Chronic oxidative stress in the RVLM modulates sympathetic control of circulation in pigs.

Oxidative stress is a key event in the pathogenesis of several cardiovascular diseases and may be similarly induced by long-term treatment with organic nitrates. We examined the effects of inhibiting extracellular oxidative stress in the rostral ventrolateral medulla (RVLM), the brain stem area which primarily controls sympathetic tone. Superoxide dismutase (SOD, 10 U/microl) was microinjected into the RVLM of anesthetized pigs that were either untreated (control, n=10), treated for 4 weeks with the organic nitrate isosorbidedinitrate (ISDN, 4 mg kg(-1) day(-1), n=6) or ISDN-treated followed by a 2-week recovery period (recovery, n=4). In control animals SOD produced moderate inhibitory effects on baseline sympathetic activity, indicated by decreases in renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP), and heart rate (HR) without causing changes in femoral vascular conductance (FC). These effects of SOD were greatly enhanced in ISDN-treated pigs. Following the recovery period, SOD again produced smaller effects in the RVLM but they were, however, still significantly greater than in untreated animals. In contrast, the transmission of sympathoexcitatory reflexes by the RVLM, as evoked by sciatic nerve stimulation, was not affected by SOD injections in either experimental group. Furthermore, the number of NO-synthase-positive neurons in the RVLM region was significantly reduced both in ISDN-treated and the recovery pigs, suggesting that oxidative stress caused sustained changes in NOS activity within the brain stem. These data suggest that excitatory actions of oxidative stress contribute significantly to the generation of baseline sympathetic tone in the RVLM during long-term treatment with organic nitrates. Similar mechanisms could promote sympathetic tone in cardiovascular diseases that are associated with endogenous oxidative stress for longer periods.

Sympathoinhibitory effects of clonidine are transmitted by the caudal ventrolateral medulla in cats.

We examined mechanisms of the central sympathoinhibitory actions of systemically administered clonidine in anesthetized cats. To avoid influences of sympathetic chemo- and baroreflexes, the animals were deafferentated by cutting the carotid sinus and vagal nerves bilaterally. Intravenous (i.v.) injections of clonidine (25-250 nmol/kg) caused significant (50-90%) decreases in preganglionic sympathetic nerve activity (SNA) recorded from the white ramus of the third thoracic segment. Microinjections (500 nl) into the rostral ventrolateral medulla (RVLM) of clonidine at doses (50-500 pmol in 500 nl), which probably produced higher local concentrations than produced by systemic administration, caused only slight reductions of SNA and small decreases in arterial blood pressure (BP). Furthermore, sympathoinhibition and hypotension caused by intravenous clonidine was almost unaffected by prior microinjection of alpha2-receptor antagonist rauwolscine (500 pmol) into the RVLM. Microinjections of clonidine into the caudal ventrolateral medulla (CVLM), which provides important inhibitory input to the RVLM, had no significant effects. However, chemical lesions of the CVLM with kainate (5.0 nmol), effectively blocked the sympathoinhibitory effects of subsequently administered intravenous clonidine. The results suggest that the central sympathoinhibitory effects of therapeutically relevant doses of systemically administered clonidine may be primarily mediated by pathways that activate the CVLM rather than by direct actions within the RVLM.

Nitric oxide in the ventrolateral medulla regulates sympathetic responses to systemic hypoxia in pigs.

The role of nitric oxide (NO) in the regulation of sympathetic activity during hypoxia was studied in anesthetized pigs (n = 21). Hypoxia (fractional concentration of O2 in inspired air = 0.1) increased pulmonary arterial pressure and decreased arterial blood pressure and peripheral vascular resistance. Renal sympathetic nerve activity (RSNA) was moderately increased during hypoxia but decreased instantaneously on reoxygenation. Blockade of NO synthesis by NG-nitro-L-arginine (L-NNA, 0.3 mmol/l) administered to the ventral surface of the medulla oblongata (VLM) significantly enhanced RSNA increases induced by hypoxia and abolished the RSNA response to reoxygenation. Furthermore, L-NNA significantly reduced peripheral hypoxic vasodilation but did not affect pulmonary vasoconstriction. The inactive enantiomer D-NNA had no measurable effects at the same concentration. Actions of L-NNA were effectively counteracted by the NO donor S-nitroso-N-acetyl-penicillamine (0.1 mmol/l). Deafferentiation (carotid sinus and vagal nerves cut) abolished sympathetic responses to hypoxia and their modulation by NO. The results suggest that activation of peripheral chemoreceptors induces NO release in the VLM that buffers sympathoexcitation during hypoxia and contributes to sympathoinhibition during reoxygenation.

