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PubMed2000

Central injections of noradrenaline and adrenaline differentially affect plasma free fatty acid and glucose in conscious pigeons (Columba livia).

The possible involvement of central noradrenergic and/or adrenergic circuits in central mechanisms controlling free fatty acids and glucose levels was investigated in conscious pigeons. The effects of intracerebroventricular injections of noradrenaline (80 nmol) or adrenaline (80 nmol) on plasma free fatty acids and glucose concentrations were examined. The possible role of the autonomic nervous system, of sympathetic terminals and of pituitary hormone release in the metabolic responses induced by intracerebroventricular injections of adrenaline and noradrenaline was investigated by systemic pretreatment with a ganglionic blocker (hexamethonium, 1 mg/100 g), guanethidine (5 mg/100 g), and somatostatin (15 microg/100 g), respectively, 15 min before intracerebroventricular administration of adrenaline, noradrenaline or vehicle. Intracerebroventricular noradrenaline injections strongly increased plasma free fatty acid concentration but evoked no change in blood glucose levels, while adrenaline treatment increased glycemia without affecting free fatty acid levels. Hexamethonium did not block the increase in plasma free fatty acids induced by noradrenaline, while somatostatin pretreatment abolished noradrenaline-induced lipolysis during the experimental period. Adrenaline-induced hyperglycemia was blocked by systemic injections of somatostatin, hexamethonium and guanethidine. The present results suggest that: (1) adrenergic and noradrenergic mechanisms may participate in central control of blood glucose and free fatty acids, respectively, as observed in mammals. (2) noradrenaline-induced lipolysis may be mediated by pituitary mechanisms, and (3) postganglionic sympathetic fibers, possibly innervating the endocrine pancreas, may be involved in adrenaline-induced hyperglycemia.

Animals↗
PubMed2003

Noninvasive remote ischemic preconditioning for global protection of skeletal muscle against infarction.

The aim of this study was to investigate the efficacy and mechanism of action of a noninvasive remote ischemic preconditioning (IPC) technique for the protection of multiple distant skeletal muscles against ischemic necrosis (infarction). It was observed in the pig that three cycles of 10-min occlusion and reperfusion in a hindlimb by tourniquet application reduced the infarction of latissimus dorsi (LD), gracilis (GC), and rectus abdominis (RA) muscle flaps by 55%, 60%, and 55%, respectively, compared with their corresponding control (n = 6, P < 0.01) when they were subsequently subjected to 4 h of ischemia and 48 h of reperfusion. This infarct-protective effect of remote IPC in LD muscle flaps was abolished by an intravenous bolus injection of the nonselective opioid receptor antagonist naloxone (3 mg/kg) 10 min before remote IPC and a continuous intravenous infusion (3 mg/kg) during remote IPC and by an intravenous bolus injection of the selective delta 1-opioid receptor antagonist 7-benzylidenealtrexone maleate (3 mg/kg). However, this infarct-protective effect of remote IPC was not affected by an intravenous bolus injection of the ganglionic blocker hexamethonium chloride (20 mg/kg) or the nonspecific adenosine receptor antagonist 8-(p-sulfophenyl)theophylline (10 mg/kg) or by a local intra-arterial injection of the adenosine1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (3 mg/muscle flap) given 10 min before remote IPC. It was also observed that this remote IPC of skeletal muscle against infarction was associated with a slower rate of muscle ATP depletion during the 4 h of sustained ischemia and a reduced muscle neutrophilic myeloperoxidase activity after 1.5 h of reperfusion. These observations led us to speculate that noninvasive remote IPC by brief cycles of occlusion and reperfusion in a pig hindlimb is effective in global protection of skeletal muscle against infarction. This infarct-protective effect is most likely triggered by the activation of opioid receptors in the skeletal muscle, and remote IPC is associated with an energy-sparing effect during sustained ischemia and attenuation of neutrophil accumulation during reperfusion.

Abdomen↗
PubMed1992

Mechanism of nasal secretion mediated via nerve reflex in guinea pigs and evaluation of antiallergic drugs.

