Preganglionic Sympathetic Nerve Activity Research Articles

Impaired hypotensive responses induced by intrathecally injected drugs in fructose-fed rats

Blood pressure responses to intrathecal (i.t.) injection of neurochemicals were examined in the fructose-fed rat, an experimental model of metabolic syndrome.Sprague-Dawley rats receiving either tap water or water containing 10% fructose during 8 weeks were anesthetized with sodium pentobarbital. The endocannabinoid anandamide (100nmol; i.t.) decreased mean blood pressure in control rats (−21.2±6.3mmHg), but had no effect in fructose-fed animals. Similarly, calcitonin gene-related peptide (CGRP; 0.125nmol; i.t.) decreased mean blood pressure in control, but not in treated rats. The high fructose diet did not cause significant changes in the pressor effects of i.t. administered noradrenaline (100nmol) and N-methyl-d-aspartate (30nmol). The nitric oxide donor sodium nitroprusside (500nmol, i.t.) induced a brief hypotension followed by a sustained increase in mean blood pressure in control rats; however, this drug only produced pressor effects in fructose-fed animals. The GABAA-receptor agonist muscimol (8.8nmol, i.t.) and the GABAB-receptor agonist baclofen (100nmol, i.t.) decreased mean blood pressure 30–35mmHg, both in control and in fructose-fed rats. Fructose potentiated the pressor effect of i.v. injected noradrenaline, but did not modify the hypotensive responses to i.v. administered sodium nitroprusside and acetylcholine.These results could suggest that, in pentobarbital-anesthetized rats, fructose feeding could alter spinal mechanisms of regulation of preganglionic sympathetic nerve activity. It is proposed that the spinal cord could be involved in the sympathetic dysfunction associated with the metabolic syndrome.

Captopril does not affect reflex increases in adrenal or lumbar sympathetic nerve activity to hypoglycemia in rats

Blockade of angiotensin II (ANGII) receptors or converting enzyme inhibition attenuates reflex increases in epinephrine during insulin-induced hypoglycemia. Because ANGII receptors are found in several sites within the central nervous system, the aim of this study was to examine whether acute captopril attenuates the reflex increase in adrenal preganglionic sympathetic nerve activity (SNA) induced by hypoglycemia. We infused vehicle (control) or insulin (30 U/kg IV) in anesthetized rats or in rats pretreated with captopril (Cap-insulin; 2.5 mg/kg, then 1 mg/kg per hour IV) while measuring hemodynamics and SNA from adrenal preganglionic, adrenal postganglionic, and lumbar sympathetic nerves. Hypoglycemia elicited similar adrenal preganglionic SNA increases in insulin-treated (260% ± 31% from 100% baseline) and Cap-insulin–treated (255% ± 34%) rats. Likewise, increases in adrenal postganglionic SNA and lumbar SNA were equivalent in the insulin and Cap-insulin groups. Hypoglycemia also elicited a tachycardia in insulin-treated rats that was attenuated in Cap-insulin–treated rats, and corresponding blood pressure decreases in insulin rats were enhanced in Cap-insulin–treated rats. Thus, blockade of ANGII formation by captopril did not affect hypoglycemia-induced activation of adrenal preganglionic SNA, indicating that the renin-angiotensin systems in the brain and spinal cord do not modulate increases in adrenal SNA during hypoglycemia.

Stimulation of NTS A1 adenosine receptors evokes counteracting effects on hindlimb vasculature

