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PubMed1985

[Histamine release due to ganglion blocking agent and muscle relaxants from rat mast cells].

The mechanisms of histamine release due to d-tubocurarine from rat mast cells have long been known to anesthesiologists, such as degranulatory process, Ca++ dependent process and energy coupled process. However, not much is known about histamine release due to some drugs such as trimethaphan and muscle relaxants other than d-tubocurarine, like alcuronium, pancuronium or succinylcholine, although many clinical reports related to hypersensitivity reactions due to muscle relaxants can be found. In this experiment, the histamine releasing activities of trimethaphan and muscle relaxants were examined using the laboratory model created by Ellis (1970) who reported the selective release of histamine due to d-tubocurarine. Also observed the effects of autonomic neuro-effective drugs such as theophylline, isoproterenol or carbamylcholine on histamine release due to d-tubocurarine. From this experiment, it is suggested that trimethaphan releases histamine through nonselective process but muscle relaxants release histamine selectively. It is also found that pancuronium had little effects on rat mast cells and its histamine releasing activity was selective, if any. Histamine release from rat mast cells due to d-tubocurarine was clearly depressed by pretreatment of theophylline or isoproterenol. In the case of carbamylcholine, low doses inhibited histamine release, but higher doses allowed histamine to be liberated from mast cells. From these findings, it is concluded that some drugs like theophylline or isoproterenol may diminish the side effects of d-tubocurarine and perhaps some other muscle relaxants. Also, as theophylline and isoproterenol are concerned, increase of cyclic AMP may play a role in the inhibition of histamine release. The data using carbamylcholine suggested that the cholinergic receptors on the rat mast cells may be involved through the process of histamine release.

Alcuronium↗
PubMed1981

Deliberate hypotension and anesthetic requirements of halothane.

Following determination of minimum alveolar anesthetic concentration (MAC) of halothane during normotension, 18 dogs were divided into three groups. Dogs in each group then received either pentolinium, trimethaphan, or sodium nitroprusside, and mean arterial pressure was decreased to 60% of control values for 1 hour. The MAC of halothane was determined during hypotension and then arterial pressure was returned to control values and MAC was redetermined at normotension. The MAC of halothane decreased significantly during hypotension in all three groups: in the pentolinium group from a control MAC of 1.2 +/- 0.14 (SEM) to a MAC of 0.7 +/- 0.11 during hypotension, in the trimethaphan group from a control MAC of 1.02 +/- 0.06 to a MAC of 0.72 +/- 0.07 during hypotension, and in the nitroprusside group from a control MAC of 1.02 +/- 0.07 to a MAC of 0.73 +/- 0.07 during hypotension. Upon return of mean arterial pressure to normotensive levels, MAC of halothane returned to control values in dogs given pentolinium and trimethaphan, but in dogs given nitroprusside MAC remained at the hypotensive value. There was no correlation between the changes in MAC and carotid blood flow or cardiac index. These data indicate that anesthetic requirements decrease during deliberate hypotension irrespective of the drug used to produce hypotension.

Anesthesia, Inhalation↗
PubMed1994

Nitroglycerin inhibits experimental thrombosis and reocclusion after thrombolysis.