Impaired modulation of sympathetic excitability by nitric oxide after long-term administration of organic nitrates in pigs.

BACKGROUND: Endogenous nitric oxide (NO) reduces sympathetic vasoconstriction by attenuating neuronal excitability in the brain stem and inhibition of postganglionic neurotransmission. We studied whether this modulation of sympathetic circulatory control by NO may be altered during chronic administration of NO donor drugs in pigs. METHODS AND RESULTS: Nitrate tolerance was induced by oral administration of isosorbide dinitrate (ISDN, 4 mg/kg per day for 4 weeks) in eight pigs. Four of them were chronically instrumented for the measurement of mean arterial blood pressure and cardiac output in the conscious state. ISDN treatment caused hemodynamic tolerance to NO donors and significantly increased the hypotensive responses to pharmacologic ganglionic blockade in conscious pigs. In general anesthesia, ISDN-treated animals and age-matched controls (n=5) had similar baseline renal sympathetic nerve activity and in both groups neither inhibition of NO synthases (NOS) nor administration of NO donors to the brain stem by intracerebroventricular (i.c.v.) infusions caused significant changes in baseline renal sympathetic nerve activity. However, whereas sympathoexcitatory responses to glutamate (0.5 mL, 0.1 mol/L, i.c.v.) or electrical stimulation of somatic nerve afferents were significantly potentiated by central NOS inhibition and attenuated by NO donors in controls, these treatments no longer had significant effects in ISDN-treated pigs. Furthermore, reflex sympathetic activation in response to intravenous NO donor treatment was more pronounced in nitrate tolerant animals, which suggests loss of central sympathoinhibitory effects of NO. Subsequent histology on brain stem slices with NADPH-diaphorase as NOS marker revealed significant reduction of NOS density in ISDN-treated pigs. CONCLUSIONS: Long-term administration of organic nitrates reduces the number of NO-producing neurons in the brain stem and causes loss of inhibitory effects of NO on sympathetic excitability. This component of tolerance to organic nitrates may be important in patients confronted frequently with sympathetic activation caused by mental and/or physical stressors.

Activation of chemosensitive neurons in the ventrolateral medulla by capsaicin in cats.

We examined effects of centrally administered capsaicin on sympathetic nerve activity (SNA), blood pressure (BP) and heart rate (HR) in chloralose anesthetized cats (n = 18). Upon perfusion of the lower brain stem via the left vertebral artery, capsaicin (0.1-1.0 microM) caused dose-dependent increases in preganglionic SNA (recorded from the white ramus T3) that were associated with rises in BP and HR. These responses resembled closely those obtained during perfusions with CO2-enriched (40-80%) saline. Coadministration of capsaicin and CO2 resulted in additively increased responses. The effects of capsaicin, but not those of CO2, were significantly counteracted by the capsaicin antagonist capsazepine and ruthenium red. These results suggest that a specific central chemosensitivity activated by vanilloid receptor agonists may modulate hypercapnic and/or acidic sympathoexcitatory stimuli in vivo.

Neuronal nitric oxide reduces sympathetic excitability by modulation of central glutamate effects in pigs.

