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PubMedDate not supplied

Cardioacceleration provoked by intrathecal administration of vasoactive intestinal peptide (VIP): mediation by a non-central nervous system mechanism.

Intrathecal administration of VIP to the thoracic spinal cord in the urethane anaesthetized rat provoked a dose-dependent increase in heart rate without any change in arterial pressure. The cardioacceleration observed following administration of 6.5 nmol of VIP at the T9 level (n = 8) occurred within 1-2 min of administration, with a peak effect of 70-85 bpm, 10-30 min after administration. The magnitude of the maximum change when this dose was given at the T2 level (n = 8) was approximately 100 beats per min, 7-8 min after administration. However, the differences between T2 and T9 administration were not statistically significant. Intravenous administration of 6.5 nmol of VIP (n = 6) mimicked the cardioacceleratory effect of intrathecal administration, and also decreased systolic and diastolic arterial pressure by 9-13 mmHg 6-13 min after administration. The cardioacceleration observed following intrathecal administration at T9 was not blocked by prior systemic administration of the autonomic ganglion blocker hexamethonium (5 mg/kg) or by bilateral vagotomy. Nor was the effect blocked by prior intrathecal administration of the local anaesthetic lidocaine (250 micrograms), although lidocaine did block the tachycardia and hypertension resulting from intrathecal administration of substance P. Considered collectively, the findings that the cardioacceleration observed following intrathecal VIP injection is mimicked by i.v. administration, is not reversed by blockade of nicotinic transmission of autonomic ganglia or by bilateral vagotomy, and is not blocked by lidocaine suggest that VIP's tachycardic effect does not result from a direct action on spinal mechanisms mediating autonomic control of the cardiovascular system, but occurs via diffusion to a site of action outside the central nervous system.

Animals↗
PubMed1987

Investigation of the vagally induced changes in transmural potential difference in the ferret jejunum in vivo.

This study was designed to determine whether the non-cholinergic, non-adrenergic rise in transmural potential difference (PD), induced by vagal nerve stimulation is an efferent effect or one caused by the antidromic stimulation of afferent fibers. Unilateral left supranodose vagotomy was performed, which caused degeneration of efferent fibers within the vagus nerve, leaving the nodose ganglion, and consequently afferent cell bodies, undamaged. After stimulating the unoperated nerve there was an increase in jejunal motility, a rise in transmural PD and a fall in systemic blood pressure. Although cholinergic blockade with atropine and adrenergic blockade with or a combination of phentolamine and propranolol abolished this vagally induced motor activity and fall in systemic blood pressure, the transmural PD response induced by stimulation of the unoperated nerve was only partially inhibited. However, the subsequent administration of the nicotinic ganglionic blocker, hexamethonium, abolished this transmural PD response. In contrast, stimulation of the operated vagus nerve failed to produce these effects. Therefore, cholinergic and non-cholinergic efferent fibers are responsible for the vagally induced rise in transmural PD and thus fluid secretion in the ferret jejunum.

Animals↗
PubMed1987

Substance P given intrathecally at the spinal T9 level increases arterial pressure and heart rate in the rat.

Administration of 10 micrograms of substance P intrathecally at the spinal T9 level of the unanaesthetized and the anaesthetized rat provoked an increase in arterial pressure and an increase in heart rate. Both cardiovascular responses began within 1-2 min of administration, and the peak of each occurred at 4-10 min. In the anaesthetized rat, which gave rise to the bulk of the responses reported, peak arterial pressure was ca 20 mm Hg greater than pre-administration levels, and peak heart rate was greater by ca 50 beats per min. Similar administration of vehicle failed to alter either parameter. Arterial pressure and heart rate in substance P-treated rats were significantly different from those in vehicle-treated rats up to 15-20 min after administration. Pretreatment with the sympathetic ganglion blocker, hexamethonium (10 mg/kg, i.v.), prevented the responses to intrathecal administration of substance P. Pretreatment with [D-Pro2, D-Phe7, D-Trp9]-substance P, an analogue with antagonist properties in the central nervous system, blocked both responses to substance P but failed to alter similar responses provoked by intrathecal administration of angiotensin II. Pretreatment with vehicle had no effect on responses to substance P or to angiotensin II. The antagonist also had partial agonistic effects. Both arterial pressure and heart rate were transiently increased, but this effect was reversed within 6 min; in the case of heart rate, values returned to the pre-application level but arterial pressure fell to a ca 15 mm Hg below this level. These results demonstrate a pharmacologically specific excitatory effect of substance P on spinal mechanisms controlling sympathetic output to the vessels and the heart; this output can be either via the adrenal medullae or via nerve pathways to the vessels and the heart. Our results also support the possibility that dysfunction of substance P systems at the spinal level may underly some models of hypertension and may be involved in some cases of essential hypertension in man, as well as in autonomic dysfunction associated with some neurological disorders.