In order to confirm the mechanism of nasal secretion mediated via a nerve reflex in guinea pigs, the secretory response from the contralateral side was studied which was induced by local application of various stimulators. There was no difference in the nasal secretion between the contralateral and the stimulated sides when the secretion was induced by allergen, histamine, and capsaicin at lower doses. Methacholine caused a nasal secretion only on the stimulated side. Pretreatment with local anesthetic and ganglionic blockers blocked the secretory response bilaterally which was induced by allergen, histamine, and capsaicin. Antihistaminics also blocked the secretory response induced by allergen and histamine on both sides, but not the capsaicin-induced nasal secretion. Unilateral pretreatment with local anticholinergics prevented all secretory responses only on the stimulated side. Thus, exogenous and endogenous histamine released by the allergen-antibody reaction may stimulate histamine H1 receptors located in the sensory nerve endings as trigger, resulting in the secretory response mediated via a nerve reflex, while methacholine may act directly on nasal glands. Ketotifen and azelastine, which are chemical mediators releasing inhibitor with antihistaminergic activity, prevented the nasal secretion induced by histamine and allergen. On the other hand, disodium cromoglycate, amlexanox, and tranilast had only a slight effect on the allergen-induced nasal secretion. The secretory response on the contralateral side induced by various stimulators would be useful in the in vivo evaluation of anti-allergic drugs to demonstrate the difference in their modes of action.

Allergens↗
PubMed2003

Role of prostaglandin, endothelin and sympathetic nervous system on the L-NAME-induced pressor responses in spontaneously hypertensive rats.

We tested the hypothesis that in spontaneously hypertensive rat (SHR) NO produced centrally influences the resting arterial blood pressure by attenuating mechanisms involving prostaglandins, angiotensin II, endothelin and sympathetic nervous system. L-NAME (200 micro g/5 micro l), an inhibitor of NO synthase, administered intracerebroventricularly (i.c.v.) to awake and freely moving rats increased mean arterial blood pressure (MABP) in a biphasic pattern: an early transient increase within 1 min and a late prolonged response starting at 45 min and persisting for the duration of experiment (180 min). The two pressor responses involve different neurochemical mechanisms and, based on their latencies, they appear to reflect different anatomical sites of action of L-NAME. The late, but not the early pressor response, was prevented by pretreatment with chlorisondamine (2.5 mg/kg, i.v.), a ganglionic blocker, indicating its dependence on the sympathetic nervous system. Both pressor responses were abolished by i.c.v. pretreatment with indomethacin (200 micro g/5 micro l, i.c.v.), an inhibitor of cyclo-oxygenase, showing that they are mediated by prostaglandin(s). In contrast, losartan (25 micro g/5 micro l), an angiotensin II AT(1) receptor antagonist, had no effect. The initial pressor response was also attenuated by pretreatment with the endothelin ET(A)/ET(B) receptor antagonist, PD 145065 (48 micro g/2 micro l, i.c.v.). Intravenous pretreatment with another ET(A)/ET(B) receptor antagonist, L-754,142 (15 mg/kg as a bolus+15 mg/kg/h for 180 min), however, attenuated both responses to L-NAME. It is possible that L-754,142 crossed the blood-brain barrier and blocked, in addition, central ET(A)/ET(B) receptors. These studies show that NO synthesized in the brain attenuates pressor mechanisms involving prostaglandin, endothelin and sympathetic nervous system, but not angiotensin II, to modulate resting arterial blood pressure.

Acetamides↗
PubMedDate not supplied

Forebrain ischemia in the rat. Relation between duration of ischemia, use of adjunctive ganglionic blockade and long-term recovery.

The relation between duration of ischemia, use of adjunctive ganglionic blockade and long-term recovery was studied in a rat model giving reversible subtotal forebrain ischemia. Ischemia was induced by bilateral carotid artery clamping and controlled hemorrhage to a mean arterial pressure of 50 mm Hg in animals artificially ventilated under 70% N2O. After variable lengths of time, the clamps were removed and the drawn blood was reinfused. In some animals, the ganglion blocker Arfonad was given (group A+) on induction of ischemia to facilitate hypotension. There was a strict dose-response relationship between duration of ischemia and mortality. Mortality was higher among animals not given Arfonad (group A-; 37% after 10 min of ischemia and 100% after 13 min) than in group A+ (about 20% after 12-13 min of ischemia, 50% after 15 min and 80% after 19 min). In group A+ more than half of the animals died later than 24 h after ischemia. All of them were hyperexcitable and 12% died during witnessed epileptic fits. Group A- animals regularly died within the first 24 h, with no indication of central nervous system involvement. Less blood had to be drawn to attain hypotension (mean arterial pressure 50 mm Hg) in group A+ (1.5 +/- 0.3 ml/100 g b.w.) than in group A- (2.5 +/- 0.2 ml/100 g b.w.). Group A+ also had less "washout" acidosis 5 min after reinfusion of the shed blood than group A- (15 min of ischemia: pH 7.24 +/- 0.07 v 6.96 +/- 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Modulation of cardiac autonomic neurotransmission by epicardial superfusion. Effects of hexamethonium and tetrodotoxin.