Mechanisms of the modulation of sympathetic activity by neuronal NO were studied in vagotomized anesthetized pigs. Inhibition of neuronal NO synthase (nNOS) within the brain stem by intracerebroventricular (ICV) administration of 7-nitroindazole (7-NI, 1 mmol/L) or S-methyl-L-thiocitrulline (MeTC, 0.1 mmol/L) caused slight increases in renal sympathetic nerve activity (RSNA) but did not affect arterial blood pressure (BP) or cardiac output (CO). However, the sympathoexcitatory effects of glutamate (0.5 mL, 0.1 mol/L ICV) that were associated with marked increases in BP, CO, and heart rate were potentiated by both nNOS inhibitors. Furthermore, 7-NI and MeTC significantly enhanced the responses of RSNA, BP, and CO to activation of somatosympathetic reflexes via stimulation of the left greater sciatic nerve (nervus ischiadicus, 10 to 20 V, 30 Hz, 1-millisecond pulses). Subsequent systemic inhibition of either the neuronal (by 7-NI) or all isoforms of NOS by NG-nitro-L-arginine-methyl ester (20 mg/kg) had no significant additional effects on these responses. The effects of NOS inhibition were effectively counteracted by the endogenous NOS substrate L-arginine and by S-nitroso-N-acetyl-penicillamine (SNAP), a stable analogue of endogenous S-nitroso factors. Disruption of sympathoinhibitory baroreflex mechanisms by bilateral cutting of the carotid sinus nerves caused increases in RSNA and slightly increased responses to all excitatory stimuli but had no effects on the actions of the NOS inhibitors or SNAP. These results suggest that modulation of glutamate effects by nNOS-derived NO may be an important mechanism by which NO affects sympathetic activity in pigs.

Role of calcium-dependent K+ channels in the regulation of arterial and venous tone by nitric oxide in pigs.

Effects of inhibition of calcium-dependent potassium channels (K+Ca channels) on the regulation of arterial and venous tone by nitric oxide (NO) were studied in anaesthetized pigs following vagotomy and blockade of autonomic ganglia. Selective inhibition of K+Ca channels by charybdotoxin (CTX, 2 microg/kg iv) or iberiotoxin (IbTX, 1 microgram/kg) significantly augmented mean total peripheral resistance (TPR) to levels 30-60% above control. Venous and pulmonary vascular tone were assessed by changes in effective compliances of the venous (EVC) and pulmonary (EPC) vascular beds as calculated from changes in central venous and diastolic pulmonary arterial blood pressure during haemorrhagia (-5 ml/kg) and hypervolaemia (+5 ml/kg). Blockade of K+Ca channels significantly decreased both EVC (-20 to -30%) and EPC (-30 to -50%). Both CTX and IbTX significantly diminished the vasodilation caused by the NO-donor S-nitroso-N-acetylpenicillamine (SNAP) both during control conditions and following experimental vasoconstriction induced by systemic inhibition of NO-synthesis by NG-nitro-L-arginine methyl ester (L-NAME) or infusion of vasoconstrictor agonists. Dilator effects of the adenosine 3',5'-cyclic monophosphate (cAMP)-dependent agonist adenosine were only slightly reduced. However, blockade of K+Ca channels did not increase vasoconstriction induced by L-NAME significantly. These results suggest that activation of vascular K+Ca channels is an important mechanism by which NO attenuates the constrictor tone of resistance and capacitance vessels in vivo.

Lack of nitric oxide sensitivity of carotid sinus baroreceptors activated by normal blood pressure stimuli in cats.

We examined the effects of inhibition of nitric oxide (NO) synthesis and local administration of NO-donors on baroreceptor activity in anaesthetized cats. Baroreceptor activity was assessed by measuring changes in the pulse synchronous carotid sinus nerve discharge in a modified blind sack preparation. Within physiological mean arterial blood pressure (BP) ranges (BP = 70-150 mmHg), neither abluminal (in a pool around the carotid sinus, n = 15) nor intravascular (via the A. lingualis, n = 10) administration of the NO-synthase inhibitor N(G) nitro-L-arginine (L-NNA, 30 mu M) significantly modulated baroreceptor activity. The NO donors S-nitroso-N-acetylpenicillamine, sodium nitroprusside and glyceryltrinitrate caused significant decreases in baroreceptor activity only when applied intravascularly at concentrations > or = 100 mu M. In contrast, prostacyclin (1 mu M, n = 5) attenuated and indomethacin (10 mu M, n = 5) enhanced baroreceptor activity significantly upon intravascular administration. Baroreceptor activity was also effectively inhibited by gadolinium (Gd(3+), 1 mM). These results suggest that carotid sinus baroreceptor function in cats is rather insensitive to changes in the supply of endogenous or exogenous NO.