Nitroglycerin inhibits platelet aggregation in vitro, but its effect on thrombosis and platelet function in vivo is controversial. This study assessed the effect of nitroglycerin on primary thrombus formation in response to vessel wall injury and secondary thrombus formation, or rethrombosis, after lysis of an existing thrombus. In the first protocol the right carotid artery was instrumented with a flow probe, stenosis, an anodal electrode, and a proximal infusion line. A 300 microA anodal current was used to induce endothelial injury and subsequent thrombotic occlusion of the vessel. Anisoylated plasminogen streptokinase activator complex (APSAC; 0.05 U/kg intraarterially) was injected proximal to the thrombus 30 minutes after occlusion. After APSAC, nitroglycerin (1 microgram/kg/min intraarterially, n = 7) or vehicle (n = 6) was infused proximal to the thrombus for 3 hours. Reocclusion occurred in two of seven nitroglycerin-treated dogs and six of six vehicle-treated dogs (p < 0.05). In the second protocol both carotid arteries were instrumented as described previously. Anodal current (300 microA, 180 minutes) was applied to the right carotid (n = 12) artery to determine control times to occlusion. The left carotid artery served as the test vessel, receiving either nitroglycerin (1 microgram/kg/min intraarterially, n = 6) or trimethaphan (0.05 mg/kg/hr intraarterially, n = 6). Trimethaphan was used to produce controlled hypotension to match the approximately 10% decrease in mean arterial blood pressure that was observed during nitroglycerin infusion. Control arteries and those treated with trimethaphan formed occlusive thrombi in all instances. Nitroglycerin infusion resulted in a lower incidence of occlusion (1 of 6; p < 0.05 vs control value) and inhibited ex vivo platelet aggregation to adenosine diphosphate and arachidonic acid (p < 0.05). Local infusion of nitroglycerin reduced the formation of primary thrombi, independent of the hypotensive effect of the drug, and exerted systemic effects on platelet aggregation. Furthermore, platelet inhibition with nitroglycerin reduced the incidence of secondary thrombus formation (rethrombosis) after thrombolysis. The results suggest that a potential benefit of nitroglycerin therapy may be derived from its ability to inhibit thrombotic events in patients with unstable angina or myocardial infarction.

Animals↗
PubMed1989

Mechanism of action of neurotensin at the ileocecal sphincter region.

UNLABELLED: Neurotensin, a neuropeptide identified in the distal small intestine, plays an unclear role in ileocecal sphincter regional function. The purpose of this study was to determine the effect and mechanism of action of neurotensin on the feline ileocecal sphincter (ICS), proximal colon, and distal ileum. Intraluminal pressures were recorded at these sites in anesthetized cats after superior mesenteric artery injection of neurotensin. Dose dependent tonic and phasic contractions were seen at all sites. Peak pressure responses were seen at the maximal dose used and were greater for the ICS than the distal ileum and the proximal colon. The threshold dose for peak pressures for neurotensin was 0.05 microgram/kg for all sites with the maximal peak pressures occurring at the maximal dose used (100 micrograms/kg). The motility index (MI [number of contractions x mean amplitude of contractions]) was determined for three minutes before and after neurotensin injection. The change in the motility index after neurotensin increased at doses above 0.05 micrograms/kg for the ileum and the ICS and 0.25 microgram/kg for the colon. Maximal responses for the motility index were seen at 1 microgram/kg for the distal ileum, and 10 micrograms/kg for the ICS and the proximal colon, with the greatest response seen at the ICS. Neurotensin-induced ICS relaxation was seen at 1 microgram/kg (50 +/- 10%, p less than 0.01) in 33% of cats. The contractile responses of the distal ileum and the proximal colon were not inhibited by naloxone, trimethaphan, tetrodotoxin, or atropine. The ICS contractile response was decreased by tetrodotoxin by 53%, p less than 0.05. The alpha 2 antagonist, yohimbine reduced the neurotensin induced ICS contraction from 31.6 +/- 3.4 to 21.9 +/- 3.3 mm Hg, p less than 0.05. Prazosin had no effect on neurotensin-induced contractions. In the presence of cimetidine and diphenhydramine, trimethaphan did not affect the neurotensin-induced contractile response at all three sites. However, neurotensin inhibited contractions induced by trimethaphan alone at all three sites. CONCLUSIONS: 1. Neurotensin causes a dose-dependent contractile response at the distal ileum, ICS, and proximal colon. 2. Neurotensin has an inhibitory effect at all three sites. 3. The contractile response at the distal ileum and the proximal colon is mediated via smooth muscle receptors. 4. The contractile response of neurotensin at the ICS is mediated partly via alpha 2 receptors and partly via smooth muscle receptors.

