglionic NANC inhibitory nerve stimulation in the guinea-pig trachea differ in maximum amplitude, frequency-response characteristics and the contributions of cotransmitters. We suggest that these differences may be explained by filtering of preganglionic input to postganglionic NANC neurons. These results have implications in all studies where EFS is considered to be representative of physiological stimulation of post-ganglionic nerve stimulation.  (+info)

Inhibitory effects of clonidine and BS 100-141 on responses to sympathetic nerve stimulation in cats and rabbits. (3/66)

1. In pithed cats, the spinal sympathetic outflow was stimulated preganglionically at segments C7 and T1 and heart rate responses and nictitating membrane tone were measured in parallel. 2. Clonidine and a related drug, BS 100-141 (N-amidino-2(2,6-dichlorophenyl)acetamide hydrochloride), caused a dose-dependent inhibition of the stimulation-induced tachycardia but did not inhibit responses of the nictitating membrane. The inhibition of heart rate was antagonized by the alpha-adrenoceptor blocking drug, phentolamine. 3. In isolated hearts of rabbits, noradrenaline release in response to adrenergic nerve stimulation was reduced by clonidine and BS 100-141 and the effect was antagonized by phentolamine. 4. The results support the view that presynaptic alpha-adrenoceptors are involved in the regulation of transmitter release from adrenergic nerves. Cardiac adrenergic nerves appear more sensitive to alpha-adrenoceptor-mediated inhibition of inpulse transmission than the sympathetic nerves to the nictitating membrane.  (+info)

Innervation both of peri-orbital structures and of the heart by the cervical sympathetic nerves in mouse, rat, guinea-pig, rabbit and cat. (4/66)

1 In anaesthetized rats electrical stimulation of the intact cervical sympathetic nerve produced frequency-dependent lower eyelid contractions and tachycardia. 2 The tachycardia was caused by excitation of efferent fibres since it was equally evident in the pithed rat preparation, and the right nerve was more effective than the left. By contrast, no differences were seen between the responses to right and left vagal stimulation in either rats or rabbits. 3 Guanethidine inhibited both cardiac and eyelid responses, propranolol only the former and phentolamine only the latter, therby revealing the adrenergic nature of the nerves. Hexamethonium caused partial inhibition and the block was intensified by atropine. 4 The inferior eyelid of mice, guinea-pigs and rabbits as well as the nictitating membrane of rabbits and cats were contracted by cervical sympathetic nerve stimulation. In these species too, tachycardia occurred; this was more pronounced with the right than the left sympathetic nerve. The order of cardiac responsiveness was mouse greater than rat greater than guinea-pig greater than rabbit greater than cat. 5 In guinea-pigs histamine-induced bronchoconstriction was reduced by cervical sympathetic nerve stimulation. 6 That discrete cardiac pathways exist in the cervical sympathetic nerves is suggested by the reproducibility of the effects within any one species. The accessibility of the nerves greatly simplifies the examination of drugs in vivo on two different structures innervated by the sympathetic nervous system.  (+info)

Functional and structural changes in mammalian sympathetic neurones following interruption of their axons. (5/66)

The effects of interrupting the axons of principal neurones in the superior cervical ganglion of adult guinea-pigs were studied by means of intracellular recording, and light and electron microscopy. 1. Within 72 hr of axon interruption, the amplitude of exitatory postsynaptic potentials potentials (e.p.s.p.s) recorded in principal neurons in response to maximal preganglionic stimulation declined. E.p.s.p.s were maximally reduced (by more than 70% on average) 4-7 days following interruption, and failed to bring many cells to threshold. E.p.s.p.s. recorded in nearby neurones whose axons remained intact were unaffected. 2. In ganglia in which axon interruption was achieved by means of nerve crush (thus allowing prompt regeneration), mean e.p.s.p. amplitudes began to increase again after about 1-2 weeks. One month after the initial injury many neurones had e.p.s.p.s of normal amplitude, and by 2 months affected neurones were indistinguishable from control cells. Functional peripheral connexions were re-established during the period of synaptic recovery. 3. The mean number of synapses identified electron microscopically in ganglia in which all the major efferent branches had been crushed decreased by 65-70% in parallel with synaptic depression measured by intracellular recording. However synapse counts did not return to normal levels even after 3 months. 4. During the period of maximum synaptic depression, numerous abnormal profiles which contained accumulations of vesicular and tubular organelles, vesicles, and mitochondria were observed in electron microscopic sections. Injection of horseradish peroxidase into affected neurones demonstrated dendritic swelling which probably correspond to these profiles. 5. Little or no difference was found in the electrical properties of normal neurones and neurones whose axons had been interrupted 4-7 days previously. However, the mean amplitude of spontaneously occurring synaptic potentials was reduced, and the amplitude distribution was shifted. This abnormality of the synapses which remain on affected neurones also contributes to synaptic depression. 6. Counts of neurones in normal and experimental ganglia showed that approximately half the principal cells died 1-5 weeks after crushing the major efferent brances. This finding presumably explains the failure of synapse counts to return to control levels after recovery. 7. If axons were prevented from growing back to their target organ by chronic ligation, surviving neurones whose axons were enclosed by the ligature did not generally recover normal synaptic function. Following ligation, most affected cells died within a month. 8. Thus the integrity of a principal cell's axon is necessary for the maintenance of preganglionic synaptic contacts, and ultimately for neuronal survival. The basis of neuronal recovery from the effects of axon interruption appears to be some aspect of regeneration to the peripheral target.  (+info)

