Mechanistic involvement of noradrenergic neuronal neurotransmitter release in cutaneous vasoconstriction during autonomic dysreflexia in persons with spinal cord injury.

INTRODUCTION: Autonomic dysreflexia (AD) is a potentially life-threatening consequence in high (above T6) spinal cord injury that involves multiple incompletely understood mechanisms. While peripheral arteriolar vasoconstriction, which controls systemic vascular resistance, is documented to be pronounced during AD, the pathophysiological neurovascular junction mechanisms of this vasoconstriction are undefined. One hypothesized mechanism is increased neuronal release of norepinephrine and co-transmitters. We tested this by examining the effects of blockade of pre-synaptic neural release of norepinephrine and co-transmitters on cutaneous vasoconstriction during AD, using a novel non-invasive technique; bretylium (BT) iontophoresis followed by skin blood flow measurements via laser doppler flowmetry (LDF). METHODS: Bretylium, a sympathetic neuronal blocking agent (blocks release of norepinephrine and co-transmitters) was applied iontophoretically to the skin of a sensate (arm) and insensate (leg) area in 8 males with motor complete tetraplegia. An nearby untreated site served as control (CON). Cutaneous vascular conductance (CVC) was measured (CVC = LDF/mean arterial pressure) at normotension before AD was elicited by bladder stimulation. The percent drop in CVC values from pre-AD vs. AD was compared among BT and CON sites in sensate and insensate areas. RESULTS: There was a significant effect of treatment but no significant effect of limb/sensation or interaction of limb x treatment on CVC. The percent drop in CVC between BT and CON treated sites was 25.7±1.75 vs. 39.4±0.87, respectively (P = 0.004). CONCLUSION: Bretylium attenuates, but does not fully abolish vasoconstriction during AD. This suggests release of norepinephrine and cotransmitters from cutaneous sympathetic nerves is involved in cutaneous vasoconstriction during AD.

Bretylium, a Class III Antiarrhythmic, Returns to the Market.

Bretylium, with an extensive pharmacologic and medicinal history, was approved by the United States Food and Drug Administration in 1986 for "short-term prevention and treatment of ventricular fibrillation (VF) and treatment of life-threatening ventricular arrhythmias and ventricular tachycardia (VT) unresponsive to adequate doses of a first-line antiarrhythmic agent, such as lidocaine." The NDA sponsor withdrew bretylium from the market in 2011, largely due to unavailability of raw materials required for its production; prior to this, bretylium was removed from the 2000 ACLS Guidelines algorithm for VF/pulseless VT given the challenges obtaining raw materials for drug manufacture. Recently, bretylium has been reintroduced into the US market by a generic pharmaceutical company with the same indications as before. This article provides a history of the salient trials evaluating the efficacy and safety of bretylium and looks to the future as bretylium finds its place in the modern day management of ventricular arrhythmia.

Comparative effectiveness of antiarrhythmics for out-of-hospital cardiac arrest: A systematic review and network meta-analysis.

BACKGROUND: Despite their wide use in the prehospital setting, randomized control trials (RCTs) have failed to demonstrate that any antiarrhythmic agent improves survival to hospital discharge following out-of-hospital cardiac arrest. OBJECTIVE: To assess the use of antiarrhythmic drugs for patients experiencing out-of-hospital cardiac arrest (OHCA). METHODS: Electronic searches of Medline, EMBASE and Cochrane Central Register of Controlled Trials were conducted and reference lists were hand-searched. Randomized controlled trials (RCTs) investigating the use of antiarrhythmic agents administered during resuscitation for adult (≥18years) patients suffering non-traumatic OHCA were included. Direct and indirect evidence were combined in a network meta-analysis (NMA) using a frequentist approach with fixed-effects models and reported as relative risks (RR) with 95% confidence intervals (CIs). For each pairwise comparison, the certainty of direct, indirect, and network evidence was assessed using the GRADE approach. RESULTS: 8 RCTs involving 4464 patients were combined to compare the effectiveness of 5 antiarrhythmic agents and placebo administered during resuscitation following OHCA. Lidocaine was associated with a statistically significant increase in ROSC compared to placebo (1.15; 95% CI: 1.03-1.28) and was also superior to bretylium (1.61; 95% CI: 1.00-2.60) for ROSC. When compared to placebo, both amiodarone (1.18; 95% CI: 1.08-1.30) and lidocaine (1.18; 95% CI: 1.07-1.30) were associated with a statistically significant increase in survival to hospital admission. However, no antiarrhythmic was statistically more effective than placebo for survival to hospital discharge or neurologically intact survival, and no antiarrhythmic was convincingly superior to any other for any outcome. CONCLUSIONS: Amiodarone and lidocaine were the only agents associated with improved survival to hospital admission in the NMA. For the outcomes most important to patients, survival to hospital discharge and neurologically intact survival, no antiarrhythmic was convincingly superior to any other or to placebo.