Animals↗
PubMed2002

Is autonomic support of arterial blood pressure related to habitual exercise status in healthy men?

We determined if the tonic autonomic nervous system (ANS) contribution to arterial blood pressure (BP) maintenance in humans is related to habitual endurance exercise status. Twenty-three healthy young (age 18-31 years) males, 11 endurance exercise-trained and 12 untrained, were studied. Maximal oxygen consumption was higher (P < 0.001) and resting heart rate and body fatness were lower (P < 0.05) in the exercise-trained men. Plasma noradrenaline concentrations and BP decreased from baseline levels in response to ganglionic blockade (intravenous trimethaphan) in both groups (all P < 0.001). The absolute (Delta mmHg: systolic = -35 +/- 2 vs. -32 +/- 4; diastolic = -13 +/- 2 vs. -10 +/- 2; mean = -21 +/- 2 vs. -17 +/- 3) and relative (Delta%: systolic = -35 +/- 2 vs. -31 +/- 3; diastolic = -26 +/- 3 vs. -20 +/- 3; mean = -31 +/- 2 vs. -26 +/- 3) decreases in BP were not significantly different between the endurance-trained and untrained men. There were no significant group differences in the heart rate, stroke volume, cardiac output or systemic vascular resistance (conductance) responses to trimethaphan. Systemic vascular alpha-adrenergic sensitivity (slope of the increase in mean BP with incremental phenylephrine infusion during ganglionic blockade) also did not differ in the two groups (endurance-trained: 3.2 +/- 0.5; untrained: 3.2 +/- 0.7 mmHg (ng phenylephrine)(-1) (ml plasma)(-1)). In the pooled sample, the decrease in mean BP during trimethaphan was related to baseline and changes in plasma noradrenaline concentrations (r = 0.58-0.65, P < 0.001) and alpha-adrenergic sensitivity (r = 0.49, P < 0.02). Our results suggest that the endurance exercise-trained state is not obviously associated with altered ANS support of BP in healthy young men. Basal sympathetic nervous system (SNS) activity and alpha-adrenergic vascular sensitivity are significant physiological correlates of ANS support of BP in this population.

Adolescent↗
PubMed1999

Effects of central and peripheral nicotinic blockade on human nicotine discrimination.

Nicotine produces interoceptive stimulus effects in humans, which may be critical in understanding tobacco use. It has not yet clearly been demonstrated that discrimination of nicotine, or any drug, in humans is due to its central effects. We compared effects of mecamylamine (10 mg p.o.), a central and peripheral nicotine antagonist, on nicotine discrimination with those of trimethaphan (10-40 microg/kg per min i.v.), a peripheral nicotine antagonist only, and placebo. Smokers (n = 6) were first trained to reliably discriminate 0 versus 20 microg/kg nicotine by nasal spray and then tested on generalization of this discrimination across a range of nicotine doses (0, 3, 6, 12, 20 microg/kg) following antagonist/placebo pretreatment. Nicotine self-administration was also assessed after generalization testing by having participants intermittently choose between nicotine versus placebo spray. Compared with responding following placebo pre-treatment, discrimination of the highest dose of nicotine was significantly attenuated following mecamylamine but not trimethaphan. Similar results were observed for some subjective responses to nicotine. Mecamylamine also tended to increase nicotine self-administration. Consistent with previous animal studies, these results suggest that discriminative stimulus effects of nicotine in humans are mediated at least in part by its central effects.

Adult↗
PubMed1999

Cerebral blood-flow responses to induced hypotension and to CO2 inhalation in patients with major cerebral artery occlusive disease: a positron-emission tomography study.

