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1.
J Hypertens ; 42(1): 70-78, 2024 01 01.
Article in English | MEDLINE | ID: mdl-37889604

ABSTRACT

BACKGROUND: Myocardial ischemia causes the release of bradykinin, which stimulates cardiac afferents, causing sympathetic excitation and chest pain. Glutamatergic activation of the paraventricular hypothalamic nucleus (PVN) in the spontaneously hypertensive rat (SHR) drives elevated basal sympathetic activity. Thus, we tested the hypothesis that inactivation of the PVN attenuates the elevated reflex response to epicardial bradykinin in the SHR and that ionotropic PVN glutamate receptors mediate the elevated reflex. METHODS: We recorded the arterial pressure and renal sympathetic nerve activity (RSNA) response to epicardial bradykinin application in anesthetized SHR and Wistar Kyoto (WKY) rats before and after PVN microinjection of GABA A agonist muscimol or ionotropic glutamate receptor antagonist kynurenic acid. RESULTS: Muscimol significantly decreased the arterial pressure response to bradykinin from 180.4 ±â€Š5.8 to 119.5 ±â€Š6.9 mmHg in the SHR and from 111.8 ±â€Š7.0 to 84.2 ±â€Š8.3 mmHg in the WKY and the RSNA response from 186.2 ±â€Š7.1 to 142.7 ±â€Š7.3% of baseline in the SHR and from 201.0 ±â€Š11.5 to 160.2 ±â€Š9.3% of baseline in the WKY. Kynurenic acid significantly decreased the arterial pressure response in the SHR from 164.5 ±â€Š5.0 to 126.2 ±â€Š7.7 mmHg and the RSNA response from 189.9 ±â€Š13.7to 168.5 ±â€Š12.7% of baseline but had no effect in the WKY. CONCLUSION: These results suggest that tonic PVN activity is critical for the full manifestation of the CSAR in both the WKY and SHR. Glutamatergic PVN activity contributes to the augmented CSAR observed in the SHR.


Subject(s)
Bradykinin , Paraventricular Hypothalamic Nucleus , Rats , Animals , Rats, Inbred SHR , Bradykinin/pharmacology , Rats, Inbred WKY , Kynurenic Acid/pharmacology , Muscimol/pharmacology , Reflex/physiology , Sympathetic Nervous System , Blood Pressure
2.
Front Physiol ; 11: 865, 2020.
Article in English | MEDLINE | ID: mdl-32792982

ABSTRACT

Modest recovery of somatic function after incomplete spinal cord injury (SCI) has been widely demonstrated. Recently we have shown that spontaneous recovery of baroreflex regulation of sympathetic activity also occurs in rats. Dietary restriction in the form of every other day fasting (EODF) has been shown to have beneficial effects on the recovery of motor function after SCI in rats. The goal of this study was to determine if EODF augments the improvement of baroreflex regulation of sympathetic activity after chronic left thoracic (T8) surgical spinal hemisection. To determine this, we performed baroreflex tests on ad-lib fed or EODF rats 1 week or 7 weeks after left T8 spinal hemisection. One week after T8 left hemisection baroreflex testing revealed that gain of baroreflex responsiveness, as well as the ability to increase renal sympathetic nerve activity (RSNA) at low arterial pressure, was significantly impaired in the ad-lib fed but not the EODF rats compared with sham lesioned control rats. However, baroreflex tests performed 7 weeks after T8 left hemisection revealed the inability of both ad-lib and EODF rats to decrease RSNA at elevated arterial pressures. While there is evidence to suggest that EODF has beneficial effects on the recovery of motor function in rats, EODF did not significantly improve the recovery of baroreflex regulation of sympathetic activity.