Amiodarone supplants lidocaine in ACLS and CPR protocols.

Amiodarone is an antiarrhythmic medication used to treat and prevent certain types of serious, life-threatening ventricular arrhythmias. Amiodarone gained slow acceptance outside the specialized field of cardiac antiarrhythmic surgery because the side-effects are significant. Recent adoption of amiodarone in the ACLS (Advanced Cardiac Life Support) protocol has somewhat popularized this class of antiarrhythmics. Its use is slowly expanding in the acute medicine setting of anesthetics. This article summarizes the use of Amiodarone by anesthesiologists in the operating room and during cardiopulmonary resuscitation.

Cold-induced vasoconstriction at forearm and hand skin sites: the effect of age.

During mild cold exposure, elderly are at risk of hypothermia. In humans, glabrous skin at the hands is well adapted as a heat exchanger. Evidence exists that elderly show equal vasoconstriction due to local cooling at the ventral forearm, yet no age effects on vasoconstriction at hand skin have been studied. Here, we tested the hypotheses that at hand sites (a) elderly show equal vasoconstriction due to local cooling and (b) elderly show reduced response to noradrenergic stimuli. Skin perfusion and mean arterial pressure were measured in 16 young adults (Y: 18-28 years) and 16 elderly (E: 68-78 years). To study the effect of local vasoconstriction mechanisms local sympathetic nerve terminals were blocked by bretylium (BR). Baseline local skin temperature was clamped at 33 degrees C. Next, local temperature was reduced to 24 degrees C. After 15 min of local cooling, noradrenaline (NA) was administered to study the effect of neural vasoconstriction mechanisms. No significant age effect was observed in vasoconstriction due to local cooling at BR sites. After NA, vasoconstriction at the forearm showed a significant age effect; however, no significant age effect was found at the hand sites. [Change in CVC (% from baseline): Forearm Y: -76 +/- 3 vs. E: -60 +/- 5 (P < 0.01), dorsal hand Y: -74 +/- 4 vs. E: -72 +/- 4 (n.s.), ventral hand Y: -80 +/- 7 vs. E: -70 +/- 11 (n.s.)]. In conclusion, in contrast to results from the ventral forearm, elderly did not show a blunted response to local cooling and noradrenaline at hand skin sites. This indicates that at hand skin the noradrenergic mechanism of vasoconstriction is maintained with age.

Survival after prolonged resuscitation with 99 defibrillations due to Torsade De Pointes cardiac electrical storm: a case report.

A 48-year-old previously healthy woman suffered witnessed cardiac arrest in hospital. She achieved return of spontaneous circulation and was transferred to the intensive care unit. During the following 3 hours, she suffered a cardiac electrical storm with 98 episodes of Torsade de Pointes ventricular tachycardia rapidly degenerating to ventricular fibrillation. She was converted with a total of 99 defibrillations. There was no response to the use of any recommended anti arrhythmic drugs. However, the use of bretylium surprisingly stabilized her heart rhythm and facilitated placing of a temporary pacemaker. Overdrive pacing prevented further arrhythmias and was life saving. A number of beneficial factors may have contributed to the good neurological outcome. Further investigations gave no explanation for her cardiac electrical storm.

Nervous and humoral catecholaminergic control of blood pressure and cardiac performance in the Antarctic fish Pagothenia borchgrevinki.