The heart contains superficial cardiac nerves whose effects may be modulated by pericardial fluid bathing the epicardium. We tested this hypothesis in open-chest dogs anesthetized with secobarbital. Oxygenated normal Tyrode's solution (NT) or NT containing hexamethonium, a ganglionic blocker (500 microM), or tetrodotoxin, a blocker of axonal neurotransmission (5 microM, TTX), was instilled into the pericardial cavity to superfuse the epicardium of the whole heart. During each superfusion, effective refractory period (ERP) was determined in deep intramyocardium (greater than or equal to 4 mm in depth from the epicardium) of anterior and posterior left ventricle and in the subendocardium of the right ventricle in the baseline state and during bilateral cervical vagal stimulation (VS) or ansae subclaviae stimulation (SS). Lengthening of ERP induced by VS during superfusion with NT (6.9 +/- 0.3 msec, mean +/- SEM, n = 36) was eliminated during subsequent superfusion with hexamethonium (0.9 +/- 0.5 msec, p less than 0.001). Hexamethonium also prevented sinus arrest induced by VS but did not affect shortening of ERP induced by SS (17.3 +/- 1.3 to 16.6 +/- 1.0 msec, n = 26). TTX suppressed VS-induced changes in ERP (6.3 +/- 0.3 to 1.5 +/- 0.5 msec, n = 32, p less than 0.001) and SS-induced changes in ERP (18.8 +/- 1.6 to 6.0 +/- 0.9 msec, n = 23, p less than 0.001) but did not affect changes in ERP induced by intravenous administration of norepinephrine or methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Multiple actions of anticholinesterase agents on chemosensitive synapses: molecular basis for prophylaxis and treatment of organophosphate poisoning.

The present study demonstrates that the reversible and irreversible anti-ChE agents have direct actions on the nicotinic acetylcholine receptor-ionic channel (AChR) and on the locust glutamatergic neuromuscular junction. In addition, the prophylaxis of lethality of organophosphorus anti-ChE compounds was studied. The lethality of VX and sarin was diminished when the rats were pretreated with physostigmine and atropine. The effectiveness of this protection, however, was markedly increased when a ganglionic blocker, either mecamylamine or chlorisondamine, was added, such that all the animals survived after receiving four times a lethal dose of VX. Pretreated animals receiving sarin showed significant recovery of morphological and functional properties of the neuromuscular junction as compared to the damage of structures from animals without pretreatment. Blood ChE inhibition was slightly decreased while brain and muscle AChE levels were significantly recovered (from 98 and 70% to 56 and 32%, respectively) by the pretreatment. This effect may partially explain the protection given by physostigmine but not that afforded by addition of a non-anti-ChE agent. Physostigmine, at concentrations greater than 20 microM, showed both a marked depression of the peak amplitudes of the endplate current (EPC) and a shortening of the decay time constants tau EPC. These effects were mostly due to a direct drug interaction with the nicotinic AChR blocking the ionic channel in its open conformation. Single-channel recordings showed that physostigmine decreases conductance and open times of the channels activated in the presence of ACh and in addition has an agonistic property on the nicotinic AChR. VX, on the other hand, only shortened the open times of ACh-activated channels without affecting the conductance. No agonist property was detected with VX. On glutamatergic synapses, the ChE inhibitors generated spontaneous firing of end-plate potentials (EPPs) and action potentials (APs). This effect was blocked in the presence of low external Ca2+ concentration or tetrodotoxin. It seems that the spontaneous EPP and AP firing resulted from an increased transmitter release induced by an increase in Na+ influx at the presynpatic nerve terminal. Physostigmine and some irreversible ChE inhibitors (VX and DFP) also blocked the postjunctional glutamate receptors. Similar to the nicotinic AChR, this effect was mostly related to a blockade of the open channels. In conclusion, the present studies showed significant protection of rats by physostigmine in combination with some ganglionic antagonists against lethality by organophosphate agents.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Corticotropin-releasing factor: long-lasting facilitation of the acoustic startle reflex.