Effects of inhibitors of enzymatic and cellular pH-regulating systems on central sympathetic chemosensitivity.

Previous studies in cats using isolated NaCl-CO2 perfusion of the lower brainstem demonstrated an intrinsic chemosensitivity of sympathoexcitatory bulbospinal neurones within the rostroventrolateral medulla (RVLM). In the present experiments, the effects of inhibitors of enzymatic and cellular systems, known to be involved in pH regulation, were investigated. Isolated perfusion of the lower brainstem with CO2-enriched solutions was performed and preganglionic sympathetic nerve activity (SNA) was recorded. Drugs were locally injected into the left RVLM with glass micropipettes. Perfusion of the RVLM with CO2-enriched solutions over a period of 15 s induced a marked increase in SNA. The magnitude of absolute changes in SNA during perfusion depended on the level of basal SNA before perfusion. Microinjections of 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and acetazolamide (ACZ) induced a marked rise in basal SNA, whereas diethylpyrocarbonate (DEPC) and ethylisopropylamiloride (EIPA) had no significant effect on basal SNA. After application of DIDS and DEPC, the peak change in SNA due to perfusion of the RVLM with CO2-enriched solutions was slightly diminished. Furthermore, neither ACZ nor EIPA produced any significant influence on the slope, peak change and time course of the increase in SNA compared with control perfusions. We conclude that the enzymatic and cellular carrier systems tested in this study are not or only slightly involved in central sympathetic chemosensitivity.

Effects of nitric oxide on sympathetic baroreflex transmission in the nucleus tractus solitarii and caudal ventrolateral medulla in cats.

We have previously shown that nitric oxide (NO) attenuates baseline sympathetic tone in the rostral ventrolateral medulla (RVLM), while having no effects on baroreflex transmission in this region in cats. In the present study, we tested the effects of microinjections (500 nl) of NG-nitro-L-arginine (L-NNA, 0.3 mM) or the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 10 microM) in the nucleus tractus solitarii (NTS) and in the caudal ventrolateral medulla (CVLM) which are the two other relays of the sympathetic baroreflex within the brainstem. Neither L-NNA nor SNAP significantly changed the length of inhibition of renal sympathetic nerve activity (SNA) evoked by electrical stimulation of the ipsilateral carotid sinus nerve. In contrast, glutamate (1 mM) in the NTS markedly increased baroreflex inhibition of SNA and the glutamate receptor antagonist kynurenate (5 mM) in the CVLM significantly decreased baroreflex transmission in the same experiments. These results suggest that sympathetic baroreflex function is preserved during both impaired endogenous synthesis and excess exogenous supply of NO in the brainstem.

Inhibition of basal and reflex-mediated sympathetic activity in the RVLM by nitric oxide.

We examined possible functional roles for nitric oxide (NO) in the rostral ventrolateral medulla (RVLM), which is the final area for integration of sympathetic nerve activity (SNA) within the brain stem. Chloralose-anesthetized cats were completely baro- and chemoreceptor denervated, the RVLM was exposed for microinjections, and preganglionic SNA was recorded from the white ramus of the 3rd thoracic segment. Injections of NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, but not of NG-nitro-D-arginine, caused distinct increases in SNA and arterial blood pressure (BP). Excitatory somatosympathetic reflex amplitudes evoked by electrical stimulation of the 4th intercostal nerve were significantly increased by L-NNA whereas inhibitory responses to baroreflex activation by stimulation of the carotid sinus nerve were not affected. The effects of L-NNA were counteracted by the NO-donor compounds glyceryltrinitrate and S-nitroso-N-acetylpenicillamine, which decreased BP and SNA below control values at higher doses. These results suggest that endogenous NO, in addition to its peripheral actions, modulates the central nervous control of cardiovascular functions by reduction of basal sympathetic tone and by attenuation of excitatory reflex responses.