Our aim was to study the relationship between cerebral blood flow (CBF) responses to induced hypotension and to CO2 inhalation in patients with occlusive disease of the carotid or middle cerebral arteries. In 13 patients (8 men, 5 women) aged 31-73 years (mean +/- 1 SD = 63.2 +/- 10.6), regional CBF values during the resting state (CBFrest), 7% CO2 inhalation (CBFhypercapnia), and hypotension induced by 10-20 microg/kg/min intravenous trimethaphan (CBFhypotension) were measured using positron-emission tomography (PET) with H2(15)O. The % CBF change during induced hypotension (% CBFhypotension) was defined as (CBFhypotension - CBFrest)/CBFrest multiplied by 100. The % CBF change during CO2 inhalation (% CBFhypercapnia) was defined as (CBFhypercapnia - CBFrest)/CBFrest/mm Hg arterial partial pressure of CO2 x 100. We defined symptomatic hemispheres as those with a stenotic or occlusive lesion with neurological symptoms or signs and asymptomatic hemispheres as those which had a similar lesion and/or were influenced by the collateral flow pattern without neurological symptoms. In the territory of the occlusive lesion, % CBFhypotension correlated significantly with % CBFhypercapnia (r = 0.793, P < 0.002) in the symptomatic hemispheres. In the brain regions in which trimethaphan did not induce a reduction in CBF. % CBFhypercapnia was 6.13 +/- 1.79. In those in which % CBFhypotension ranged from 0 to -5, from -5 to -10, and more than -10%, % CBFhypercapnia was 4.05 +/- 1.99, 3.21 +/- 1.17, and 1.73 +/- 1.61, respectively, with significant differences between each pair of groups. In the asymptomatic hemispheres, % CBFhypotension also correlated with % CBFhypercapnia (r = 0.979, P < 0.0001). Failure to maintain CBF during induced hypotension was associated with diminished cerebrovascular vasoreactivity to hypercapnia in patients with arterial disease. This may indicate that failure of autoregulation can be assessed by the CBF response to both induced hypotension and CO2 inhalation. From the technical point of view, estimation of the CO2 response may be useful for assessing failure of autoregulation.

Administration, Inhalation↗
PubMed2002

Local sympathetic function in human skeletal muscle and adipose tissue assessed by microdialysis.

BACKGROUND: In response to stressors and pathophysiologic conditions, sympathetic neuronal outflows can change heterogeneously among body organs and tissues. This study examined the validity of microdialysis and measurements of microdialysate concentrations of catechols, to assess local sympathetic function in skeletal muscle and adipose tissue in humans. METHODS: Based on preliminary experiments, a microdialysate perfusion rate of 3 microl/min and collection duration of 30 minutes were chosen. To assess responses to a stimulus that increases sympathetic outflow to skeletal muscle, microdialysate norepinephrine and dihydroxyphenylglycol concentrations in quadriceps muscle, abdominal subcutaneous adipose tissue, and plasma were measured during orthostasis in 8 healthy normal volunteers. To assess responses to decreased postganglionic sympathetic nerve traffic, norepinephrine and dihydroxyphenylglycol concentrations were measured during i. v. infusion of trimethaphan in 5 volunteers. RESULTS: All subjects had detectable norepinephrine and dihydroxyphenylglycol in microdialysate from both skeletal muscle and adipose tissue. Orthostasis significantly increased microdialysate norepinephrine in skeletal muscle (0.38 +/- (SEM) 0.07 nmol/L supine to 1.48+/-0.24 nmol/L standing, p < 0.01) and in adipose tissue (0.31+/-0.02 nmol/L supine to 0.68+/-0.11 nmol/L standing, p < 0.01). Orthostasis also increased microdialysate dihydroxyphenylglycol in both tissues (1.76+/-0.30 nmol/L to 3.08+/-0.43 nmol/L, p < 0.01; 1.37+/-0.15 nmol/L supine to 1.99+/-0.34 nmol/L standing, p < 0.01). Trimethaphan decreased norepinephrine concentrations in skeletal muscle microdialysate by 50%, adipose tissue by 70%, and antecubital venous plasma 50%, with non-significant decreases in dihydroxyphenylglycol concentrations at each site. CONCLUSIONS: Microdialysate concentrations of norepinephrine and dihydroxyphenylglycol can be detected reliably and respond appropriately during manipulations that increase or decrease the sympathetically mediated release and turnover of norepinephrine. This approach may provide a means to assess sympathetic neuronal function in skeletal muscle and adipose tissue in humans with known or suspected dysautonomias.