Our previous studies concluded that stimulation of the nucleus of the solitary tract (NTS) A2a receptors evokes preferential hindlimb vasodilation mainly via inducing increases in preganglionic sympathetic nerve activity (pre-ASNA) directed to the adrenal medulla. This increase in pre-ASNA causes the release of epinephrine and subsequent activation of beta-adrenergic receptors that are preferentially located in the skeletal muscle vasculature. Selective activation of NTS A1 adenosine receptors evokes variable, mostly pressor effects and increases pre-ASNA, as well as lumbar sympathetic activity, which is directed to the hindlimb. These counteracting factors may have opposite effects on the hindlimb vasculature resulting in mixed vascular responses. Therefore, in chloralose-urethane-anesthetized rats, we evaluated the contribution of vasodilator versus vasoconstrictor effects of stimulation of NTS A1 receptors on the hindlimb vasculature. We compared the changes in iliac vascular conductance evoked by microinejctions into the NTS of the selective A1 receptor agonist N6-cyclopentyladenosine (330 pmol in 50 nl volume) in intact animals with the responses evoked after beta-adrenergic blockade, bilateral adrenalectomy, bilateral lumbar sympathectomy, and combined adrenalectomy + lumbar sympathectomy. In intact animals, stimulation of NTS A1 receptors evoked variable effects: increases and decreases in mean arterial pressure and iliac conductance with prevailing pressor and vasoconstrictor effects. Peripheral beta-adrenergic receptor blockade and bilateral adrenalectomy eliminated the depressor component of the responses, markedly potentiated iliac vasoconstriction, and tended to increase the pressor responses. Lumbar sympathectomy tended to decrease the pressor and vasoconstrictor responses. After bilateral adrenalectomy plus lumbar sympathectomy, a marked vasoconstriction in iliac vascular bed still persisted, suggesting that the vasoconstrictor component of the response to stimulation of NTS A1 receptors is mediated mostly via circulating factors (e.g., vasopressin, angiotensin II, or circulating catecholamines released from other sympathetic terminals). These data strongly suggest that stimulation of NTS A1 receptors exerts counteracting effects on the iliac vascular bed: activation of the adrenal medulla and beta-adrenergic vasodilation versus vasoconstriction mediated by neural and humoral factors.

5-hydroxytryptamine 2A receptors regulate sympathetic nerves constricting the cutaneous vascular bed in rabbits and rats

Hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is partially due to sympathetically-mediated cutaneous vasoconstriction that impairs normal heat dissipation. MDMA acts by releasing monoamines, including 5-hydroxytryptamine (5-HT), but receptor mechanisms underlying MDMA-elicited hyperthermia and cutaneous vasoconstriction are not known. The specific 5-HT2A agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) is a potent hallucinogen that also causes marked hyperthermia, suggesting the possibility that DOI, via stimulation of 5-HT2A receptors, might also cause sympathetically mediated cutaneous vasoconstriction. We tested this hypothesis in conscious unrestrained rabbits and rats. Blood flow was assessed by chronically implanted Doppler ultrasonic flow probes. Body temperature was measured by i.p. telemetric probes. We compared effects of DOI on cutaneous blood flow (ear pinna in rabbits, tail in rats) with effects on mesenteric blood flow and arterial pressure. Hyperthermia induced by DOI (5–100 μg/kg i.v. in rabbits and 100 μg/kg s.c. in rats) was preceded and accompanied by markedly reduced blood flow to the cutaneous bed, with no change in flow to the mesenteric bed. In rabbits, DOI (5 μg/kg i.v.) did not affect arterial pressure or heart rate. DOI (100 μg/kg i.v.) caused a moderate rise in arterial pressure. In rabbits, the 5-HT2A receptor antagonists ketanserin (0.3 mg/kg i.v.) and AC90179 (0.5 mg/kg i.v.) reversed the ear pinna vasoconstriction induced by DOI (5 μg/kg i.v.). In rats, ketanserin (3 mg/kg s.c.) reversed tail vasoconstriction and hyperthermia induced by DOI (100 μg/kg s.c.). In rabbits, the cutaneous vasoconstricting effect of DOI (5 μg/kg i.v.) was substantially abolished in the ipsilateral ear pinna after interruption of preganglionic sympathetic nerve activity by unilateral section of the cervical sympathetic trunk. Thus hyperthermia evoked by direct stimulation of 5-HT2A receptors is associated with marked sympathetically mediated vasoconstriction, selective for the cutaneous bed. Impairment of the ability to dissipate heat following drug-induced stimulation of 5-HT2A receptors is likely to contribute to hyperthermia induced by MDMA and by hallucinogenic drugs such as LSD.