A study of peripheral input to and its control by post-ganglionic neurones of the inferior mesenteric ganglion. (6/66)

1. Intracellular recordings were made, in vitro, from neurones of guinea-pig inferior mesenteric ganglia (IMG) attached, via the lumbar colonic nerves, to segments of distal colon. 2. 'Spontaneous' synaptic input from colonic afferent fibres was observed in 79% of the neurones tested. In any given preparation, the level and pattern of this synaptic input to different neurones varied considerably. 3. Superfusion of colonic segments with drugs (papaverine, isoprenaline, and adenosine triphosphate) which reduce colonic motility decreased colonic afferent input to IMG neurones. 4. Superfusion of colonic segments with acetylcholine or stimulation of pelvic nerves, both of which increase colonic motility, increased colonic afferent input to IMG neurones. 5. Superfusion of colonic segments with either atropine or tubocurarine reduced the level of 'spontaneous', colonic afferent input. However, distension of these relaxed segments increased the colonic afferent input. 6. Repetitive stimulation of preganglionic inputs to the IMG inhibited afferent input from drug relaxed segments of colon that were moderately distended by the injection of air into the lumen. Superfusion of the colon with phentolamine blocked this inhibition. 7. The results of this study suggest that IMG neurones receive afferent input from mechanoreceptors located in the distal colon and that the mechanosensitivity of this afferent pathway is in part controlled by efferent noradrenergic neurones of the IMG. The IMG-colon neural circuitry can therefore be considered to form a feed-back control system which participates in the regulation of colonic motility.  (+info)

The relation between stimulus frequency and the relative size of the components of the biphasic response of the vas deferens to electrical stimulation at different temperatures. (7/66)

1. Electrical stimulation of the guinea-pig or rat vas deferens (pre- or post-ganglionically) at frequencies from 2-5 to 40 Hz with trains of stimuli of 30 sec duration induced a biphasic response. A rapid contraction (component A) was followed after a brief relaxation by a slower contraction (component B); the two phases were seen most clearly with stimulation frequencies of less than 10 Hz. 2. The responses to post-ganglionic stimulation were always larger than those to preganglionic stimulation. In general, at low frequencies component A exceeded component B whilst at high frequencies component B was the larger. Separation of the two components on the basis of their frequency response characteristics was better for rat than for guinea-pig vasa. 3. Log. frequency-response curves to transmural (post-ganglionic) electrical stimulation and log dose-response curves to noradrenaline were recorded for guinea-pig and rat vasa deferentia at 32 degrees, 22 degrees and 12 degrees C. For the guinea-pig reduction of bath temperature to 12 degrees C increased the amplitude of component A at 2-5 and 5 Hz; component B could not confidently be distinguished at this temperature. At 22 degrees C there was potentiation of B at lower frequencies and depression of B at higher frequencies. There was no response to noradrenaline at 12 degrees C. At 22 degrees C the response to noradrenaline was increased except to doses at or near the maximum to which the response was reduced. 4. For the rat was deferens component A was little changed by reduction of temperature. Component B at 12 degrees C was greatly depressed at higher frequencies. The response to noradreanaline was increased to lower doses and decreased to higher doses as the temperature was lowered. 5. The B component of the response of guinea-pig vasa at 22 degrees C and rat vasa at 32 degrees C was more sensitive than the A component to inhibition by thymoxamine. 6. Further analysis of the mechanisms underlying the A and B components of the biphasic response may be facilitated by relative isolation of each component by the appropriate selection of parameters of electrical stimulation and of temperature for the species being investigated. The contractions of the B component are similar to, if not identical with, those produced by exogenously applied noradrenaline.  (+info)

Synthesis of nitric oxide in postganglionic myenteric neurons during endotoxemia: implications for gastric motor function in rats. (8/66)

We have investigated the mechanisms underlying acute changes in gastric motor function triggered by endotoxemia. In fundal strips from rats pre-treated with endotoxin (40 microg/kg, i.p. 30 min), mechanical activity was analyzed and the source of nitric oxide (NO) was visualized by confocal microscopy of tissue loaded with the fluorescent dye DAF-FM. NOS expression was determined by quantitative RT-PCR and Western blot, and enzyme activity by the citrulline assay. Strips from endotoxin-treated rats were hypo-contractile. This was prevented by pre-incubation with the neurotoxin tetrodotoxin, the gangliar blocker hexamethonium, or non-selective and neuronal-specific NOS inhibitors (L-NOARG and TRIM, respectively). The soluble guanylyl cyclase (sGC) inhibitor ODQ and the inhibitor of small conductance Ca2+-activated K+ channels apamin prevented relaxation induced by endotoxin, nicotine, exogenous NO (DETA-NONOate), and the NO-independent sGC activator BAY 41-2272. NO synthesis was observed in neuronal soma, axons, and nerve endings of the myenteric plexus in the fundus of endotoxin-treated rats and was prevented by L-NAME, tetrodotoxin, and hexamethonium. nNOS and iNOS mRNA and protein contents were unchanged. Our findings demonstrate synthesis of NO in post-ganglionic myenteric neurons during early endotoxemia that mediates gastric hypo-contractility. The effect of NO is mediated via sGC and small conductance Ca2+-activated K+channels.  (+info)

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