Increase In Sympathetic Nerve Discharge Research Articles

Firing properties of pre‐inspiratory neurons are altered in female rats exposed to chronic intermittent hypoxia

Female rats submitted to chronic intermittent hypoxia (CIH) presented a reduced time of inspiration, sympathetic overactivity and hypertension. The increase in sympathetic nerve discharge in CIH‐female rats is associated to an increase in the inspiratory modulation of sympathetic activity. In this context, we hypothesized that inspiratory neurons at the brainstem have change their activity in CIH‐female rats, which in turn, modulates the presympathetic neurons producing an increase in sympathetic activity during inspiration. To test this hypothesis, juvenile female Wistar rats (P20–21) underwent intermittent hypoxia for 10 days. One day after CIH, we performed the extracellular single unit recordings of respiratory neurons at the ventral surface of the medulla using the ventral approach of the working heart‐brainstem preparation. All the experimental protocols were approved by the institutional ethical committee (#091/2013). Pre‐inspiratory neurons (Pre‐I/I) of CIH‐female rats (n=16) have reduced their firing frequency (58.3 ± 9 vs 107.6 ± 12Hz, p=0.0027) compared to Pre‐I/I neurons of control (n=15). Synaptic blockade demonstrated that Pre‐I/I neurons (n=3) have auto‐depolarization property. Ramp‐I, Early‐I and Late‐I neurons presented no changes in their firing properties after CIH. Regarding the expiratory neurons, post‐inspiratory neurons (Post‐I) have increased the firing time relative to duration of expiration (92.2 ± 2 vs 81.3 ± 3 % of total duration of expiration, p=0.0127) in CIH‐female rats (n=15) compared to control (n=17). We conclude that CIH produces a reduction in the activity of pacemaker Pre‐I/I neurons that could explain the reduced time of inspiration and the increase in inspiratory modulation of sympathetic activity in CIH‐female rats. These findings contribute to a better understanding of the respiratory network activity associated with sympathetic overactivity and hypertension in female rats exposed to CIH.Support or Funding InformationFapesp, CAPES and CNPq

The depletion of monoamines blocks the sympathoinhibitory response to cocaine

Recent studies have shown that cocaine decreases, rather than increases sympathetic nerve discharge (SND). Whether these sympathoinhibitory responses are the result of cocaine's actions on monoaminergic transmission (i.e. blockade of neuronal uptake or stimulation of transmitter release) or its local anesthetic actions is not known. The purpose of the present study was to determine the degree to which cocaine's actions on monoaminergic transmission are involved in mediating the sympathoinhibitory response to this drug. We examined the mean arterial pressure, heart rate and splanchnic sympathetic nerve responses elicited by cocaine (I mg/kg, i.v.) in pentobarbital-anesthetized rats depleted of monoamines. Monoamines were depleted by administering reserpine (10 mg/kg, i.p.) either 24, or 48 and 24 h before the experiment. The rats were also given α-methyl- p-tyrosine (200 mg/kg, i.p.) 2 h before the experiment. Vehicle-treated rats served as controls. Depletion of monoamines markedly reduced resting arterial pressure and heart rate and significantly attenuated the pressor response and tachycardia elicited by tyramine (1 mg/kg, i.v.). In control rats, cocaine elicited marked (−64 ± 4%) and prolonged (44 ± 4 min) decreases in SND. The magnitude (−34 ± 11%) and duration (23 ± 6 min) of these responses were significantly attenuated after 1 day of monoamine depletion. After 2 days of depletion, the sympathoinhibitory response was abolished and was replaced by a small, brief increase in SND (l0 3%). The pressor responses were similar in control and depleted rats, while the bradycardic response (−33 ± 4 bpm) was significantly reduced after 1 and 2 days of monoamine depletion to −20 ± 3 and −15 ± 2 bpm, respectively. We conclude that a functionally intact monoaminergic system is essential for the sympathoinhibitory response to cocaine. Whether the pressor responses result from a non-monoaminergic or a reserpine and/or α-methyl- p-tyrosine resistant catecholaminergic mechanism is unknown.

Tonic sympathetic chemoreflex after blockade of respiratory rhythmogenesis in the rat.