Adipose Tissue↗
PubMed1994

Prevention of organophosphate intoxication with presynaptic cholinergic blockers.

In Vivo cardiovascular neuromuscular preparation of rats was used to study the prophylaxis and mechanism of diisopropyl fluorophosphate (DFP) intoxication by presynaptic cholinolytic agents (ganglionic blocking agents), including hexamethonium, trimethaphan and mecamylamine. The lethal action of DFP was partially or completely prevented by pretreatment of rats with hexamethonium (10 mg/kg), trimethaphan (80 mg/kg) and mecamylamine (30 mg/kg). Combined use of these drugs with 2-PAM (100 mg/kg) improved further the prophylaxis of DFP lethality. The mechanism of prophylaxis could be due to the reduction of acetylcholine turnover and accumulation at the synaptic cleft as hemicholinium prevented the DFP intoxication efficiently. In all cases, DFP caused cardiovascular suppression before neuromuscular blockade indicating that the cardiovascular system is much more sensitive than the neuromuscular junction to DFP intoxication.

Animals↗
PubMed1986

Nicotinic-cholinergic involvement in arginine-vasopressin response to insulin-induced hypoglycemia in normal men.

In order to establish whether arginine-vasopressin (AVP) release in response to insulin-induced hypoglycemia is mediated by a muscarinic and/or nicotinic cholinergic pathway, 12 normal men had an insulin tolerance test (ITT) in basal conditions and after treatment with the muscarinic receptor blocker pirenzepine (40 mg IV (intravenously) ten minutes before ITT in six subjects) or the nicotinic receptor antagonist trimethaphan (0.3 mg/min X 30 min IV before ITT in six subjects). The drugs did not modify arterial blood pressure nor produce side effects capable of altering AVP secretion. Pirenzepine administration did not change AVP response to hypoglycemia, whereas trimethaphan significantly reduced AVP increase by about 50% during the ITT. These data suggest the involvement of a cholinergic-nicotinic mechanism in regulation of AVP response to hypoglycemia.

Adult↗
PubMed1989

Dopaminergic, but not cholinergic, involvement in regulation of hypoglycemia-induced oxytocin release in man.

The plasma oxytocin response to insulin-induced hypoglycemia was evaluated in 20 normal male subjects in the basal state (insulin tolerance test (ITT) alone) and after pretreatment with the muscarinic antagonist pirenzepine (40 mg IV 10 min before the ITT in six subjects), the nicotinic antagonist trimethaphan (0.3 mg/min IV for 30 min before the ITT in six subjects), and the dopaminergic receptor agonist bromocriptine (2.5 mg PO 1 hr before the ITT in eight subjects). The drugs did not modify arterial blood pressure nor produce side effects capable of altering oxytocin secretion. Neither pirenzepine nor trimethaphan administration changed the oxytocin response to hypoglycemia, whereas bromocriptine significantly reduced the oxytocin increase during the ITT. These data suggest the involvement of dopaminergic, but not of cholinergic, muscarinic or nicotinic, receptors in the oxytocin response to hypoglycemia.

Adult↗
PubMed2001

Pharmacological differences between immunoisolated native brain and heterologously expressed rat alpha4beta2 nicotinic receptors.