3.
J Pharmacol Toxicol Methods ; 88(Pt 1): 64-71, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28658603

ABSTRACT

The purpose of this study was to evaluate functional measures of diminished sympathetic activity after postganglionic neuronal loss in the conscious rat. To produce variable degrees of sympathetic postganglionic neuronal loss, adult rats were treated daily with toxic doses of guanethidine (100mg/kg) for either 5days or 11days, followed by a recovery period of at least 18days. Heart rate, blood pressure, cardiac baroreflex responsiveness, urinalysis (for catecholamine metabolite, 3-methoxy-4-hydroxyphenylethylenglycol; MHPG), and pupillometry were performed during the recovery period. At the end of the recovery period stereology of superior cervical ganglia (SCG) was performed to determine the degree of neuronal loss. Total number of SCG neurons was correlated to physiological outcomes using regression analysis. Whereas guanethidine treatment for 11days caused significant reduction in the number of neurons (15,646±1460 vs. 31,958±1588), guanethidine treatment for 5days caused variable levels of neuronal depletion (26,009±3518). Regression analysis showed that only changes in urinary MHPG levels and systolic blood pressure significantly correlated with reduction of SCG neurons (r2=0.45 and 0.19, both p<0.05). Although cardiac baroreflex-induced reflex tachycardia (345.7±19.6 vs. 449.7±20.3) and pupil/iris ratio (0.50±0.03% vs. 0.61±0.02%) were significantly attenuated in the 11-day guanethidine treated rats there was no significant relationship between these measurements and the number of remaining SCG neurons after treatment (p>0.05). These data suggest that basal systolic blood pressure and urinary MHPG levels predict drug-induced depletion of sympathetic activity in vivo.


Subject(s)
Guanethidine/toxicity , Neurons/drug effects , Superior Cervical Ganglion/drug effects , Sympatholytics/toxicity , Toxicity Tests, Acute/methods , Animals , Baroreflex/drug effects , Blood Pressure/drug effects , Catecholamines/metabolism , Consciousness , Heart Rate/drug effects , Male , Methoxyhydroxyphenylglycol/urine , Rats , Rats, Sprague-Dawley
4.
Article in English | MEDLINE | ID: mdl-27085835

ABSTRACT

The goal of this study was to determine the degree of sympathetic postganglionic neuronal loss required to impair cardiovascular-related sympathetic activity. To produce neuronal loss separate groups of rats were treated daily with guanethidine for either 5days or 11days, followed by a recovery period. Sympathetic activity was measured by renal sympathetic nerve activity (RSNA). Stereology of thoracic (T13) ganglia was performed to determine neuronal loss. Despite loss of more than two thirds of neurons in T13 ganglia in both treated groups no effect on resting blood pressure (BP) or heart rate (HR) was detected. Basal RSNA in rats treated for 5days (0.61±0.10µV∗s) and 11days (0.37±0.08µV∗s) was significantly less than vehicle-treated rats (0.99±0.13µV∗s, p<0.05). Increases in RSNA by baroreceptor unloading were significantly lower in 5-day (1.09±0.19µV∗s) and 11-day treated rats (0.59±0.11µV∗s) compared with vehicle-treated rats (1.82±0.19µV∗s, p<0.05). Increases in RSNA to chemoreceptor stimulation were significantly lower in 5-day treated rats (1.54±0.25µV∗s) compared with vehicle-treated rats (2.69±0.23µV∗s, p<0.05). Increases in RSNA in 11-day treated rats were significantly lower (0.75±0.15µV∗s, p<0.05) compared with both vehicle-treated and 5-day treated rats. A positive correlation of neurons to sympathetic responsiveness but not basal activity was detected. These data suggest that diminished capacity for reflex sympathetic responsiveness rather than basal activity alone must be assessed for complete detection of neurophysiological cardiovascular impairment.


Subject(s)
Anesthesia/adverse effects , Cardiovascular System/drug effects , Sympathetic Fibers, Postganglionic , Sympathetic Nervous System/drug effects , Animals , Blood Pressure/drug effects , Body Weight/drug effects , Cardiovascular System/innervation , Guanethidine/toxicity , Heart Rate/drug effects , Kidney/drug effects , Kidney/innervation , Male , Pressoreceptors/drug effects , Rats , Rats, Sprague-Dawley , Sympatholytics/toxicity , Thoracic Nerves
5.
J Neurotrauma ; 30(3): 181-90, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-22934782