1. We sought to determine whether the increase in sympathetic nerve discharge (SND) caused by carotid chemoreceptor stimulation requires the integrity of ventrolateral medullary structures involved in generating respiratory rhythm and pattern. Experiments were done in urethane-anaesthetized, vagotomized, aortic deafferented, ventilated rats except when indicated (see paragraph 3). 2. Brief hypoxia (N2 for 5-12 s) or I.V. NaCN (50-100 micrograms kg-1) activated SND in bursts synchronized with the phrenic nerve discharge (PND). No effect was produced in chemo-deafferented rats. 3. In unanaesthetized vagotomized decerebrated rats, ligation of the internal carotid arteries preserved peripheral chemoreceptor function but abolished baroreflexes. In this preparation, stimulation of peripheral chemoreceptors (N2 for 2-6 s) also activated SND in bursts synchronized with PND. 4. Bilateral microinjection of the GABAA receptor agonist muscimol into the caudal ventrolateral medulla (CVLM) instantly blocked the sympathetic baroreflex, eliminated PND at rest and during chemoreceptor stimulation but did not change the mean increase in SND produced by chemoreceptor stimulation. Sympathoactivation in response to chemoreceptor stimulation became tonic after 1-13 min and was still totally dependent on the integrity of the carotid sinus nerves. 5. Muscimol injection instantly eliminated the respiratory outflow of the Xth and XIIth cranial nerves, both at rest and during chemoreceptor stimulation. 6. Muscimol eliminated the on-off respiratory pattern of neurons in the rostral ventrolateral medulla (RVLM). During chemoreceptor stimulation, these cells became activated or inhibited tonically. 7. Muscimol injection raised the resting discharge rate of vasomotor presympathetic cells in RVLM, blocked their baroreceptor inputs but did not change the magnitude of their excitation by chemoreceptor stimulation. Muscimol injection eliminated their respiratory modulation. 8. In conclusion, the sympathetic response to chemoreceptor stimulation may be due to convergence and integration in RVLM of two processes: respiration-independent excitatory input to RVLM neurons and respiratory patterning of their activities via inputs from the pre-Bötzinger complex.

Sympathetic nerve responses elicited by cocaine in anesthetized and conscious rats

Recent evidence suggests that cocaine decreases rather than increases sympathetic nerve discharge (SND). The purpose of the present study was to provide the first complete characterization of the dose-response relationships of cocaine (0.005–3 mg/kg, IV) for arterial pressure, heart rate, and lumbar, splanchnic, or renal SND in pentobarbital-anesthetized rats. Cocaine was also tested in conscious rats. In pentobarbital-anesthetized rats cocaine elicited prolonged (lasting up to 56 min), dose-dependent decreases in SND on all three nerves. The splanchnic nerve was significantly more sensitive to the inhibitory actions of cocaine than was the lumbar nerve. Cocaine increased arterial pressure and elicited bradycardia at doses above 0.5 mg/kg. Comparison of the dose-response curves of cocaine for splanchnic SNDin sham-operated and sinoaortically deafferentated (SAD) rats showed that the baroreceptor reflex made only a minor contribution to the magnitude of sympathoinhibitory response. However, the duration of the sympathoinhibitory response was significantly shorter in SAD than in sham animals. In conscious rats, cocaine (0.1 and 1.0 mg/kg ) elicited a pattern of neural and cardiovascular responses similar to that seen in anesthetized rats, except that the prolonged sympathoinhibitory responses were preceded by a brief (lasting < 10 s) increase in SND. From these data we conclude that cocaine produces prolonged decreases in SND in conscious and anesthetized rats. These sympathoinhibitory responses do not appear to result from baroreceptor reflex activation and may involve a central mechanism of action.

5-HT 2 receptor agonists increase spontaneous sympathetic nerve discharge

The selective 5-HT 2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced a marked increase in spontaneous sympathetic nerve discharge recorded from the inferior cardiac nerve in chloralose anesthetized cats. DOI (0.01–1.0 mg/kg i.v.) increased sympathetic nerve discharge to a maximum of 1750% of control values. The increase in sympathetic nerve discharge produced by DOI was reversed by the 5-HT 2 antagonists ketanserin and LY 53857. In addition, pretreatment with ketanserin, but not prazosin, completely prevented the increase in sympathetic nerve discharge produced by DOI. These data are discussed in relationship to the role of serotonin in the regulation of activity in central sympathetic pathways.

Sequence of activation of ventrolateral and dorsal medullary sympathetic neurons.

A unique approach to the problem of evaluating potential regions of origin of the cardiac-related component in basal sympathetic nerve discharge (SND) is described in the present investigation. Specifically a comparison was made of the firing times of cat ventrolateral and dorsal medullary neurons with sympathetic nerve-related activity. These two medullary regions are known to play a role in the maintenance of blood pressure. Spike-triggered averaging and post-R wave interval analysis were used to identify single medullary neurons with spontaneous discharges temporally related to those in the renal or inferior cardiac sympathetic nerve. The results obtained using a ventricular pacing test previously developed in our laboratory allowed us to classify some of these neurons as elements of networks that control SND (i.e., medullary sympathetic neurons). The test is based on the assumption that brain stem sympathetic neurons should exhibit discharges that remain locked in time to the peak of the cardiac-related component of SND during changes in heart rate that shift the phase relations between baroreceptor and sympathetic nerve activity. Electrical stimulation of sites from which the discharges of such units were recorded elicited increases in SND, thus suggesting that these neurons subserved a sympathoexcitatory function. On the average, ventrolateral medullary neurons fired 48 ms later than dorsal medullary neurons during the cardiac-related component in SND. This observation does not support the previous suggestion [R. A. L. Dampney and E. A. Moon. Am. J. Physiol. 239 (Heart Circ. Physiol. 8): H349-H358, 1980] that basal sympathetic tone originates exclusively in circuits of ventrolateral medullary neurons. Possibilities concerning the interconnections of dorsal and ventrolateral medullary neurons involved in maintaining blood pressure are discussed.