Anesthetics↗
PubMed1988

Cholinergic nerve terminals in the ventrolateral medullary pressor area: pharmacological evidence.

This investigation was designed to demonstrate the presence of cholinergic nerve terminals in the pressor area of the ventrolateral medulla (VLPA) and to study the effects of the release of endogenous acetylcholine in this area. Bilateral microinjections (0.1-2 nmol)/site) of 3,4-diaminopyridine (DAP), which releases acetylcholine from cholinergic nerve terminals, into the VLPA in anesthetized rats evoked an increase in blood pressure and heart rate which lasted for 20-40 min. Intravenous injections of the same doses of this agent failed to evoke a response. The ganglion blocker, chlorisondamine (3 mg/kg, i.v.) abolished the responses to microinjections of DAP indicating that the responses were mediated by the sympathetic nervous system. Microinjections of scopolamine or a specific M2 muscarinic receptor antagonist (AFDX-116) into the VLPA prevented the pressor and tachycardic responses to subsequent microinjections of DAP at the same sites indicating that the responses were mediated via M2 receptors. Microinjections of hemicholinium (3 nmol/site; which impairs acetylcholine synthesis) attenuated the responses to the subsequent microinjections of DAP at the same sites. These results indicate that the substance released from the terminals in the VLPA may be predominantly acetylcholine which evokes pressor and tachycardic responses via M2 muscarinic receptors. The origin and physiological significance of these cholinergic terminals in the VLPA are not known.

4-Aminopyridine↗
PubMed1990

Cardiovascular responses elicited by chemical stimulation of the rostral ventrolateral medulla in conscious, unrestrained rats.

The cardiovascular effects of microinjection of L-glutamic acid into the rostral ventrolateral medulla have been investigated in anaesthetized and in conscious, unrestrained rats. In conscious rats L-glutamic acid (0.36, 1.2 and 2.4 nmol) produced significant increases in blood pressure, generally accompanied by a bradycardia. A lower dose of L-glutamic acid (0.12 nmol) had no effect on blood pressure or heart rate. The cardiovascular responses elicited by L-glutamic acid (2.4 nmol) were completely abolished by intravenous infusion of the ganglion blocker, pentolinium. However, in urethane-anaesthetized rats, the pressor response (+27 +/- 2/+21 +/- 2 mmHg) to microinjection of L-glutamic acid (2.4 nmol) was markedly less than that seen in conscious rats (+64 +/- 6/+47 +/- 3 mmHg) and there was a tachycardia (+21 +/- 2 beats/min) rather than a bradycardia. These results corroborate previous studies, carried out in anaesthetized animals, indicating that stimulation of the rostral ventrolateral medulla provides direct and/or indirect excitatory drive to the preganglionic sympathetic neurons of the spinal cord to increase blood pressure, but demonstrate a marked difference in sensitivity in conscious vs urethane-anaesthetized animals.

Animals↗
PubMed1992

Selective excitation of parasympathetic nerve fibers to elicit the vasodilatation in cat lip.

Electrical stimulation of the tongue and the proximal cut end of the lingual nerve caused a blood flow to increase in a stimulus-intensity dependent manner in the ipsilateral lower lip of the cats. Pretreatment with hexamethonium (an autonomic ganglionic blocker, 1.0 mg/kg) abolished the vasodilator response, while atropine, phentolamine, propranolol and tripelennamine had no effect on these vasoresponses. Ipsilateral sections of either the glossopharyngeal nerve root, inferior alveolar nerve or mental nerve at the main mental foramen, but not at the posterior mental foramen, abolished the vasodilator response caused by electrical stimulation of the tongue and the lingual nerve. Electrical stimulation of the distal cut ends of the glossopharyngeal nerve root and inferior alveolar nerve caused the vasodilator and vasoconstrictor responses, whereas stimulation of the tongue and the proximal cut ends of the lingual nerve did not elicit the vasoconstrictor response. These results suggest that reflex vasodilatation in the cat mandibular division is exclusively mediated via activation of the parasympathetic nerve fibers, and that selective excitation of the parasympathetic nerve fibers in the oral area is possible.