ABSTRACT

Axon regeneration in the central nervous system is severely hampered, limiting functional recovery. This is in part because of endogenous axon regeneration inhibitors that accumulate at the injury site. Therapeutic targeting of these inhibitors and their receptors may facilitate axon outgrowth and enhance recovery. A rat model of spinal cord contusion injury was used to test the effects of two bacterial enzyme therapies that target independent axon regeneration inhibitors, sialidase (Vibrio cholerae) and chondroitinase ABC (ChABC, Proteus vulgaris). The two enzymes, individually and in combination, were infused for 2 weeks via implanted osmotic pumps to the site of a moderate thoracic spinal cord contusion injury. Sialidase was completely stable, whereas ChABC retained>30% of its activity in vivo over the 2 week infusion period. Immunohistochemistry revealed that infused sialidase acted robustly throughout the spinal cord gray and white matter, whereas ChABC activity was more intense superficially. Sialidase treatment alone resulted in improved behavioral and anatomical outcomes. Rats treated exclusively with sialidase showed significantly increased hindlimb motor function, evidenced by higher Basso Beattie and Bresnahan (BBB) and BBB subscores, and fewer stepping errors on a horizontal ladder. Sialidase-treated rats also had increased serotonergic axons caudal to the injury. ChABC treatment, in contrast, did not enhance functional recovery or alter axon numbers after moderate spinal cord contusion injury, and dampened the response of sialidase in the dual enzyme treatment group. We conclude that sialidase infusion enhanced recovery from spinal cord contusion injury, and that combining sialidase with ChABC failed to improve outcomes.


Subject(s)
Chondroitin ABC Lyase/administration & dosage , Nerve Regeneration/drug effects , Neuraminidase/administration & dosage , Neuroprotective Agents/administration & dosage , Recovery of Function/drug effects , Spinal Cord Injuries/drug therapy , Animals , Disease Models, Animal , Enzyme Stability , Female , Immunohistochemistry , Rats , Rats, Sprague-Dawley
6.
Am J Physiol Regul Integr Comp Physiol ; 303(6): R590-8, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22814663

ABSTRACT

Neurons in the rostroventrolateral medulla (RVLM) mediate baroreflex regulation (BR) of spinal sympathetic preganglionic neurons. Previously, our laboratory has shown that recovery of BR occurs in the rat after spinal hemisection. (Zahner MR, Kulikowicz E, and Schramm LP. Am J Physiol Regul Integr Comp Physiol 301: R1584-R1590, 2011). The goal of these experiments was to determine whether the observed recovery of BR is mediated by the reorganization of ipsilateral pathways or by compensation by spared contralateral pathways. To determine this, we infected the left kidney in rats with the retrograde transynaptic tracer, pseudorabies virus (PRV), either 1 or 8 wk after left spinal hemisection at either T(3) or T(8), or after a sham lesion. In sham-lesioned rats, PRV infection of RVLM neurons was bilateral. In all rats with a left hemisection, regardless of the location of the lesion (T(3) or T(8)) or postlesion recovery time (1 or 8 wk), PRV infection of left RVLM neurons was significantly reduced compared with sham-lesioned rats (P < 0.05). In a separate group of rats, we performed BR tests by measuring responses of left renal sympathetic nerve activity to pharmacologically induced decreases and increases in arterial pressure. In rats with T(8) left hemisection and 8-wk recovery, BR was robust, and acute right upper thoracic hemisection abolished all BR of left renal sympathetic nerve activity. Collectively, these data suggest that the recovery of BR is not mediated by reorganization of ipsilateral bulbospinal connections, but instead by improved efficacy of existing contralateral pathways.


Subject(s)
Baroreflex/physiology , Herpesvirus 1, Suid/physiology , Kidney/innervation , Spinal Cord/pathology , Adrenergic Neurons/physiology , Adrenergic Neurons/virology , Animals , Autonomic Fibers, Preganglionic/pathology , Autonomic Fibers, Preganglionic/physiology , Autonomic Fibers, Preganglionic/virology , Brain Stem/virology , Female , Rats , Rats, Sprague-Dawley , Spinal Cord/cytology , Spinal Cord/physiology , Spinal Cord/virology , Staining and Labeling , Sympathetic Nervous System/physiology , Time Factors
7.
Am J Physiol Regul Integr Comp Physiol ; 301(5): R1584-90, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21900643