Fractal properties of sympathetic nerve discharge.

Fano factor analysis and dispersional analysis were used to characterize time series of single and multifiber spikes recorded from the preganglionic cervical sympathetic nerve and cardiac-related slow-wave activity of the whole postganglionic sympathetic vertebral nerve (VN) in anesthetized cats. Fluctuations in spike counts and interspike intervals for single preganglionic fibers proved to be fractal (i.e., time-scale invariant), as reflected by a power law relationship between indices of the variance of these properties and the window size used to make the measurements. Importantly, random shuffling of the data eliminated the power law relationships. Fluctuations in spike counts in preganglionic multifiber activity also were fractal, as were fluctuations in the height and of the area of cardiac-related slow waves recorded from the whole postganglionic VN. These fractal fluctuations were persistent (i.e., positively correlated), as reflected by a Hurst exponent significantly >0.5. Although fluctuations in the interval between cardiac-related VN slow waves were random, those in the interval between heart beats were fractal and persistent. These results demonstrate for the first time that apparently random fluctuations in sympathetic nerve discharge are, in fact, dictated by a complex deterministic process that imparts "long-term" memory to the system. Whether such time-scale invariant behavior plays a role in generating the fractal component of heart rate variability remains to be determined.

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.

Possible participation of spinal nitric oxide in the control of the blood pressure in anesthetized rats

In pentobarbital-anesthetized rats the intrathecal (i.t.) injection of the nitric oxide (NO) precursor, l-arginine (10 and 20 μmol), elicited a decrease in the mean blood pressure (MBP) whereas the inhibitor of the NO synthase (NOS) N G-nitro- l-arginine methyl ester ( l-NAME; 0.1–10 μmol) produced a dose-dependent pressor effect. The pressor response to l-NAME was prevented by pretreatment with l-arginine. Neither d-arginine nor d-NAME modified the MBP. The NO donor sodium nitroprusside (SNP; 0.125 and 0.25 μmol, i.t.) induced a hypotensive response followed by a pressor effect. The dual response to SNP as well as the hypotensive effect of l-arginine were abolished by the guanylate cyclase inhibitor Methylene blue (0.3 μmol, i.t.). Nicotinic ganglionic blockade by hexamethonium (10 mg/kg, i.v.) reduced the hypotensive effects of both l-arginine and SNP and prevented almost completely the pressor effects of either l-NAME or SNP. The pressor effect of l-NAME was abolished by 2-amino-5-phosphonovaleric acid (APV; 30 nmol, i.t.), a selective antagonist of glutamate receptors of the NMDA subtype. These results suggest that in the spinal cord of pentobarbital-anesthetized rats NO exerts both inhibitory and excitatory effects on the preganglionic sympathetic nerve activity related to the control of the BP. The synthesis of NO appears to be tonically activated through the stimulation of spinal glutamate receptors of the NMDA subtype.

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 μM) 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 CO 2-enriched (40–80%) saline. Coadministration of capsaicin and CO 2 resulted in additively increased responses. The effects of capsaicin, but not those of CO 2, 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.

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.

Secretoneurin-immunoreactivity in nerve terminals apposing identified preganglionic sympathetic neurons in the rat: colocalization with substance P and enkephalin