Animals↗
PubMedDate not supplied

Local application of neurotensin to abdominal organs triggers cardiovascular reflexes in guinea pigs: possible mechanisms.

Intraabdominal (IAB) injections or topical application of neurotensin (NT) to the serosal surface of the ileum or stomach evoked dose-dependent increases of blood pressure and of heart rate in anesthetized guinea pigs. These effects were markedly reduced by prior animal treatment with a ganglion blocker, alpha and beta adrenoceptor blockers, as well as by exposure of the abdominal organs to lidocaine, a local anesthetic. The blood pressure and heart rate responses to IAB injections or topical application of NT to the ileum or stomach were both inhibited by animal pretreatment with capsaicin. Cervical vagotomy or atropine pretreatment did not prevent or alter the cardiovascular responses to IAB injections of NT. These results suggest the presence in some organs and/or tissues of the abdominal cavity of sympathetic, capsaicin-sensitive sensory nerve fibers which, upon stimulation by NT, produce reflex increases of blood pressure and of heart rate.

Administration, Topical↗
PubMedDate not supplied

Further observations on the mechanism of the cardiovascular reflexes caused by exposure of the peritoneum to neurotensin.

Intraperitoneal (IP) injections of either 1, 3 or 9 ml of neurotensin-containing solutions (NTCS) with 5.4, 54, 540 or 5400 nM of neurotensin (NT) were found to cause concentration-dependent, but volume-independent, increases of blood pressure (BP) and heart rate (HR) in anesthetized, close-abdomen guinea pigs. The duration of both effects varied between 15 to 30 min depending both on the NT concentration and volume of NTCS utilized. Indirect evidence suggested that NT inactivation within the peritoneal cavity contributed to shorten the duration of NT effects. Animal pretreatment with a ganglion blocker, adrenoceptor antagonists, clonidine or capsaicin, reduced the BP and HR increases caused by IP injection of NTCS whereas both effects were either unaffected or slightly potentiated by animal pretreatment with atropine, morphine or captopril. Addition of a local anesthetic to NTCS inhibited the hemodynamic effects of NT whereas acute bilateral cervical vagotomy was without significant effect. These results suggest that NT has the ability to trigger cardiovascular reflexes following its IP injection in guinea pigs. The activation of peritoneal, sympathetic, capsaicin-sensitive primary afferents appears to be at the basis of these reflexes, the amplitudes of which seem poorly related to the volume of NTCS utilized (at least within the range of volume examined).

Animals↗
PubMed1996

Hemodynamic profile of activation of histamine H3 receptors by R-alpha-methylhistamine in the guinea pig.

1. The effect of R-alpha-methylhistamine, a histamine H1 receptor agonist, was studied on cardiovascular hemodynamics in bilateral vagotomized, anesthetized guinea pigs. 2. R-alpha-methylhistamine (100 micrograms/kg, IV) a dose that selectively activates histamine H3 receptors, produced hypotension and bradycardia. Total peripheral resistance (TPR) and rate pressure product (RPP) were also decreased at this dose. 3. Pretreatment with the ganglionic blocker hexamethonium (20 mg/kg, IV) blocked the blood pressure (BP), heart rate (HR), TPR, and RPP effects of R-alpha-methylhistamine (100 micrograms/kg, IV). Hexamethonium did not block the hypotensive and TPR lowering actions of the muscarinic agonist methacholine (1 and 3 micrograms/kg, IV). 4. Pretreatment with the alpha 1-adrenoceptor antagonist prazosin (0.5 mg/kg IV), blocked R-alpha-methylhistamine's (100 micrograms/kg, IV) effects on BP, TPR, and RPP. Prazosin did not antagonize the bradycardia effect of R-alpha-methylhistamine. 5. Pretreatment with the beta-adrenoceptor antagonist atenolol (1 mg/kg, IV) did not alter the BP, TPR, or RPP actions of R-alpha-methylhistamine. The HR effects of R-alpha-methylhistamine were blocked by atenolol. 6. The hemodynamic effects of R-alpha-methylhistamine were compared to the hemodynamic profile of the calcium channel blocker, verapamil (0.5 mg/kg, IV). Verapamil had little effect on TRP and had a greater cardiac depressant effect as evidenced by a significant reduction in HR and cardiac output (CO). 7. In summary, these results show that activation of prejunctional H3 receptors with R-alpha-methylhistamine decreases basal, BP, HR, TPR, and RPP in anesthetized guinea pigs. The fall in BP is mediated by a decrease in TPR. Furthermore, the inhibitory effects of R-alpha-methylhistamine on sympathetic control of the vasculature appears to impart a greater physiologic effect on the H3-histamine mediated hypotension than its inhibitory effects on sympathetic agents to the heart.