ABSTRACT

Spinal cord injury (SCI) has serious long-term consequences on sympathetic cardiovascular regulation. Orthostatic intolerance results from insufficient baroreflex regulation (BR) of sympathetic outflow to maintain proper blood pressure upon postural changes. Autonomic dysreflexia occurs due to insufficient inhibition of spinal sources of sympathetic activity. Both of these conditions result from the inability to control sympathetic activity caudal to SCI. It is well established that limited motor ability recovers after incomplete SCI. Therefore, the goal of this study was to determine whether recovery of BR occurs after chronic, left thoracic spinal cord hemisection at either T(3) or T(8). Baroreflex tests were performed in rats by measuring the reflex response of left (ipsilateral) renal sympathetic nerve activity to decreases and increases in arterial pressure produced by ramped infusions of sodium nitroprusside and phenylephrine, respectively. One week after a T(3) left hemisection, BR function was modestly impaired. However, 8 wk after a T(3) left hemisection, BR function was normal. One week after a T(8) left hemisection, BR function was significantly impaired, and 8 wk after a T(8) left hemisection, BR function was significantly improved. These results indicate that BR of renal sympathetic nerve activity in rats may partially recover after spinal cord hemisections, becoming normal by 8 wk after a T(3) lesion, but not after a T(8) lesion. The nature of the spinal cord and/or brain stem reorganization that mediates this recovery remains to be determined.


Subject(s)
Autonomic Dysreflexia/physiopathology , Baroreflex , Kidney/innervation , Orthostatic Intolerance/physiopathology , Spinal Cord Injuries/physiopathology , Sympathetic Nervous System/physiopathology , Animals , Autonomic Dysreflexia/etiology , Baroreflex/drug effects , Blood Pressure , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Infusions, Intravenous , Nitroprusside/administration & dosage , Orthostatic Intolerance/etiology , Phenylephrine/administration & dosage , Posture , Rats , Rats, Sprague-Dawley , Recovery of Function , Spinal Cord Injuries/etiology , Sympathetic Nervous System/drug effects , Thoracic Vertebrae/surgery , Time Factors , Vasoconstrictor Agents/administration & dosage , Vasodilator Agents/administration & dosage
8.
Am J Physiol Regul Integr Comp Physiol ; 300(4): R910-6, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21228341

ABSTRACT

Spinal cord injury causes debilitating cardiovascular disturbances. The etiology of these disturbances remains obscure, partly because the locations of spinal cord pathways important for sympathetic control of cardiovascular function have not been thoroughly studied. To elucidate these pathways, we examined regions of the thoracic spinal cord important for reflex sympathetic control of arterial pressure (AP). In anesthetized rats, baroreceptor relationships between pharmacologically induced changes in AP and changes in left renal sympathetic nerve activity (RSNA) were generated in spinally intact rats and after acute surgical hemisection of either the dorsal, left, or right T8 spinal cord. None of these individual spinal lesions prevented the baroreceptor-mediated increases in RSNA caused by decreases in AP. Thus, baroreceptor-mediated increases in RSNA in rats are mediated by relatively diffuse, bilateral, descending, excitatory projections. The ability to reduce RSNA at increased AP was impaired after both dorsal and left hemisections, and baroreceptor gain was significantly decreased. Baroreceptor-induced maximum decreases in RSNA were not affected by right hemisections. However, baroreflex gain was impaired. Because both dorsal and left hemisections, but not right hemisections, attenuated the decrease in RSNA at elevated AP, we conclude that pathways involved in the tonic inhibition of spinal sources of sympathetic activity descend ipsilaterally in the dorsal spinal cord. Our results show that many lesions that do not fully transect the spinal cord spare portions of both descending excitatory pathways that may prevent orthostatic hypotension and descending inhibitory pathways that reduce the incidence of autonomic dysreflexia.