Preganglionic sympathetic neurons projecting to the superior cervical ganglion are innervated by nerve fibers containing classical neurotransmitters as well as neuropeptides. In this study we examined the possible participation of a novel peptide, secretoneurin (a cleavage product of secretogranin II), in regulation of sympathetic outflow to head and neck by using a retrograde labelling-technique combined with immunohistochemistry. In addition, the coexistence of secretoneurin with substance P and leu-enkephalin, peptides known to innervate preganglionic neurons, was investigated. The majority of retrogradely labeled neurons were localized in the nucleus intermediolateralis of spinal cord segments T1–T3 (maximum at T2). Nearly all of Fast Blue positive neuronal perikarya were apposed by nerve fibers and terminals exhibiting immunoreactivity to secretoneurin. The main secretoneurin-immunoreactive form found in the upper thoracic segments corresponded to the free peptide secretoneurin as revealed by chromatography and radioimmunoassay. More than half of labeled neurons were surrounded by nerve endings containing in addition substance P or leu-enkephalin which were also, however, less frequently colocalized. Our results suggest that secretoneurin influences the activity of preganglionic sympathetic neurons projecting to the superior cervical ganglion. Regarding their frequent colocalization with substance P and leu-enkephalin, functional interactions of these peptides on preganglionic sympathetic nerve activity have to be considered.

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.

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.

Developmental changes in rat adrenal enkephalin precursor: peptide ratio

Developmental changes in rat adrenal [Met 5]enkephalin (ME) immunoreactivity and [Met 5]enkephalinargininephenylalanine (MERF) immunoreactivity (which presumably reflects proenkephalin) were examined. The concentration of MERF appeared highest at the end of the first week postnatally and decreased fourfold to near adult values by day 21, while ME levels decreased only about twofold. This indicates a fall in the adrenal proenkephalin:ME ratio during the transition from the suckling to the weanling period in the rat. The elevated MERF levels during the suckling period may result from deficient processing of proenkephalin to free ME. An increase in the activity of the processing enzyme carboxypeptidase E was observed at day 15, which may contribute to the developmental fall in the adrenal proenkephalin to free ME ratio. Mimicking sympathetic activity by nicotine treatment (3 mg/kg i.p. twice daily from birth) produced a precocious decrease in the MERF:ME ratio at day 8, and also increased the activity of the processing enzyme. Denervation at day 10 markedly decreased adrenal ME and produced a three-fold increase in MERF:ME ratio when measured at day 30. Adrenal carboxypeptidase E activity was also decreased after denervation. In summary, these results suggest that increasing preganglionic sympathetic nerve activity during the third week postnatally stimulates proenkephalin processing and leads to the developmental decrease in MERF:ME ratio in the rat adrenal.

Reflex changes in post‐ and preganglionic sympathetic adrenal nerve activity and postganglionic sympathetic renal nerve activity upon arterial baroreceptor activation and during severe haemorrhage in the rat

The aim of the study was to compare pre- (pre-aSNA) and postganglionic adrenal sympathetic nerve activity (post-aSNA) and postganglionic renal sympathetic nerve activity (rSNA) in rats during arterial baroreceptor activation and haemorrhage. Adrenal multifibre nerve activity was recorded in chloralose-anaesthetized Wistar rats. To test for pre-aSNA or post-aSNA in adrenal nerves, a ganglionic blocker, trimethaphan (10 mg kg-1), was administered i.v. If the nerve activity in the adrenal nerve decreased or increased the nerve was considered to contain predominantly post- or preganglionic fibres, respectively. In contrast, the renal nerves exhibit an almost pure postganglionic activity. Baroreceptor activity was tested by activation of baroreceptors, with an alpha-receptor agonist, phenylephrine, which was slowly infused (0.5-2 micrograms kg-1 min-1), and to deactivate the baroreceptors the rats were bled down to 50 mmHg for 8 min. The experiments showed that all tested nerve types were baroreceptor dependent. There were no significant differences between the slopes relating nerve activity inhibition to increase in blood pressure (infusion of phenylephrine). During maximal inhibition there was a difference between the rSNA and pre-aSNA, 87 +/- 4%, n = 6, and 68 +/- 6%, n = 10 (P less than 0.01) of the control value, respectively. The maximal inhibition of post-aSNA was 80 +/- 3%, n = 7, of the control value. During haemorrhage there was a difference between the nerve populations. Pre-aSNA responded with a marked increase within 1.5 min (159 +/- 29% of control, n = 7) and was then maintained at that level until retransfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Static muscle contraction reflexly increases adrenal sympathetic nerve activity in rats