Changes in medullary extracellular pH, sympathetic and phrenic nerve activity during brainstem perfusion with CO2 enriched solutions.

Measurements are presented of sympathetic nerve activity (SNA), phrenic nerve activity (PNA), and local extracellular pH (ECF pH) within the rostral ventrolateral medulla (RVLM) in response to perfusions of the RVLM with CO2-enriched saline. Experiments were performed on cats anaesthetized with chloralose. The ventrolateral medullary surface was exposed, and a catheter was placed in the left vertebral artery from the axilla to allow perfusion of the RVLM. Baroreceptor and peripheral chemoreceptor denervations were performed by cutting the vagal, aortic and carotid sinus nerves. The activities of the renal and the phrenic nerve were recorded, in some experiments in parallel with the cardiac nerve. Recordings of the pH were done with ion-sensitive theta-microelectrodes. A linear relationship between the CO2 concentration of the perfusate and the evoked changes in ECF pH was found. The ECF pH did not change systematically in one or the other direction within depths between 1 and 3 mm below the surface of the medulla. The various patterns of interaction of ECF pH, SNA, and PNA are described in detail. Phrenic nerve response to perfusions was very variable; a more prolonged increase in amplitude of phasic discharges compared to the duration of changes in SNA and ECF pH was the most frequent finding, but non-phasic tonic activation and complete silence were also seen during perfusions. SNA could also deviate from ECF pH both with regard to its latency and to its time course in response to perfusions. Therefore, this study provides further evidence for deviations of cardiorespiratory adaptation from ECF pH, corroborating the notion that this parameter is not the decisive one for central chemoreception.

Inhibition of sympathetic vasoconstriction is a major principle of vasodilation by nitric oxide in vivo.

The objective of this study was to determine whether vasodilator effects of nitric oxide (NO) can be explained by the inhibition of vasoconstriction caused by peripheral sympathetic nerve activity (SNA) in vivo. For this purpose, we studied the effects of systemic inhibition of NO synthesis during experimental variation of SNA in anesthetized cats. Intravenous infusion of NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) in baroreceptor-intact animals (n = 6) caused increases in mean arterial blood pressure (MAP) from 105.8 +/- 3.4 to 192.0 +/- 4.3 mm Hg that were associated with slight decreases in preganglionic SNA recorded from the white ramus of the third thoracic segment. Higher SNA appeared in completely baroreceptor-denervated cats (n = 10) than in the intact cats, but no changes in nerve activity occurred after the subsequent administration of L-NAME. In contrast, MAP increased from 123.3 +/- 4.0 to 245.8 +/- 5.1 mm Hg. In baroreceptor-denervated cats, reversible suppression of peripheral SNA produced by cooling of the ventral surface of the rostral ventrolateral medulla oblongata (RVLM) caused significant hypotension (61.1 +/- 2.6 mm Hg) and almost completely reversed the hypertension caused by L-NAME (76.0 +/- 3.7 mm Hg). Intravenous administration of the alpha 1-adrenergic receptor antagonist prazosin after L-NAME reduced MAP to a similar extent. In contrast, hypertension induced by angiotensin II could not be reversed by RVLM cooling. The pressor effects of intravenously administered noradrenaline during RVLM cooling were markedly potentiated by L-NAME and attenuated by the NO-donor compound S-nitroso-N-acetylpenicillamine (SNAP).(ABSTRACT TRUNCATED AT 250 WORDS)

Somato-sympathetic reflex transmission in the ventrolateral medulla oblongata: spatial organization and receptor types.