Subject(s)
Baroreflex/physiology , Kidney/innervation , Spinal Cord/physiology , Sympathetic Nervous System/physiology , Animals , Blood Pressure/physiology , Kidney/physiology , Male , Models, Animal , Pressoreceptors/physiology , Rats , Rats, Sprague-Dawley , Spinal Cord/surgery , Spinal Cord Injuries/physiopathology
9.
Proc Natl Acad Sci U S A ; 107(25): 11561-6, 2010 Jun 22.
Article in English | MEDLINE | ID: mdl-20534525

ABSTRACT

Axons fail to regenerate in the injured spinal cord, limiting motor and autonomic recovery and contributing to long-term morbidity. Endogenous inhibitors, including those on residual myelin, contribute to regeneration failure. One inhibitor, myelin-associated glycoprotein (MAG), binds to sialoglycans and other receptors on axons. MAG inhibition of axon outgrowth in some neurons is reversed by treatment with sialidase, an enzyme that hydrolyzes sialic acids and eliminates MAG-sialoglycan binding. We delivered recombinant sialidase intrathecally to rats following a spinal cord contusive injury. Sialidase (or saline solution) was infused to the injury site continuously for 2 wk and then motor behavior, autonomic physiology, and anatomic outcomes were determined 3 wk later. Sialidase treatment significantly enhanced hindlimb motor function, improved bulbospinally mediated autonomic reflexes, and increased axon sprouting. These findings validate sialoglycans as therapeutic targets and sialidase as a candidate therapy for spinal cord injury.


Subject(s)
Axons/physiology , Contusions/drug therapy , Myelin Sheath/metabolism , Neuraminidase/metabolism , Spinal Cord Injuries/drug therapy , Animals , Axons/metabolism , Behavior, Animal , Contusions/physiopathology , Escherichia coli/metabolism , Female , Glycoproteins/metabolism , Injections, Spinal , Osmosis , Rats , Rats, Sprague-Dawley , Spinal Cord/pathology , Spinal Cord Injuries/physiopathology , Vibrio cholerae/metabolism
10.
Curr Opin Investig Drugs ; 10(10): 1105-16, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19777399

ABSTRACT

Tesofensine, a monoamine reuptake inhibitor, is under development by NeuroSearch A/S for the potential treatment of obesity. In vitro, the compound potently blocked dopamine, norepinephrine and serotonin reuptake. Initial development, which was conducted by NeuroSearch in collaboration with Boehringer Ingelheim Corp, demonstrated that although tesofensine was ineffective as a treatment for neurodegenerative conditions, a notable occurrence of unintended weight loss was observed in individuals treated with the drug. Preclinical data from diet-induced obese rats supported the hypothesis that tesofensine reduces body weight, and NeuroSearch has since pursued the development of the compound as an oral anti-obesity drug. In phase II clinical trials with tesofensine in obese individuals, dose-related reductions in body weight, body fat and waist circumference, as well as improvements in other obesity-related endocrine factors, were observed. Overall, tesofensine was associated with minor adverse events. Tesofensine caused dose-dependent elevations in heart rate, with significant increases in blood pressure at the highest dose tested. The initial positive findings suggest that tesofensine may be a well-tolerated long-term treatment for obesity, with minimal cardiovascular effects; this view appears to be shared by the FDA, which recently endorsed the phase III trial program for the agent.


Subject(s)
Anti-Obesity Agents/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Obesity/drug therapy , Animals , Anti-Obesity Agents/adverse effects , Anti-Obesity Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Clinical Trials as Topic , Drug Evaluation, Preclinical , Humans , Neurotransmitter Uptake Inhibitors/adverse effects , Neurotransmitter Uptake Inhibitors/pharmacology , Neurotransmitter Uptake Inhibitors/therapeutic use , Rats , Weight Loss/drug effects
11.
Am J Physiol Regul Integr Comp Physiol ; 293(1): R178-84, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17428892

ABSTRACT

Sympathetic preganglionic neurons and interneurons are closely apposed (presumably synapsed upon) by corticospinal tract (CST) axons. Sprouting of the thoracic CST rostral to lumbar spinal cord injuries (SCI) substantially increases the incidence of these appositions. To test our hypothesis that these additional synapses would increase CST control of sympathetic activity after SCI, we measured the effects of electrical stimulation of the CST on renal sympathetic nerve activity (RSNA) and arterial pressure (AP) in alpha-chloralose-anesthetized rats with either chronically intact or chronically lesioned spinal cords. Stimuli were delivered to the CST at intensities between 25-150 muA and frequencies between 25 and 75 Hz. Stimulation of the CST at the midcervical level decreased RSNA and AP. These decreases were not mediated by direct projections of the CST to the thoracic spinal cord because we could still elicit them by midcervical stimulation after acute lesions of the CST at caudal cervical levels. In contrast, caudal thoracic CST stimulation increased RSNA and AP. Neither the responses to cervical nor thoracic stimulation were affected by chronic lumbar SCI. These data show that the CST mediates decreases in RSNA via a cervical spinal system but excites spinal sympathetic neurons at caudal thoracic levels. Because chronic lumber spinal cord injury affected responses evoked from neither the cervical nor thoracic CST, we conclude that lesion-induced or regeneration-induced formation of new synapses between the CST and sympathetic neurons may not affect cardiovascular regulation.