Little is known about the mechanisms responsible for activation of sympathoadrenal function during exercise. We hypothesized that sympathoadrenal discharge is activated at the onset of exercise by a reflex arising in the contracting muscle. Adrenal sympathetic nerve activity (SNA) was recorded during 1 min stimulation of the tibial nerve at two times motor threshold, before and during neuromuscular blockade, in 12 alpha-chloralose-anesthetized rats. Static muscle contractions, induced by stimulation before neuromuscular blockade, were repeated during ganglionic blockade (n = 6) to specifically test reflex activation of preganglionic activity to the adrenal gland. During static contraction, adrenal SNA rapidly increased (P less than 0.05) to a maximum of 89 +/- 12% above basal and then declined, reaching basal levels after 30 s of muscle contraction. Tibial nerve stimulation during neuromuscular blockade had no effect on adrenal SNA. In most rats, adrenal SNA decreased with ganglionic blockade, indicating postganglionic as well as preganglionic innervation of the adrenal gland. During ganglionic blockade, static muscle contractions elicited a 140 +/- 21% increase in adrenal preganglionic SNA. In conclusion, static muscle contraction reflexly increases SNA to the adrenal gland, providing a mechanism for sympathoadrenal activation at the onset of exercise.

The noradrenaline uptake inhibitor, (+)-oxaprotiline, but not the inactive enantiomer, (−)-oxaprotiline, inhibits sympathetic nerve activity in the rabbit: involvement of adrenoceptors

The effect of the enantiomers of oxaprotiline on the sympathetic nervous system was studied in anesthetized rabbits. (+)-Oxaprotile 0.2, 0.6 and 1.8 mg kg −1 dose dependently reduced postganglionic renal sympathetic nerve activity and the clearance of [ 3H]noradrenaline from the plasma but increased the plasma noradrenaline concentration. The spillover of noradrenaline into the blood was not changed significantly, nor were blood pressure and heart rate, except transiently. The same doses of (−)-oxaprotiline had no effect on any of the parameters measured. (+)-Oxoprotiline also reduced lumbar preganglionic sympathetic nerve activity. The effect of (+)-oxaprotiline on renal sympathetic nerve activity was only minimally antagonized by yohimbine given alone. (+)-Oxaprotiline also inhibited renal sympathetic nerve activity after treatment with prazosin and propranolol. Subsequent administration of yohimbine restored sympathetic nerve activity to the value seen before the administration of (+)-oxaprotiline. The results show that inhibition of the re-uptake of released noradrenaline is the basis of the sympathoinhibition produced by (+)-oxaprotiline. Noradrenaline probably acts on α 2-adrenoceptors in the central nervous system to produce sympathoinhibition.

Cervical sympathetic and phrenic nerve responses to progressive brain hypoxia

To determine if depression of central respiratory output during progressive brain hypoxia (PBH) can be generalized to other brain stem outputs, we examined the effect of PBH on the tonic (tSCS) and inspiratory-synchronous (iSCS) components of preganglionic superior cervical sympathetic (SCS) nerve activity. Peak phrenic and SCS activity were measured in nine anesthetized, paralyzed, peripherally chemodenervated, vagotomized cats. PBH was produced by inhalation of 0.5% CO in 40% O2 while blood pressure and end-tidal CO2 were maintained constant. A progressive reduction in arterial O2 content from 14.3 +/- 0.6 to 4.5 +/- 0.3 vol% caused a 79 +/- 7% depression of peak phrenic activity and an 84 +/- 10% reduction of iSCS activity, but tSCS activity increased 42 +/- 21%. During CO2 rebreathing, iSCS activity increased in parallel with peak phrenic activity while tSCS activity was unchanged. The slopes of the CO2 responses of both phrenic (6.3 +/- 1.2%max/mmHg) and iSCS (4.6 +/- 0.8%max/mmHg) activity were unaffected by PBH. In four of nine hypocapnic and three of nine hypoxic studies, inspiratory activity in the SCS nerve was observed even after completely silencing the phrenic neurogram.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between sympathetic and phrenic nerve responses to peripheral chemoreflex in the cat