Animals↗
PubMed1992

Impulse conduction in sympathetic nerve terminals in the guinea-pig vas deferens and the role of the pelvic ganglia.

Focal extracellular recording techniques were used to study nerve impulse propagation and the intermittent transmitter release mechanism in sympathetic nerve terminals of the guinea-pig vas deferens in vitro. In particular, the nature of impulse propagation in postganglionic nerve fibres was characterized following pre- or postganglionic stimulation. Conventional intracellular recording techniques were also used to study directly ganglionic transmission in cell bodies in the anterior pelvic ganglia. When brief electrical stimuli were applied to the hypogastric nerve trunk close to the prostatic end of the vas deferens, the nerve terminal impulses recorded extracellularly could be evoked either directly by stimulation of the parent axon (i.e. postganglionically) or indirectly by stimulation of the preganglionic nerve fibre. In 364 separate recordings, nerve terminal impulse conduction failure was not observed during trains of stimuli at 1 Hz. However, apparent "intermittent conduction" of nerve impulses was noted on 16 occasions. In these fibres, the degree of intermittent conduction decreased as the frequency of stimulation was increased. Conduction in these intermittent fibres was reversibly interrupted by removing calcium from the Krebs' solution or by the addition of the ganglion blocker, hexamethonium (30-100 microM). Thus, the cause of intermittent conduction is failure of the transmission of excitation in the sympathetic ganglia. Impulses evoked by postganglionic stimulation never failed to propagate into the nerve terminals, and changes in the shape or amplitude of the nerve terminal impulse during trains of stimuli were not detected. One effect of stimulation was a frequency-dependent increase in the latency of the nerve terminal impulse which developed during the train of stimuli. Thus, intermittence of transmitter release from individual varicosities cannot be attributed to failure of impulse propagation in sympathetic nerve terminals. Transmission in the anterior pelvic ganglia was investigated directly by making intracellular recordings from cell bodies whose terminals projected to the vas deferens. Many cell bodies received a strong synaptic input which generated an action potential in the postganglionic cell body on a one-to-one basis. However, in some cell bodies there was a low safety factor for the generation of the action potential by the excitatory postsynaptic potential. The safety factor for generating an action potential in the postganglionic cell body was raised by increasing the frequency of stimulation. These findings suggest that peripheral ganglia are not simple one-to-one relay stations, but may well play an important role in controlling the patterns of nerve impulse traffic in postganglionic sympathetic neurons.

Animals↗
PubMed1995

Bombesin-induced hypothermia in rats tested at normal ambient temperatures: contribution of the sympathetic nervous system.