Intracerebroventricular infusion of corticotropin-releasing factor (CRF) (0.1-1.0 micrograms) produced a pronounced, dose-dependent enhancement of the acoustic startle reflex in rats. This excitatory effect began about 20-30 min after infusion, grew steadily over the 2 hr test period, and lasted at least 6 hr. Higher doses of CRF (10 micrograms) often produced marked facilitation and then inhibition of startle that oscillated repeatedly with a period of 10-20 min. CRF-enhanced startle did not result from an increase in sensitization produced by repetition of the startle stimulus or from a blockade of habituation. Peripheral injections of the autonomic ganglionic blockers hexamethonium (10 mg/kg) or chlorisondamine (3 mg/kg) slightly attenuated the magnitude of CRF-enhanced startle, suggesting a partial role of peripheral sympathetic activation. Intracerebroventricular infusion of the CRF antagonist alpha-helical CRF9-41 (alpha hCRF; 25 or 50 micrograms) blocked CRF-enhanced startle when infused 5 min prior to CRF, indicating a central site of action. CRF-enhanced startle also was reversed when alpha hCRF was given 90 min after infusion of CRF. This suggests that exogenously applied CRF remains in the brain for a very long time after administration or that CRF given exogenously initiates a process that results in a long-lasting activation of endogenous CRF. Because the startle reflex is elevated by both conditioned and unconditioned fear, these data lend further support to the idea that CRF infusion produces a behavioral state that resembles fear or anxiety. Because startle is mediated by a well-defined neural pathway, CRF-enhanced startle may provide a useful behavioral assay to analyze the neural systems upon which exogenous CRF acts to produce its behavioral effects.

Acoustic Stimulation↗
PubMed1994

Vagal stimulation induces increased pulmonary vascular permeability in guinea pig.

The effects of vagal stimulation on pulmonary vascular permeability were studied in guinea pigs in vivo using 125I-labeled albumin as a marker of plasma extravasation. Bilateral vagus nerve stimulation (NS) significantly increased the plasma leakage index in both parenchyma and tracheobronchial tissues. The NS-induced plasma leakage in the parenchyma was unaffected by the alpha-adrenoceptor antagonist phentolamine, the muscarinic receptor antagonist atropine, the ganglionic blocker hexamethonium, or pretreatment with 6-hydroxydopamine or capsaicin, but it was significantly potentiated by the beta-adrenoceptor antagonist propranolol. NS-induced tracheobronchial vascular leakage was markedly inhibited by pretreatment with atropine, hexamethonium, or capsaicin, although it was unaffected by pretreatment with phentolamine, propranolol, or 6-hydroxydopamine. By itself, NG-nitro L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, had no effect on pulmonary vascular leakage, but it significantly enhanced the NS-induced plasma leakage to parenchyma in a dose-related and L-arginine-reversible manner. Elevation of blood pressure to a similar extent as that induced by L-NAME by a phenylephrine infusion had no significant effect on the increased plasma leakage induced by NS. These results suggest that vagal stimulation increases plasma extravasation in lung parenchyma through the release of unidentified transmitter(s) in a process that is modulated by endogenous NO and catecholamines (via activation of beta-adrenoceptors), and that different mechanisms are involved in the vagally induced plasma extravasation in the pulmonary and tracheobronchial vascular beds.

Animals↗
PubMed1992

Cardiovascular responses to feeding in newborn piglets.