Native brain and heterologously expressed rat alpha4beta2 nicotinic receptors (in Xenopus oocytes and CV-1 cells) were immunoisolated with the anti-alpha4 antibody mAb 299 and their pharmacological properties were compared using [3H](+/-)epibatidine, the novel N-alkylnicotinium analog N-n-octylnicotinium iodide (NONI), and the ganglionic antagonist trimethaphan (TRM). The equilibrium dissociation constant (K(d)) for [3H](+/-)epibatidine binding to the native and heterologously expressed receptors ranged from 13 to 21 pM. The Hill coefficients for [3H](+/-)epibatidine binding to the native and expressed receptors ranged from 0.8 to 1.1 and were consistent with a single high-affinity site. NONI inhibited 30 pM [3H](+/-)epibatidine binding to the native and expressed receptors with similar potency (IC(50) values of 6-7 microM). However, [3H](+/-)epibatidine dissociated 2-3 times more slowly from the native, than from the expressed receptors and TRM inhibited 30 pM [3H](+/-)epibatidine binding to the native receptors (IC(50) value of 330 microM) less potently than it did to the receptors expressed in oocytes (IC(50) value of 16 microM) or CV-1 cells (IC(50) value of 55 microM). The differences between the native and expressed [3H](+/-)epibatidine dissociation rate constants and IC(50) values for TRM were significant for both host cell types, although the values for the CV-1-expressed receptors were closer to the native ones than were those for the oocyte-expressed receptors. Thus, the epibatidine and trimethaphan binding sites in native and expressed alpha4beta2 receptors appear to have significantly different structural or chemical properties.

Animals↗
PubMed1994

Aging and cardiovascular responsiveness to beta-agonist in humans: role of changes in beta-receptor responses versus baroreflex activity.

OBJECTIVES: To assess age-related changes in the cardiac chronotropic and inotropic responses and arterial responses to beta-receptor stimulation and the potential role of the arterial baroreflex on these responses. METHODS AND RESULTS: Isoproterenol alone was infused in 14 young subjects (age, 30 +/- 2 years) and 15 older healthy volunteers (age, 60 +/- 2 years) and together with ganglionic blockade (trimethaphan) in eight young and eight older subjects. Isoproterenol was infused at 3 to 4 incremental rates. Cardiac function was assessed by echocardiography and peripheral arterial responses were measured by venous occlusion plethysmography. Before ganglionic blockade, isoproterenol at infusion rates from 0.005 to 0.03 micrograms/kg/min caused similar changes in heart rate, ejection fraction, and mean normalized systolic ejection rate in the young and older subjects. With concomitant use of trimethaphan, isoproterenol at infusion rates from 0.0025 to 0.01 micrograms/kg/min caused in young subjects a larger increase in heart rate (29 +/- 2 beats/min [young] versus 20 +/- 3 [older] at peak infusion; p = 0.03), ejection fraction (11% +/- 2% [young] versus 6% +/- 1% [older]; p < 0.01), and mean normalized systolic ejection rate (1.13 +/- 0.2 ml/sec [young] versus 0.48 +/- 0.09 [older]; p < 0.01). Whereas percentage changes in total peripheral resistance were larger in the young subjects, there were no significant age-related differences in the responses of forearm blood flow and resistance before or after ganglionic blockade. CONCLUSIONS: These results indicate an age-related decrease in beta-receptor responsiveness of both sinoatrial node and ventricular myocardium that is masked by a concomitant decrease in the baroreflex control of the heart.

Adult↗
PubMed1975

Intracranial pressure during hypotension and subsequent vasopressor therapy in anesthetized cats.

The effects of vasopressor therapy on intracranial pressure (ICP) during hypotension were evaluated in 45 adult cats anesthetized with pentobarbital and hyperventilated via an endotracheal tube with nitrous oxide, 70 per cent, and oxygen, 30 per cent, to maintain Paco2 25 plus or minus 5 torr. Hypotension was induced by intravenous administration of trimethaphan camsylate or sodium nitroferricyanide and by hemorrhage. Vasopressor (norepinephrine, ephedrine, or isoproterenol) administration in the absence of hypotension caused slight transient increases in ICP. Trimethaphan produced increases in ICP averaging 4.3 mm Hg, while sodium nitroferricyanide caused no change and hemorrhage decreased ICP by 3.9 mm Hg. After hypotension was established, vasopressors caused increases in ICP of 1-21 mm Hg. The greatest increase was seen with norepinephrine administration during sodium nitroferricyanide-induced hypotension. Increases in ICP were pronounced in absolute magnitude and rapidity of rise but were of short duration (2 to 5 minutes). The elevation of pressure might be of clinical significance in patients who have pre-existing intracranial hypertension or space-occupying lesions.