Tonic sympathetic activity in vivo is continuously modulated by inhibitory and excitatory reflex mechanisms. We studied the properties of somato-sympathetic excitatory reflex transmission in the rostral ventrolateral medulla (RVLM) of baroreceptor-denervated and vagotomized chloralose-anesthetized cats. Electrical stimulation of the left intercostal nerve of the 4th thoracic segment (IC-T4) elicited an early spinal and a late supraspinal reflex in the ipsilateral white ramus T3 from which recordings were made. Bilateral cooling of the ventral surface of the RVLM reversibly reduced the supraspinal reflex amplitude to 18.0 +/- 3.1% of control (100%). The spinally evoked reflex was enhanced to maximally 154.7 +/- 5.3%. Cooling of only the ipsilateral side of the RVLM was nearly equieffective in both, suppressing the supraspinal and enhancing the spinal reflex component. In contrast, cooling of the contralateral side had no significant effects on supraspinal reflex transmission but caused slight increases of the spinal reflex amplitudes. Similar effects were obtained by microinjection (RVLM) of the glutamate antagonist kynurenic acid (5 x 10(-3) M, n = 7) and the specific non-NMDA receptor antagonist CNQX (4 x 10(-3) M, n = 4) which, however, blocked the supraspinal reflex less effectively. These results demonstrate that the RVLM represents an essential relay in the transmission of both somatosympathetic reflex components. The experiments further suggest an almost completely ipsilateral neuronal pathway for the supraspinal reflex component which projects from the RVLM to the intermediolateral cell column (IML). The descending inhibition of the spinal reflex, however, receives neuronal inputs from the contralateral side.

Excitatory somato-sympathetic reflexes are relayed in the caudal ventrolateral medulla in the cat.

The caudal ventrolateral medulla (CVLM) modulates sympathetic outflow from the rostral ventrolateral medulla (RVLM). We studied the possible role of the CVLM in the transmission of excitatory somato-sympathetic reflexes in baro- and chemoreceptor denervated chloralose-anesthetized cats. Neurotoxic doses of kainate, injected in the CVLM, caused marked increases in baseline sympathetic nerve activity (SNA) and arterial blood pressure (BP). Concomitantly, excitatory somato-sympathetic reflex responses evoked by electrical stimulation of the 4th intercostal nerve disappeared almost completely. Similar effects on SNA and BP but not on somato-sympathetic reflexes were observed when the GABA-antagonist bicuculline was injected in the RVLM. Bicuculline injected in the RVLM after kainate had no additional effects. These results suggest that in addition to a tonic GABA-ergic inhibition on the RVLM, the CVLM controls somato-sympathetic reflex transmission through interneurons located in this region.

Different effects of respiratory and metabolic acidosis on preganglionic sympathetic nerve activity.

We studied sympathetic nerve activity (SNA) responses, recorded in multifiber preparations of left third thoracic white ramus, to respiratory or isocapnic metabolic acidosis or to CO2 enhancement at constant pH in chloralose-anesthetized paralyzed artificially ventilated cats. Cardiopulmonary, baro-, and peripheral chemoreceptors were denervated by bilaterally cutting vagus and carotid sinus nerves. Acidosis was induced by either decreasing artificial ventilation or infusing HCl (0.5 M i.v.). Both respiratory and isocapnic metabolic acidosis induced a decrease in local extracellular pH, measured directly with pH-sensitive microelectrodes within medulla region containing sympathoexcitatory bulbospinal neurons. The magnitude of changes in medullary pH was independent of the way systemic acidosis was generated. Despite uniformity of changes in local medullary extracellular pH due to systemic respiratory or isocapnic metabolic acidosis, different responses were observed in preganglionic SNA. Isocapnic metabolic acidosis resulted in a slight increase in SNA, averaging 6.4% per 0.05 systemic pH unit decrease. In contrast, respiratory acidosis induced by decreasing artificial ventilation produced a more pronounced increase of SNA, reaching peak changes of approximately 70% compared with control level with normal blood gases, an average increase of 13% per 0.05 systemic pH unit decrease. We conclude that systemic CO2 and H+ concentrations represent different stimuli to sympathetic nervous system. Despite similar changes of local extracellular pH within rostral ventrolateral medulla during systemic acidosis, different responses of SNA suggest other sites or as yet unknown additional effects of CO2 as being responsible for excitation of sympathetic activity.

Characteristics of sympathetic reflexes evoked by electrical stimulation of phrenic nerve afferents.