Subject(s)
Kidney/innervation , Pyramidal Tracts/physiology , Spinal Cord Injuries/physiopathology , Sympathetic Nervous System/physiology , Animals , Blood Pressure/physiology , Cervical Vertebrae/physiology , Chronic Disease , Electric Stimulation , Electrophysiology , Heart Rate/physiology , Lumbar Vertebrae/physiology , Male , Microelectrodes , Rats , Rats, Sprague-Dawley , Thoracic Vertebrae/physiology
12.
Neuropharmacology ; 52(2): 467-75, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17045312

ABSTRACT

Presympathetic neurons in the paraventricular nucleus (PVN) of the hypothalamus receive inputs from gamma-aminobutyric acid (GABA)-containing neurons, which regulate sympathetic outflow and cardiovascular function. Benzodiazepines can decrease blood pressure and sympathetic nerve activity when used for induction of anesthesia, but the sites and mechanisms of action are uncertain. In this study, we determined the effect of the benzodiazepine agonist diazepam on GABAergic inhibitory postsynaptic currents (IPSCs) and the firing activity of rostral ventrolateral medulla (RVLM)-projecting PVN neurons. RVLM-projecting PVN neurons were retrogradely labeled by fluorescent microspheres injected into the RVLM in rats. Whole-cell and cell-attached recordings were performed on labeled PVN neurons in the hypothalamic brain slice. Bath application of 1-10 microM diazepam significantly increased the decay time constants of the GABAergic miniature IPSCs and evoked IPSCs in a dose-dependent manner. Also, diazepam significantly increased the amplitude of evoked IPSCs but not of miniature IPSCs. Pretreatment with the benzodiazepine antagonist flumazenil completely blocked the diazepam-induced increases in the amplitude and decay time constants of the evoked IPSCs. Furthermore, diazepam significantly decreased the firing activity of PVN-RVLM neurons that responded with increased firing to the GABA(A) receptor antagonist bicuculline. In contrast, diazepam had no significant effect on the firing activity of bicuculline-unresponsive PVN-RVLM neurons. This study provides new information that the benzodiazepine suppresses the firing activity of PVN presympathetic neurons by potentiation of GABAergic inputs.


Subject(s)
Benzodiazepines/antagonists & inhibitors , Inhibitory Postsynaptic Potentials/drug effects , Neurons/drug effects , Paraventricular Hypothalamic Nucleus/cytology , Sympathetic Nervous System/physiology , gamma-Aminobutyric Acid/metabolism , Action Potentials/drug effects , Action Potentials/physiology , Animals , Diazepam/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , GABA Modulators/pharmacology , In Vitro Techniques , Inhibitory Postsynaptic Potentials/physiology , Male , Medulla Oblongata/drug effects , Medulla Oblongata/physiology , Neural Pathways/drug effects , Neural Pathways/physiology , Patch-Clamp Techniques/methods , Rats , Rats, Sprague-Dawley
13.
Am J Physiol Regul Integr Comp Physiol ; 288(2): R420-6, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15472008