To test the hypothesis that peripheral chemoreflex effect on the preganglionic cervical sympathetic nerve (PSN) activity is entirely mediated by the central respiratory drive (CRD), as expressed in the phrenic nerve (PN) activity, we studied the relationship between PN and PSN activities under controlled conditions of carotid chemosensory excitation in the anesthetized cats. The cats were vagotomized, paralyzed and artificially ventilated. Tracheal pO 2 and pCO 2, systemic blood pressure, activities of single or a few PSN and PN fibers and a PN bundle were simultaneously recorded. The PSN preparations, which were responsive to hypoxia and showed PN rhythm, were selected for the study. Carotid chemoreceptor excitation, produced by hypoxia (end-tidal pO 2 ≈ 50 Torr) or by sodium cyanide injection (50–100 μ, i.v.), elicited 3 types of responses: (1) the PSN discharged during the silent period of PN activity, although the PSN peak activity was still coupled to the PN peak activity, (2) PSN discharged only during PN activity, and (3) during the absence of PN discharge induced by hyperventilation hypocapnia, cyanide injection stimulated the PSN without PN activity. These observations suggest a model of chemoreflex control of sympathetic nerve activity which consists of two parts: one is dependent on PN activity and the other is not. Accordingly, all PSN chemoreflex responses may not be integrated with all inspiratory chemoreflexes.

Examination of the effects of some 5-HT2 receptor antagonists on central sympathetic outflow and blood pressure in anaesthetised cats.

Thoracic preganglionic sympathetic nerve activity, blood pressure, heart rate and femoral arterial conductance were recorded in anaesthetised, paralysed cats. Cumulative dose response curves were constructed for the 5-HT2 antagonists cinanserin, ritanserin, cyproheptadine, methiothepin, metergoline and ICI 169,369. These antagonists showed differing effects on the above parameters. Methiothepin and cyproheptadine caused hypotension and sympathoinhibition at low and high doses, whilst metergoline and ritanserin caused these effects at high doses, above 1 mg kg-1. Cinanserin and ICI 169,369 did cause large transient changes in heart rate, blood pressure and sympathetic outflow. However, all the antagonists except ICI 169,369 and methiothepin caused an increase in femoral arterial conductance which was not associated with hypotension. It was therefore concluded that using the above antagonists it was difficult to attribute changes in blood pressure and central sympathetic outflow to blockade of 5-HT2 receptors. However, it is suggested that 5-HT2 receptors may be involved in the control of skeletal muscle and/or skin vascular beds.

Evidence that the novel antihypertensive agent, flesinoxan, causes differential sympathoinhibition and also increases vagal tone by a central action

The effects of flesinoxan were studied on thoracic preganglionic, splanchnic and renal sympathetic nerve activity, carotid sinus nerve activity, blood pressure and heart rate in anaesthetised cats. In some experiments femoral or renal arterial conductance was also recorded. Flesinoxan (3–300 μg kg −1) caused a dose-related fall in blood pressure and heart rate and also caused sympathoinhibition. This fall in blood pressure was not associated with changes in femoral arterial conductance but was with a large increase in renal arterial conductance. In this respect flesinoxan had a greater sympathoinhibitory action on the renal nerve compared with the other sympathetic outflows. The bradycardia was unaffected by the 5-HT 3 antagonist, MDL 72222, but was reversed by atropine and was abolished in bi-vagotomised cats. Flesinoxan also caused sympathoinhibition in bi-vagotomised cats and decreased carotid sinus nerve activity and blood pressure. It is concluded that flesinoxan acts centrally to cause sympathoinhibition and an increase in vagal tone.