Cardiovascular responses to feeding have been observed in several species during various periods of development and have been implicated in the development of cardiovascular regulation. In the rat, these responses are characterized by short-lasting, large increases in blood pressure (BP) and moderate increases in heart rate. These responses appear to be sympathetically mediated because pretreatment with ganglionic blockers eliminates the increase in BP associated with milk ingestion. The present study was designed to determine if similar cardiovascular responses occur during feeding in the newborn piglet. Piglets were obtained on postnatal d 2 and fed a milk diet via automatic feeder 6 times a day. On postnatal d 6, the piglets were instrumented with an external carotid artery catheter and an internal jugular vein catheter. On postnatal d 8 and 9, direct arterial BP and heart rate were recorded during feeding. BP responses to milk ingestion were immediate, and they reached a maximum increase of 50% above baseline on both test days and followed a response profile similar to that previously described in the 15-d-old rat. An increase in heart rate was also observed, reaching a maximum of 42% above baseline. The results show that early in life piglets have large cardiovascular responses to milk ingestion similar to those observed in young rats and human infants. These responses appear to model the cardiovascular responses to feeding observed in human infants and might be useful as a noninvasive method for assessing neonatal autonomic reactivity. These responses also have the potential to cause adverse effects in newborns already at risk for cardiovascular and cerebrovascular disease.

Animals↗
PubMed1998

Role of neurosympathetic pathways in the vascular response to sepsis.

PURPOSE: The aim of this study was to determine the role of sympathetic neural activity in the hemodynamic adaptations to sepsis in pigs with an emphasis on circuit adaptations. A fall in resistance to venous return (RVR) was predicted in contrast to what was previously observed in sympathetically intact animals that had no change in RVR. MATERIALS AND METHODS: We anesthetized and ventilated 13 pigs and gave 5 mg/kg of indomethacin. We measured cardiac output (CO) by thermodilution and measured pulmonary arterial (PAP), pulmonary capillary wedge (Pcw), right atrial pressure (Pra), and arterial pressure (MAP). Intermittent inflation of a 50-mL balloon in the right atrium was used to transiently arrest the circulation for the measurement of mean circulatory filling pressure (MCFP). RVR was calculated from (MCFP - Pra)/CO. Animals were divided into two groups; 6 received 10 mg/kg of the ganglionic blocker, hexamethonium and norepinephrine to maintain MAP; 7 had their spinal cords cut at C-2. After baseline measurements, all animals received 10 microg/kg/h of endotoxin for 2 hours, and hemodynamic measurements were repeated. Plasma samples were obtained for measurements of immunoreactive endothelin-1 (ET-1), which was assayed by a radioimmunoassay. RESULTS: Hexamethonium had no significant effect on hemodynamics except for an increase in heart rate. After endotoxin, MAP and SVR fell, PAP rose, and CO and RVR did not change. Spinal section resulted in an increase in heart rate and small increase in PAP and MCFR After endotoxin, there was a further increase in heart rate, PAP, and MCFP with a marked fall in MAP and CO. RVR increased from 2.1 +/- 0.46 after spinal section to 3.6 +/- 54 mm x min/L (P < .05). ET-1 in the hexamethonium group (n = 2) rose from 2.21 +/- .14 to 11.5 +/- 2.1 pg/ml at 2 hours, and in the spinal group (n = 7) from 2.04 +/- 0.77 to 6.85 +/- 3.9 pg/mL at 45 minutes. CONCLUSION: Spinal section resulted in a more profound fall in blood pressure and less increase in MCFP than in previously studied animals with sympathetic nervous system intact, but there was still an increase in RVR and PAP ET-1 is a possible mediator of the increase in RVR and PAP.

Adaptation, Physiological↗
PubMed2001

Thermogenesis induced by intravenous infusion of hypertonic solutions in the rat.

1. Intravenous administration of 20-60 % glucose, 3.2-9.7 % NaCl or 20 % mannitol solutions (1.66 ml kg(-1)) for 5 min increased oxygen consumption in urethane-anaesthetized rats, whereas administration of physiological saline had no effect. Administration of 7.7-18.3 % urea slightly increased the oxygen consumption, but the increase was significantly smaller than that measured after the administration of other hypertonic solutions. The magnitude of the thermogenic effect correlated with the osmolality of the applied solutions. These results suggest that the thermogenesis was caused mainly by changes in osmolality rather than by a specific action of the different solute molecules. 2. Neither pretreatment with the ganglion blocker hexamethonium (20 mg kg(-1), I.P.) or the beta-adrenergic antagonist propranolol (10 mg kg(-1), I.P.), nor bilateral cervical vagotomy or bilateral adrenalectomy had any effect on the osmotically induced thermogenesis. Therefore, the autonomic nervous system and the adrenal gland were not involved in this metabolic response. 3. In response to osmotic stimulation, the temperature of the skeletal muscle increased significantly, whereas that of brown adipose tissue did not change and that of the colon and liver decreased. Accordingly, the site of osmotic thermogenesis is probably in the skeletal muscle, although osmotic stimulation was not accompanied by electromyographic activity and was not blocked by pretreatment with muscle relaxants such as dantrolene sodium or pancuronium bromide, or with the Na(+)-Cl(-) co-transport inhibitor bumetanide. 4. The increases in plasma osmolality observed after the administration of 20 % (1.3 osmol kg(-1)) glucose and 4.1 % (1.3 osmol kg(-1)) NaCl were 4.50 +/- 0.88 and 5.57 +/- 0.71 mosmol kg(-1), respectively. Since the slight increase in osmolality is well within the physiological range of changes that occur after food ingestion, diet-induced thermogenesis may have a component that is mediated by an increase in plasma osmolality, which results from the prandial increase in circulating nutrients.

