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H Seller

Publications and source records attributed to H Seller.

At least 19 recordsLinked to original sources
PubMed1999

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.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1998

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.

Animals↗
PubMed1998

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.

Animals↗
PubMed1997

Species differences in the distribution of nitric oxide synthase in brain stem regions that regulate sympathetic activity.

The distribution of nitric oxide synthases (NOS) in the lower brain stem was studied by NADPH-diaphorase staining with emphasis on the nucleus of the solitary tract and the ventrolateral medulla. The order of NOS density was hamster > rabbit = rat > mouse > guinea-pig > cat with little variation within species or between regions. This heterogeneity may partly explain qualitatively and quantitatively variable effects of NO on sympathetic activity in different species.

Animals↗
PubMed1997

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.

Analysis of Variance↗
PubMed1997

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.

Animals↗
PubMed1996

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.

Animals↗
PubMed1996

Convergence of visceral and somatic afferents on single neurones in the reticular formation of the lower brain stem in dogs.

The reticular formation of the lower brain stem contains neuronal circuits for the generation of sympathetic tone, respiratory rhythm, muscle tone and the control of vigilance. In anesthetized dogs single neurone activities were recorded in the medial two-thirds of the reticular formation to investigate the organizing principles of this multifunctional system. The results from 110 recordings demonstrate that single neurones receive information from somatosensory afferents of skin, joints and muscles together with afferents from baro-, chemo- and lung inflation and deflation receptors. Whereas the composition of afferent spectra from somatosensory sources was different from neurone to neurone, baroreceptors had a more generalized activity-decreasing effect and chemoreceptors had a generalized activity-increasing influence, the former directing physiological systems to a trophotropic and the latter towards an ergotropic state. The functional significance of the results for the co-ordination of different physiological systems is discussed.

Afferent Pathways↗
PubMed1996

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.

Angiotensin II↗
PubMed1996

Carl Ludwig and the localization of the medullary vasomotor center: old and new concepts of the generation of sympathetic tone.

In Carl Ludwig's laboratories in Leipzig, P. Owsjannikow (1871) and C. Dittmar (1873) performed precise, histologically controlled lesioning experiments into the question of the location of the vasomotor center in the medulla oblongata. A small area in the ventrolateral parts of the medulla with its caudal border 3 mm cranial to the obex and an extension of 3-4 mm in cranial direction was described as the vasomotor area which has to be left intact for normal vasomotor tone and reflexes. This finding, ignored for more than 100 years, is the most precise description of what is known today as the location of spinally projecting sympatho-excitatory neurones, named the RVML region. Already in these early publications the question of the origin of basic vasomotor tone within these areas was raised and the possibilities of automaticity and reflexogenic input were discussed. Both possibilities are still valid today and under current investigation. A specific chemosensitivity of the RVLM neurones has been demonstrated during the recent decade and its role with regard to the generation of the sympathetic tone and the nervous control of the entire cardiovascular system is being discussed.

Animals↗
PubMed1995

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.

Animals↗
PubMed1995

The importance of baroreceptor afferents for the decrease in brain glucose utilization during stimulation of the rostroventrolateral medulla of the rat.

The rostroventrolateral medulla (RVLM) is the main integration center for the regulation of the sympathetic outflow. The present study had the aim of investigating the effects of stimulation of the RVLM on the glucose utilization of the brain. Local cerebral glucose utilization (LCGU) can be regarded as an indicator of the brain functional activity. In anesthetized (chloralose-urethan), paralyzed (pancuronium) and ventilated rats, the medulla was exposed by a ventral craniotomy. The RVLM was stimulated by microinjection of 100 nl of 0.5 M sodium glutamate (n = 6). The effective stimulation was verified by the increase in arterial blood pressure. In a control group (n = 7), an identical volume of saline was injected into the RVLM. Local cerebral glucose utilization was measured in both groups using the 2-[14C]deoxyglucose method. The results showed a significant decrease in LCGU in the stimulated group in 33 of 39 brain structures examined. In order to investigate whether the decrease in brain glucose utilization is secondary to the stimulation of baroreceptor afferents by the increase in arterial blood pressure the carotid sinus nerves and both vagal nerves were cut. In this denervated group (n = 5) the decrease in LCGU was abolished in all brain structures although blood pressure was increased to a degree comparable to the innervated group. It is concluded that cerebral glucose metabolism is decreased during stimulation of the RVLM and that this decrease is secondary to the activation of baroreceptor afferents by the increase in blood pressure.

Afferent Pathways↗
PubMed1995

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.

Animals↗
PubMed1995

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.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1995

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.

Animals↗
PubMed1994

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.

Animals↗
PubMed1994

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.

6-Cyano-7-nitroquinoxaline-2,3-dione↗