Rats infused centrally with bombesin become hypothermic at normal ambient temperatures when acutely deprived of food, but not while allowed unrestrained access to food. Ad lib-fed rats, tested at normal ambient temperatures, become hypothermic after receiving intracerebroventricular (ICV) bombesin when they have ventromedial hypothalamic lesions or when administered insulin or 2-deoxy-D-glucose peripherally. All of these conditions have been linked to reductions of sympathetic nervous system activity to brown adipose tissue (BAT), a major thermogenic mechanism of many homeotherms. A between group design was used to examine the effects of ICV bombesin infusions on the response to peripheral injections of a) the sympathetic ganglionic blocker chlorisondamine (2.5 mg/kg, IP) in ad lib-fed rats, b) the nonspecific beta-agonist isoproterenol (30 mg/kg, IP) in food-deprived rats, and c) the combination of isoproterenol and chlorisondamine in ad lib-fed rats. Ad lib-fed rats receiving ICV bombesin (100 ng/5 microliters), in combination with peripheral chlorisondamine injection, became hypothermic 60 min postbombesin administration (-2.84 +/- 0.33 degrees C), while ad lib-fed rats receiving ICV bombesin infusion and peripheral injections of saline did not (-0.08 +/- 0.37 degrees C). Isoproterenol blocked hyperthermia in ad lib-fed rats injected with chlorisondamine and ICV bombesin. Food-derived rats receiving ICV bombesin infusion and peripheral saline injection exhibited hypothermia 60 min postbombesin administration (-2.51 +/- 0.29 degrees C). Peripheral injections of isoproterenol prevented bombesin-induced hypothermia in food-deprived rats. These data suggest that bombesin induces hypothermia at normal ambient temperatures when the sympathetic nervous system drive to BAT cannot be (or is not) activated.

Adipose Tissue, Brown↗
PubMed1995

Neurogenic goblet cell secretion and bronchoconstriction in guinea pigs sensitised to trimellitic anhydride.

Trimellitic anhydride is a cause of occupational asthma in humans. We have previously found that tracheal instillation of trimellitic anhydride conjugated to guinea pig serum albumin induces acute bronchoconstriction and airway plasma exudation in sensitised animals, responses mediated primarily via histamine release. In the present study, neural mechanisms mediating bronchoconstriction and goblet cell secretion were determined in trimellitic anhydride-sensitised guinea pigs using the ganglionic blocker hexamethonium to eliminate efferent reflex mechanisms, pretreatment with capsaicin to eliminate afferent mechanisms, or cimetidine and mepyramine to eliminate histamine-mediated mechanisms. The magnitude of secretion of intracellular mucus from tracheal goblet cells was quantified morphometrically as a mucus score which is inversely related to the degree of discharge. Guinea pigs were injected intradermally either with 0.1 ml 0.3% trimellitic anhydride in corn oil or with corn oil alone as control. Fourteen to eighteen days later all sensitised animals had developed specific immunoglobulin (Ig) G1 antibodies whereas the controls had not. Tracheal instillation of conjugated trimellitic anhydride in anaesthetised animals significantly increased airway lung resistance (RL) 24-fold in sensitised guinea pigs (34.3 +/- 7.9 cm H2O.ml-1.s) compared with controls (1.4 +/- 0.1 cm H2O.ml-1.s). Mucus score was significantly reduced by 51% (indicating goblet cell secretion) in sensitised guinea pigs (183 +/- 22 mucus score units) compared with controls (372 +/- 41 mucus score units). The antihistamines significantly inhibited conjugated trimellitic anhydride-induced bronchoconstriction by 89%, but did not significantly affect goblet cell discharge. Hexamethonium alone did not significantly affect conjugated trimellitic anhydride-induced bronchoconstriction or goblet cell secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed2004

Salsolinol, an antagonist of prolactoliberine, induces an increase in plasma catecholamine levels in the rat.

It has been recently observed that salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a putative endogenous prolactin-releasing factor is a potent inhibitor of stress-induced release of epinephrine and norepinephrine. The prolactin release caused by salsolinol was inhibited by 1-methyl-3,4-dihydroisoquinoline (1MeDIQ). Therefore, the aim of our present studies was to investigate the effect of 1MeDIQ on plasma catecholamine levels. It has been found that 1MeDIQ is able to induce a massive increase in plasma catecholamine levels. Pretreatment of the animals with a ganglionic blocker, chlorisondamine, could completely abolish the effect of 1MeDIQ on plasma norepinephrine, and plasma epinephrine levels were only significantly attenuated. Spinal cord transection between cervical and thoracic segments eliminated 1MeDIQ induced increase in epinephrine, whereas increase in plasma norepinephrine was not affected. Hence, this effect of 1MeDIQ on sympathoadrenal system activity is most probably mediated through the level of sympathetic ganglia or partially at more centrally located sites of the nervous system. These results suggest that elevation of plasma catecholamines is involved in the mechanism of action of 1MeDIQ inhibiting the biological effect of salsolinol.

Animals↗
PubMed2005

A neurophysiological evidence of capsaicin-sensitive nerve components innervating interscapular brown adipose tissue.