Adipose Tissue, Brown↗
PubMed1993

Innervation of the cat lip by two groups of parasympathetic vasodilator fibres.

1. Electrical stimulation of the peripheral cut ends of the chorda tympani nerve proper (CTNP) and the chorda-lingual nerve (CLN) elicited a blood flow increase in the ipsilateral lower lip, tongue and submandibular gland in a stimulus intensity-dependent manner in anaesthetized cats. 2. Pretreatment with hexamethonium (1.0 mg kg-1, i.v.), an autonomic ganglionic blocker, significantly reduced the CTNP-induced blood flow increases in all of the above three sites as well as the CLN-induced blood flow in the lower lip, but it had no effects on the CLN-induced blood flow increases in the tongue and submandibular gland. 3. The CTNP stimulation-induced lower lip blood flow was not influenced by sectioning the lingual nerve proper, but it was abolished by section of either the CLN or the inferior alveolar nerve (IAN) in the mandibular canal. 4. The lip blood flow increases elicited reflexly by electrical stimulation of the upper gingiva, the central cut ends of the mylohyoid nerve and CLN were not affected by cutting of the CTNP, but were markedly reduced by pretreatment with hexamethonium and abolished by the section of the inferior alveolar nerve just distal to the mylohyoid nerve. These observations imply that the parasympathetic vasodilator fibres involved in trigeminally induced reflex vasodilatation responses do not travel with the CTNP. 5. These results suggest that there is a dual innervation of the cat lower lip by two groups of parasympathetic vasodilator fibres; in one case fibres originating from the facial nerve root are distributed to the lower lip via the CTNP, CLN and IAN and in the other fibres emanating from the glossopharyngeal nerve root project to the lower lip via the mandibular nerve and the IAN.

Anesthesia↗
PubMed2006

Autonomic contribution to blood pressure and metabolism in obesity.

Obesity is associated with alterations in the autonomic nervous system that may contribute to the increase in blood pressure and resting energy expenditure present in this condition. To test this hypothesis, we induced autonomic withdrawal with the ganglionic blocker trimethaphan in 10 lean (32+/-3 years) and 10 obese (35+/-3 years) subjects. Systolic blood pressure fell more in obese compared with lean subjects (-17+/-3 versus -11+/-1 mm Hg; P=0.019) because of a greater decrease in total peripheral resistance (-310+/-41 versus 33+/-78 dynes/sec/cm(-5); P=0.002). In contrast, resting energy expenditure decreased less in obese than in lean subjects, (-26+/-21 versus -86+/-15 kcal per day adjusted by fat-free mass; P=0.035). We confirmed that the autonomic contribution to blood pressure was greater in obesity after including additional subjects with a wider range of blood pressures. Systolic blood pressure decreased -28+/-4 mm Hg (95% CI: -38 to -18.0; n=8) in obese hypertensive subjects compared with lean (-9+/-1 mm Hg; 95% CI: -11 to -6; n=22) or obese normotensive subjects (-14+/-2 mm Hg; 95% CI: -18 to -10; n=20). After removal of autonomic influences, systolic blood pressure remained higher in obese hypertensive subjects (109+/-3 versus 98+/-2 mm Hg in lean and 103+/-2 mm Hg in obese normotensive subjects; P=0.004) suggesting a role for additional factors in obesity-associated hypertension. In conclusion, sympathetic activation induced by obesity is an important determinant to the blood pressure elevation associated with this condition but is not effective in increasing resting energy expenditure. These results suggest that the sympathetic nervous system could be targeted in the treatment of obesity-associated hypertension.