Anesthesia, Inhalation↗
PubMed1990

Attenuation of arterial baroreceptor reflex response to acute hypovolemia during induced hypotension.

Preservation of the arterial baroreflex response is important to restore cardiac output and blood pressure by reflex sympathetic nerve activation in the event of sudden hypotension caused by acute blood loss during surgery. However, the arterial baroreflex may be significantly attenuated by both anesthetics and hypotensive agents. In isoflurane-anesthetized dogs, the authors investigated the arterial baroreflex response 1) to bolus injections of sodium nitroprusside (SNP), prostaglandin E1 (PGE1) and trimethaphan (TM); and 2) to rapid blood loss (5 ml/kg) before and during induced hypotension with SNP, PGE1, and TM by measuring mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA). Hypotension produced by both SNP and PGE1 was accompanied by an increase in RSNA and HR. The increase in RSNA and HR following the SNP bolus injection was significantly greater than that following injection of PGE1 (P less than 0.05). Trimethaphan was associated with a decrease in RSNA and HR. Rapid blood loss resulted in the same degree of MAP reduction (20 +/- 2 mmHg) before and during induced hypotension. Sensitivities of baroreflex, as evaluated by ratios of maximum changes in RSNA or HR to MAP (delta RSNA/delta MAP, delta HR/delta MAP), in response to rapid blood loss, were significantly suppressed during continuously induced hypotension, as compared with responses before induced hypotension. Despite the same degree of induced hypotension (70 +/- 5 mmHg of MAP), delta RSNA/delta MAP and delta HR/delta MAP in response to rapid blood loss were significantly greater with PGE1 than those with SNP (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗
PubMed1998

Hypoxia causes apnea during epidural anesthesia in rabbits.

BACKGROUND: Although pulmonary function is minimally changed by neuraxial blockade in most cases, ventilatory arrest may ensue in rare cases. The authors examined the mechanism of apnea in a rabbit model of sudden ventilatory arrest during the combination of epidural anesthesia and hypoxia. METHODS: Rabbits were studied during alpha-chloralose sedation and spontaneous ventilation through a tracheostomy tube. Heart rate and mean arterial pressure were monitored by intraarterial cannulation. Respiratory rate and tidal volume were measured by pneumotachograph. Responses were recorded during administration of oxygen at inspired oxygen concentrations of 11% for 2.5 min and 0% for 40 s, before and after either thoracolumbar epidural blockade (0.4 ml/kg lidocaine, 1.5%) or intramuscular lidocaine (15 mg/kg). In a third group of animals, epinephrine was given intravenously during epidural blockade to return mean arterial pressure to baseline values before hypoxia. In a fourth group of animals, which did not get lidocaine, sympathetic blockade and hypotension were produced with intravenously administered trimethaphan rather than epidural blockade. RESULTS: Thoracolumbar epidural anesthesia decreased mean arterial pressure from 76 +/- 4 mmHg (mean +/- SE) to 42 +/- 2 mmHg. Apnea during hypoxia occurred in 90% of these animals (nine of ten) but in only 11% of animals (one of nine) after intramuscularly administered lidocaine (P < 0.01). Treatment of epidural hypotension with epinephrine prevented apnea (zero of nine animals). Apnea during hypoxia occurred in 50% (three of six) of animals given trimethaphan. Apnea in all groups was sudden in onset, with no preceding decreases in respiratory rate or tidal volume. CONCLUSIONS: Epidural anesthesia results in a narrowed margin of safety for oxygen delivery to the brain and predisposes subjects to ventilatory arrest during hypoxia. This results from the combined effects of decreased blood oxygen content, which is due to decreased inspired oxygen concentration superimposed on circulatory depression due to neural blockade.