Neurophysiological basis for the heterogeneity of the nerve components in the brown adipose tissue (BAT) was examined in this experiment. Efferent nerve signals were recorded from the central cut end of the small nerve filament dissected from the nerve fibers innervating the interscapular BAT (IBAT). By focusing on qualitative aspects of observed compound action potentials (spikes), we found two distinctive types of spikes exhibited by the intercostal nerves innervating IBAT. The spikes mainly appeared upon sympathetic stimulations (cold stimulation and glucose administration) were characterized by low amplitude with relatively short duration (small spike) and their sensitivity to the ganglion blocker, hexamethonium (C6). On the other hand, the spikes seen throughout the experiments were characterized by high amplitude with long duration (large spike) and their insensitivity to C6. Since BAT is activated by cold and feeding via sympathetic nervous system, the small spikes seemed to be exhibited by sympathetic fibers. On the other hand, appearance of the large C6-insensitive spikes was strongly attenuated in capsaicin-desensitized rats. Even though the functional link between IBAT and C6 insensitive fibers remains unanswered, our results suggest that IBAT is under control of various nerve types including capsaicin-sensitive fibers in addition to the control of sympathetic nervous system.

Action Potentials↗
PubMed2006

Pressor effects of noradrenaline injected into the lateral septal area of unanesthetized rats.

The lateral septal area (LSA) is involved in central cardiovascular control. In the present study, we report on the cardiovascular effects of noradrenaline (NA) injection into the LSA of unanesthetized rats, as well as on local receptors and peripheral mechanisms involved in their mediation. Microinjections of NA (9, 15, 21, 27 or 45 nmol) caused long-lasting, dose-related pressor and bradycardic responses in unanesthetized rats. No responses were observed when the dose of 21 nmol of NA was microinjected into medial septal area or lateral ventricle suggesting a main action at the LSA. No changes were observed in arterial pressure and heart rate when NA was injected in the LSA of anesthetized rats. The effects of 21 nmol of NA were abolished by local pretreatment with 10 nmol of the specific alpha1-receptor antagonist WB 4101, but were not affected by pretreatment with 10 nmol of the specific alpha2-receptor antagonist RX 821002. The magnitude of pressor response to NA in the LSA was increased by i.v. pretreatment with the ganglion blocker pentolinium (10 mg/kg) and significantly reduced by i.v. pretreatment with the V1-vasopressin receptor antagonist dTyr (CH2)5(Me) AVP (50 microg/kg). No pressor response to NA was observed in hypophysectomized rats. The present observation of alpha1-adrenoceptor-mediated pressor responses after local injection of NA confirms earlier evidence of a LSA involvement in central cardiovascular control. Pretreatment with the alpha1-adrenoceptor antagonist WB-4101 did not affect baseline blood pressure or heart rate suggesting no tonic involvement of septal adrenergic mechanisms suggesting a modulatory LSA influence on cardiovascular control. Additionally, the blockade of the pressor response by the i.v. pretreatment with a V1-vasopressin antagonist indicates that noradrenergic LSA mechanisms modulate vasopressin release.

Animals↗
PubMed2005

Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system.

OBJECTIVES: The aim of this study was to characterize the time course and neuronal mechanism of remote ischemic preconditioning (RIPC) of the vasculature in humans. BACKGROUND: Non-lethal ischemia of internal organs induces local (ischemic preconditioning) and systemic (RIPC) resistance to lethal ischemia-reperfusion (IR) injury. Experimental RIPC has two temporal components, is neuronally mediated, is induced by limb ischemia, and reduces infarct size. In humans, RIPC prevents IR-induced vascular injury. Determining the time course and mechanism is a prelude to clinical outcome studies of RIPC. METHODS: Endothelial IR injury was induced by arm ischemia (20 min) and reperfusion, and measured by flow-mediated dilation. To establish if there are early and late phases, RIPC (three 5-min cycles of ischemia of the contralateral arm) was applied immediately, 4, 24, and 48 h before IR. To determine neuronal involvement, trimetaphan (autonomic ganglion blocker; 1 to 6 mg/min intravenous) was infused during the application of the RIPC stimulus. RESULTS: Flow-mediated dilation was reduced by IR (8.7 +/- 1.1% before IR, 4.9 +/- 1.2% after IR; p < 0.001), but not when preceded by RIPC (8.0 +/- 0.8% after IR; p = NS); RIPC did not protect after 4 h (4.9 +/- 1.1% after IR; p < 0.001), but protected at 24 (8.7 +/- 1.1% after IR; p = NS) and 48 h (8.8 +/- 1.4% after IR; p = NS). Trimetaphan attenuated early (8.3 +/- 1.1% before IR, 4.2 +/- 0.9% after IR; p < 0.05) and delayed (7.3 +/- 1.0% before IR, 2.3 +/- 0.6% after IR, p < 0.001) RIPC. CONCLUSIONS: Remote ischemic preconditioning in humans has two phases of protection against endothelial IR injury; an early (short) and late (prolonged) phase, both of which are neuronally mediated. The potential for late phase RIPC to provide prolonged protection during clinical IR syndromes merits investigation.