Adult↗
PubMed1996

Effects of adenosine A2A receptor agonist, CGS 21680, on blood pressure, cardiac index and arterial conductance in anaesthetized rats.

The effects of 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680) on blood pressure, total peripheral resistance, cardiac index, heart rate and arterial conductance in different vascular beds in the presence and absence of hexamethonium (ganglionic blocker) and phenylephrine (alpha 1-adrenoceptor agonist) were investigated in pentobarbitone-anaesthetized rats using a radioactive microsphere technique. CGS 21680 (0.1, 0.3 and 1.0 microgram/kg/min) significantly decreased blood pressure and total peripheral resistance, and increased heart rate and cardiac index. In addition, after infusion with CGS 21680 (0.1, 0.3 and 1.0 microgram/kg/min) arterial conductance in coronary bed significantly increased. However, while CGS 21680 (0.3 and 1.0 microgram/kg/min) significantly increased conductance in skeletal muscle, it significantly decreased splenic arterial conductance. Moreover, CGS 21680 (1.0 microgram/kg/min) significantly increased conductance in cerebral arterial bed. Infusion with hexamethonium (200 micrograms/kg/min) resulted in significant reduction in blood pressure, heart rate and cardiac index whereas stroke volume and total peripheral resistance remained unchanged. In animals that were pretreated with hexamethonium (200 micrograms/kg/min), further administration of CGS 21680 (0.3 microgram/kg/min), compared to CGS 21680 alone, significantly reduced blood pressure, heart rate and cardiac index but did not affect total peripheral resistance or conductance in any vascular bed. Administration of phenylephrine (7 micrograms/kg/min) resulted in a significant increase in blood pressure and total peripheral resistance, and a significant reduction in cardiac index and heart rate. In animals infused with phenylephrine and CGS 21680 combined, in comparison to those animals that received CGS 21680 alone, no significant differences in blood pressure, heart rate, total peripheral resistance, cardiac index or conductance in any vascular beds were found. Our present findings suggest that CGS 21680 decreased blood pressure by decreasing total peripheral resistance, and increased cardiac index possibly through a reflex-mediated increase in heart rate. Moreover the coronary arterial bed is the most sensitive and cerebral arterial bed is the least sensitive to the effects of CGS 21680. In addition, the autonomic nervous system did not appear to play a major role in the actions of CGS 21680 on arterial conductance, and there was no difference in the action of this compound in the states of normal and raised vascular tone.

Adenosine↗
PubMed1991

Neuropeptide Y and catecholamine synthesizing enzymes and their mRNAs in rat sympathetic neurons and adrenal glands: studies on expression, synthesis and axonal transport after pharmacological and experimental manipulations using hybridization techniques and radioimmunoassay.

The effects of reserpine treatment (10 mg/kg, i.p.) on the content of neuropeptide Y-like immunoreactivity and catecholamines were compared with the levels of mRNA coding for neuropeptide Y, tyrosine hydroxylase and phenylethanolamine N-methyltransferase in rat sympathetic neurons and adrenal gland. A reversible depletion of neuropeptide Y-like immunoreactivity was observed in the right atrium of the heart, kidney and masseter muscle, while the immunoreactive neuropeptide Y content in the stellate and lumbar sympathetic ganglia and its axonal transport in the sciatic nerve increased following reserpine. The increase in the stellate ganglion was maximal at 48 h and absent 9 days after reserpine treatment. The expression of neuropeptide Y mRNA and tyrosine hydroxylase mRNA in both the stellate and the superior cervical ganglion increased earlier than the neuropeptide Y content, with a clear cut two-fold elevation at 24 h after reserpine. The increase in both mRNAs in the superior cervical ganglion and the depletion of neuropeptide Y, but not of noradrenaline, in terminal areas was prevented after pretreatment both with a nicotinic receptor antagonist (chlorisondamine) and with surgical preganglionic denervation. A marked (75-90%) depletion of neuropeptide Y-like immunoreactivity and adrenaline in the adrenal gland, concomitant with 3-4-fold increases in neuropeptide Y mRNA and tyrosine hydroxylase mRNA expression, was present at 24 h after reserpine treatment. Also in the adrenal gland, there was a reversal of the reserpine-induced increase in neuropeptide Y mRNA and tyrosine hydroxylase mRNA and depletion of neuropeptide Y and adrenaline following splanchnic denervation. Pharmacological, ganglionic blockade prevented the depletion of neuropeptide Y and the increased expression of neuropeptide Y mRNA, but not fully, the tyrosine hydroxylase mRNA elevation. In addition, a marked decrease in phenylethanolamine N-methyltransferase mRNA levels was noted after reserpine. This decrease was reversed by denervation and by ganglionic blockade. Denervation alone led to a small but significant decrease in all mRNAs examined both in the superior cervical ganglion and the adrenal medulla. The present data suggest that the depletion of neuropeptide Y-like immunoreactivity in sympathetic nerves and in the adrenal gland after reserpine is associated with a compensatory increase in neuropeptide Y synthesis and axonal transport, most likely due to increased nicotinic receptor stimulation. Whereas the reserpine depletion of neuropeptide Y in both sympathetic nerves and adrenal gland is related to neuronal activation, adrenal but not nerve terminal depletion of catecholamines can be prevented by the ganglionic blocker chlorisondamine.4+e difference in effect of pharmacological ganglionic