ABSTRACT

Myocardial ischemia stimulates cardiac spinal afferents to initiate a sympathoexcitatory reflex. However, the pathways responsible for generation of increased sympathetic outflow in this reflex are not fully known. In this study, we determined the role of the paraventricular nucleus (PVN) in the cardiogenic sympathetic reflex. Renal sympathetic nerve activity (RSNA) and blood pressure were recorded in anesthetized rats during epicardial application of 10 microg/ml bradykinin. Bilateral microinjection of muscimol (0.5 nmol), a GABA(A) receptor agonist, was performed to inhibit the PVN. In 10 vehicle-injected rats, epicardial bradykinin significantly increased RSNA 178.4 +/- 48.5% from baseline, and mean arterial pressure from 76.9 +/- 2.0 to 102.3 +/- 3.3 mmHg. Microinjection of muscimol into the PVN significantly reduced the basal blood pressure and RSNA (n = 12). After muscimol injection, the bradykinin-induced increases in RSNA (111.6 +/- 35.9% from baseline) and mean arterial pressure (61.2 +/- 1.3 to 74.5 +/- 2.7 mmHg) were significantly reduced compared with control responses. The response remained attenuated even when the basal blood pressure was restored to the control. In a separate group of rats (n = 9), bilateral microinjection of the ionotropic glutamate antagonist kynurenic acid (4.82 or 48.2 nmol in 50 nl) had no significant effect on the RSNA and blood pressure responses to bradykinin compared with controls. These results suggest that the tonic PVN activity is important for the full manifestation of the cardiogenic sympathoexcitatory response. However, ionotropic glutamate receptors in the PVN are not directly involved in this reflex response.


Subject(s)
Heart/innervation , Paraventricular Hypothalamic Nucleus/physiology , Sympathetic Nervous System/physiology , Afferent Pathways/drug effects , Afferent Pathways/physiology , Animals , Blood Pressure/physiology , Bradykinin/pharmacology , Kidney/innervation , Kidney/physiology , Kynurenic Acid/pharmacology , Male , Muscimol/pharmacology , Paraventricular Hypothalamic Nucleus/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Glutamate/drug effects , Receptors, Glutamate/physiology , Reflex/physiology
14.
J Physiol ; 551(Pt 2): 515-23, 2003 Sep 01.
Article in English | MEDLINE | ID: mdl-12829722

ABSTRACT

Myocardial ischaemia causes the release of metabolites such as bradykinin, which stimulates cardiac sensory receptors to evoke a sympathoexcitatory reflex. However, the molecular identity of the afferent neurons and fibres mediating this reflex response is not clear. In this study, we tested the hypothesis that the cardiogenic sympathoexcitatory reflex is mediated by capsaicin-sensitive afferent fibres. Enhanced immunofluorescence labelling revealed that vanilloid receptor 1 (VR1)-containing afferent nerve fibres were present on the epicardial surface of the rat heart. Resiniferatoxin (RTX), a potent analogue of capsaicin, was used to deplete capsaicin-sensitive afferent fibres in rats. Depletion of these fibres was confirmed by a substantial reduction of VR1 immunoreactivity in the epicardium and dorsal root ganglia. The thermal sensitivity was also diminished in RTX-treated rats. Renal sympathetic nerve activity (RSNA) and blood pressure were recorded in anaesthetized rats during epicardial application of bradykinin or capsaicin. In vehicle-treated rats, epicardial bradykinin (10 microg ml-1) or capsaicin (10 microg ml-1) application produced a significant increase in RSNA and arterial blood pressure. The RSNA and blood pressure responses caused by bradykinin and capsaicin were completely abolished in RTX-treated rats. Furthermore, epicardial application of iodo-RTX, a highly specific antagonist of VR1 receptors, blocked capsaicin- but not bradykinin-induced sympathoexcitatory responses. Thus, these data provide important histological and functional evidence that the heart is innervated by VR1-expressing afferent nerves and these afferent nerves are essential for the cardiogenic sympathoexcitatory reflex during myocardial ischaemia.


Subject(s)
Heart/physiology , Neurons, Afferent/physiology , Receptors, Drug/physiology , Reflex/physiology , Sympathetic Nervous System/physiology , Animals , Blood Pressure/drug effects , Bradykinin/pharmacology , Capsaicin/pharmacology , Diterpenes , Fluorescent Antibody Technique , Ganglia, Spinal/physiology , Heart/innervation , Hot Temperature , Kidney/innervation , Kidney/physiology , Male , Microscopy, Confocal , Myocardium/metabolism , Neurons, Afferent/metabolism , Nociceptors/drug effects , Pain Measurement/drug effects , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Receptors, Drug/biosynthesis
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