In chloralose-anaesthetized cats, sympathetic reflex responses were recorded in left cardiac and renal nerve during stimulation of afferent fibres in the ipsilateral phrenic nerve. In cardiac nerve, a late reflex potential with a mean onset latency of 75.6 +/- 13.8 ms was regularly recorded which, in 20% of the experiments, was preceded by an early, very small reflex component (latency between 35 and 52 ms). In contrast, in renal nerve only a single reflex component after a mean latency of 122.1 +/- 13.1 ms was observed. Bilateral microinjections of the GABA-agonist muscimol into the rostral ventrolateral medulla oblongata resulted in a nearly complete abolition of sympathetic background activity and in an 88% reduction of the late reflex amplitude with only small effects on the latency of the evoked potentials. Under this condition, an early reflex component was never observed to appear. After subsequent high cervical spinalization, the residual small potentials which persisted after bilateral muscimol injections were completely abolished and in cardiac nerve an early reflex potential with a mean latency of 45 +/- 10 ms was observed in all but one experiment. The early reflex was therefore referred to as a spinal reflex component which, however, is suppressed in most animals with an intact neuraxis. In the renal nerve a spinal response was only observed in one experiment after spinalization. The results suggest that sympathetic reflexes evoked by stimulation of phrenic nerve afferent fibres possess similar spinal and supraspinal pathways as previously described for somato-sympathetic and viscero-sympathetic reflexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Central action of alpha-adrenoceptor agents on the baroreceptor reflex.

In chloralose-anaesthetized cats the effects of intravenous application of the alpha 1- and alpha 2-adrenoceptor agonistic and antagonistic agents methoxamine, prazosin, B-HT 933 and rauwolscine were tested on baroreceptor reflex, sympathetic background activity and blood pressure. Sympathetic activity was recorded from the renal nerve and the efficacy of the central transmission of the baroreceptor reflex was measured by the duration of the complete inhibition of renal nerve activity during electrical stimulation of the left carotid sinus nerve. All baroreceptors were denervated by sectioning both carotid sinus and vagal nerves. The alpha 1-agonist methoxamine increased baroreceptor-induced sympatho-inhibition, sympathetic background activity and blood pressure. The alpha 1-antagonist prazosin had the opposite effects. The alpha 2-agonist B-HT 933 was most effective in augmenting the inhibitory response in sympathetic activity to baroreceptor stimulation; sympathetic background activity and blood pressure were also decreased. At low doses (50 micrograms/kg) the alpha 2-antagonist rauwolscine reduced the baroreceptor sympathetic reflex inhibition and increased sympathetic activity and blood pressure. The effect of B-HT 933 upon the baroreceptor reflex could be completely antagonized by rauwolscine. These findings demonstrate a very effective facilitation of the baroreceptor reflex transmission by stimulation of central alpha 2-adrenoceptors. Through such humoral-neuronal interaction circulating catecholamines are likely to modulate cardiovascular control.

Cardiac sympathetic nervous activity during myocardial ischemia, reperfusion and ventricular fibrillation in the dog--effects of intravenous lidocaine.

In 12 open-chest dogs, cardiac sympathetic nervous activity (CSNA) was recorded before and after occlusion of the left anterior descending coronary artery as well as during reperfusion and ventricular fibrillation (VF). In 7 control animals, CSNA did not significantly differ from preocclusion levels when determined 20 min after occlusion (+3.5 +/- 1.5%, mean +/- SEM) and up to 15 min following reperfusion (+1.5 +/- 0.6%). However, VF was associated with a potential increase in CSNA by 106 +/- 15.5% (p less than 0.001). The effect of lidocaine (6 mg/kg) on cardiac sympathetic tone was examined in 5 additional animals. Lidocaine reduced control CSNA by 23 +/- 4.7% (p less than 0.001); subsequent ischemia and reperfusion did not substantially change the level of preocclusion activity. CSNA decreased significantly also during VF (52 +/- 4.2%, p less than 0.001). In conclusion, efferent CSNA was slightly altered in the course of acute myocardial ischemia and reperfusion, but significantly increased during VF. Lidocaine produced marked attenuation of CSNA in anesthetized dogs.