Anesthesia, Epidural↗
PubMed1995

On the existence of functional angiotensin II receptors on vascular sympathetic nerve terminals in the human forearm.

OBJECTIVE: The existence of presynaptic angiotensin II receptors, modulating the release of the sympathetic neurotransmitter norepinephrine, was examined in the perfused human forearm model. DESIGN AND METHODS: In three groups out of a total of 20 healthy volunteers, intra-arterial infusions of tracer amounts of tritiated norepinephrine were given to measure forearm spillover and total plasma appearance rate of norepinephrine during intra-arterial infusions of angiotensin II (0.02, 0.2 and 2 ng/kg per min), methoxamine (0.08, 0.4 and 2 micrograms/kg per min) to produce vasoconstriction by stimulating alpha 1-adrenoceptors and saralasin (0.5 ng/kg per min) to block angiotensin II receptors. Postganglionic sympathoneural activity was stimulated by intravenous infusion of sodium nitroprusside (about 1.3 ng/kg per min) or attenuated by intravenous infusion of trimethaphan (about 1 mg/min). RESULTS: Angiotensin II failed to increase the spillover and total plasma appearance rate of norepinephrine, when given without additional treatment or during sodium nitroprusside or trimethaphan administration. In contrast, the spillover of norepinephrine even decreased during angiotensin II administration, both before and during intravenous sodium nitroprusside administration, probably because of angiotensin II-induced forearm vasoconstriction. Similar vasoconstrictor doses of angiotensin II and methoxamine produced similar changes in spillover and total plasma appearance rate of norepinephrine. The highest dose of angiotensin II increased diastolic blood pressure by 9% and decreased the pulse rate by 6%. Saralasin affected the spillover and total plasma appearance rate of norepinephrine neither before nor during intravenous sodium nitroprusside infusion. CONCLUSION: The present results fail to support the view that angiotensin II receptors exert stimulatory modulatory effects on norepinephrine release from sympathetic nerves in the human forearm, at rest or during changes in sympathoneural outflow.

Adult↗
PubMed2002

Heterogeneity of autonomic regulation in hypertension and neurovascular contact.

OBJECTIVE: Brainstem neurovascular contact (NVC) may interfere with central autonomic regulation and contribute to essential hypertension. We have previously shown that patients with autosomal-dominant hypertension, brachydactyly, and NVC feature extreme phenylephrine hypersensitivity due to impaired baroreflex buffering. We tested the hypothesis that similar abnormalities are present in patients with essential hypertension who have NVC. METHODS: Six patients with NVC and essential hypertension and five patients with NVC and monogenic hypertension and brachydactyly were studied. Responses to incremental phenylephrine doses were assessed before and during ganglionic blockade with trimethaphan. RESULTS: Supine blood pressure was 172 +/- 8.8/89 +/- 6.1 mmHg before ganglionic blockade. Blood pressure decreased 47 +/- 5/18 +/- 3 mmHg with trimethaphan (16 +/- 4.4/4 +/- 4.0 mmHg in autosomal-dominant hypertension, P < 0.05). Before ganglionic blockade, 25 microg phenylephrine increased systolic blood pressure 17 +/- 4 mmHg in patients with essential hypertension and 30 +/- 3 mmHg in patients with autosomal-dominant hypertension (P < 0.05). During ganglionic blockade, the same dose increased systolic blood pressure 32 +/- 1 and 33 +/- 4 mmHg in patients with essential and with autosomal-dominant hypertension, respectively (NS). CONCLUSIONS: Phenylephrine hypersensitivity due to baroreflex dysfunction is uncommon in patients with essential hypertension and NVC. This finding may suggest that the effect of NVC on autonomic regulation is heterogeneous. An alternative explanation is that radiological NVC is not necessarily functionally relevant.

Antihypertensive Agents↗