Adrenal Glands↗
PubMed2004

The tyrosine phosphatase inhibitor bis(maltolato)oxovanadium attenuates myocardial reperfusion injury by opening ATP-sensitive potassium channels.

Vanadate has been shown to inhibit tyrosine phosphatase, leading to an increased tyrosine phosphorylation state. The latter has been demonstrated to be involved in the signal transduction pathway of ischemic preconditioning, the most potent endogenous mechanism to limit myocardial infarct size. Furthermore, there is evidence that phosphatase inhibition may be cardioprotective when given late after the onset of ischemia, but the mechanism of protection is unknown. We tested the hypothesis that the organic vanadate compound bis(maltolato)oxovanadium (BMOV) limits myocardial infarct size by attenuating reperfusion injury and investigated the underlying mechanism. Myocardial infarction was produced in 112 anesthetized rats by a 60-min coronary artery occlusion, and infarct size was determined histochemically after 180 min of reperfusion. Intravenous infusion of BMOV in doses of 3.3, 7.5, and 15 mg/kg i.v. decreased infarct size dose-dependently from 70 +/- 2% of the area at risk in vehicle-treated rats down to 41 +/- 5% (P < 0.05 versus control), when administered before occlusion. Administration of the low dose just before reperfusion was ineffective, but administration of the higher doses was equally cardioprotective as compared with administration before occlusion. The cardioprotection by BMOV was abolished by the tyrosine kinase inhibitor genistein and by the ATP-sensitive potassium (K(+)(ATP)) channel blocker glibenclamide but was not affected by the ganglion blocker hexamethonium. We conclude that BMOV afforded significant cardioprotection principally by limiting reperfusion injury. The mode of action appears to be by opening of cardiac K(+)(ATP) channels via increased tyrosine phosphorylation.

Adenosine Triphosphate↗
PubMed1988

Hyperglycemia induced by electrical stimulation of lateral part of dorsal parabrachial nucleus.

Electrical stimulation of the lateral part of the dorsal parabrachial nucleus (PBD) induces hyperglycemia by enhancing glucagon secretion and suppressing insulin secretion in rats. The mechanism of this effect in the light period was examined by use of blockers of the autonomic nervous system. Hexamethonium, a ganglion blocker, and propranolol, a beta-adrenergic blocker, markedly inhibited the hyperglycemic response to stimulation of the lateral part of the PBD (LPBD). In contrast, phenoxybenzamine, an alpha-adrenergic blocker, and atropine methylnitrate, a muscarinic blocker, had no effect. Because previous studies showed that bilateral lesions of the suprachiasmatic nucleus (SCN) eliminated hyperglycemia induced by intracranial injection of 2-deoxy-D-glucose and that blinding largely suppressed the hyperglycemia, the effects of these two treatments on hyperglycemia induced by electrical stimulation of the LPBD were examined. SCN lesions abolished the hyperglycemic response but did not affect the hyperglucagonemic response. Results 4 wk after orbital enucleation were similar to those after SCN lesions. These findings suggest that the SCN and a beta-adrenergic mechanism are involved in the hyperglycemic response to LPBD stimulation.

Animals↗