Adult↗
PubMed2004

Endogenous ouabain-like factor (OLF) secretion is modulated by nicotinic mechanisms in rat adrenocortical cells.

This study tested the hypothesis that rat adrenocortical secretion of endogenous ouabain-like factor (OLF) is regulated by nicotinic mechanisms. OLF secreted by dispersed cell suspensions of zona glomerulosa (ZG) and fasciculata/reticularis (ZFR) cells was found to co-elute with authentic ouabain by reverse phase HPLC; OLF concentrations in cell supernatants were measured by radioimmunoassay. Nicotine (10(-6) - 10(-3) M) stimulated significant OLF secretion in rat adrenocortical cells. Acetylcholine (10(-7) - 10(-4) M) and eserine (10(-7) - 10(-3) M) stimulated OLF secretion in ZG cells at lower concentrations and stimulated at higher concentrations. Acetylcholine had no effect on ZFR secretion of OLF, but eserine stimulated OLF secretion. ACTH (10(-8) M) strongly potentiated the OLF stimulatory effect of nicotine in ZG cells; however significant interactions between nicotine and ACTH or angiotensin II on OLF secretion in ZFR cells were not apparent. The ganglionic blockers hexamethonium and mecamylamine further potentiated the effect of nicotine, implicating nicotinic acetylcholine receptors (nAChRs) in regulation of OLF secretion. The alpha7-receptor antagonist methyllycaconitine (MLA) dose-dependently inhibited the effect of nicotine in the ZG cells, and in ZFR cells MLA potentiated nicotine-induced OLF secretion. These data suggest that nicotinic regulation may underlie OLF secretion by rat adrenocortical cells, and strongly suggest presence of functional nicotinic acetylcholine receptors on these cells.

Acetylcholine↗
PubMed2004

Fenfluramine-induced hypothermia is associated with cutaneous dilation in conscious rats.

The antiobesity agent, fenfluramine, produces hypothermia in rodents by an, as yet, uncharacterized mechanism. The present study was conducted in conscious rats to determine if fenfluramine-induced hypothermia was associated with cutaneous dilation. In animals maintained at 16 degrees C, core body temperature (T(CORE)) was measured telemetrically, and tail surface temperature was monitored with thermocouples fixed to the tail (T(TAIL)). D-Fenfluramine (10 mg/kg ip) produced a rapid increase in T(TAIL) of 7.7+/-0.4 degrees C (P<.001) and a decline in T(CORE) of 4+/-0.3 degrees C (P<.001). Two findings indicate that the increase in T(TAIL) was due to the withdrawal of a sympathetic vasoconstrictor tone. First, pretreatment with the ganglionic blocker, pentolinium, prevented fenfluramine-induced changes in T(TAIL). Second, when sympathetic tone to the tail was physiologically withdrawn by increasing the environmental temperature to 28 degrees C, fenfluramine treatment produced no increase in T(TAIL). Moreover, the effects of fenfluramine on T(TAIL) and T(CORE) depended on the uptake of fenfluramine into serotonergic neurons because these effects were markedly attenuated by pretreatment with the selective serotonin re-uptake inhibitor, fluoxetine. The hypothermic effect of fenfluramine occurred despite the fact that total body oxygen consumption increased by 20%. The results suggest that heat loss due to the dilation of the cutaneous circulation contributes to fenfluramine-induced hypothermia.

Animals↗