The role of circulating and neural catecholamines for cardiovascular control in the Antarctic fish Pagothenia borchgrevinki was studied in vivo using pharmacological tools and with immunohistochemistry on isolated tissues. Adrenergic nerve blockade with bretylium decreased dorsal aortic pressure (P(da)) and systemic vascular resistance (R(sys)), while cardiac output (Q) did not change. The blockade of alpha-adrenoceptors with phentolamine reduced P(da) and R(sys) further, revealing that vasomotor tone was influenced by circulating catecholamines in bretylium treated fish. The physiological evidence for an adrenergic nervous control of the vasculature was corroborated by the presence of tyrosine hydroxylase (TH)-immunoreactive fibres associated with blood vessels in spleen, gonads and gastrointestinal tract. TH-immunoreactive fibres were not observed in the atrium and ventricle, but a dense population of TH-immunoreactive fibres was apparent in the bulbus arteriosus. The present study suggests that an adrenergic nervous mechanism is responsible for maintaining vasomotor tone in P. borchgrevinki. While experiments failed to demonstrate a tonic adrenergic nervous influence affecting cardiac performance, an adrenergic nervous control of bulbar compliance may be essential for optimizing gill blood flow dynamics in this species, which has a high relative stroke volume and displays profound changes in stroke volume in vivo.

Arrhythmia and acute coronary syndrome suppression and cardiac resuscitation management with bretylium.

It is well known that electric shock can both initiate and terminate ventricular fibrillation. Refractory ventricular fibrillation (RVF) may often be an iatrogenic paradoxical result of early, frequent, excessive salvos of DC current countershocks and inappropriate off-label drug use, particularly aggressive epinephrine administration. Evidence suggests that the current advanced cardiac life support pharmacology protocol for cardiac resuscitation may contribute to disappointing survival in patients with out-of-hospital cardiac arrest. Controlled studies and new theoretical consideration suggest the protocol may induce RVF. In contrast, studies suggest that immediate adequate intravenous bretylium administration therapy together with sustained effective chest compressions can induce chemical defibrillation or facilitate electrical defibrillation as well as reduce the intensity, or even need for potentially heart-damaging countershock, where early frequent excessive current shocks are likely to increase refractory arrhythmia as demonstrated in animals and in humans. Salvos of shocks do not allow time between shocks for uniform recovery of normal electrical parameters needed to restore a stable heart rhythm. This may occur by inadvertently administering shock during the vulnerable period of the cardiac cycle. There are compelling existing data to demonstrate that bretylium and cardiopulmonary resuscitation (CPR) delivered before initiating shock therapy is likely to provide the best outcome in cardiac arrest. But, most importantly, adequate CPR chest compressions administered while bretylium is being infused also provide the opportunity to wash out electrically destabilizing electrolytes that have leaked from or are abnormally transported by functionally damaged membranes of fibrillation-induced ischemic myocytes. This may cause abnormal compartment redistribution of electrolytes that may facilitate RVF by heterogeneously partially depolarizing ischemic myocytes. Although efforts have been made to provide hard science for advanced life support, the guidelines are a product of consensus, the give and take of collegiality and intuition rather than rigorous controlled studies. Bretylium has a direct antifibrillatory action normalizing myocyte membrane currents, which restores intracompartmental normal electrolyte balance. In addition, adrenergic blockade by bretylium dilates coronary arteries, increasing effective O2 delivery by CPR. The free and aggressive use of epinephrine is toxic. Catechalomines cause coronary spasm and puts myocardial metabolism into damaging hypermetabolic overdrive to support the "fight or flight reflex" rapidly depleting adenosine triphosphate needed for cardiac electrical and mechanical recovery. Moreover, the value of epinephrine to resuscitation has never been demonstrated in a controlled human study, whereas its potential damage has been largely ignored. Epinephrine's potential deleterious actions that might compromise resuscitation are well established and reviewed here.

Investigation of the role of adrenergic and non-nitrergic, non-adrenergic neurotransmission in the sheep isolated internal anal sphincter.

Nitric oxide is widely established as an important neurotransmitter in the control of anal sphincter tone; although, a number of other transmitters have also been tentatively implicated. Whilst alpha-adrenoceptor antagonists reduce anal sphincter pressure in man, the role of noradrenaline as a possible transmitter is poorly characterised. We have investigated the contribution of these transmitters to neurogenic relaxations, and evaluated the possible role of a non-nitrergic, non-adrenergic transmitter. The magnitude and duration of neurogenic responses were examined by measuring responses to electrical field stimulation (EFS) in segments of sheep internal anal sphincter following the development of spontaneous myogenic tone. Neurogenic relaxations induced by EFS were significantly reduced in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME) suggesting major involvement of nitric oxide as a neurotransmitter. The duration of neurogenic relaxations was inversely related to the frequency of EFS, with contractile responses often manifest at higher frequencies. The duration of relaxations at high frequencies of EFS was increased by bretylium (adrenergic neurone blocker) and prazosin (alpha(1)-adrenoceptor antagonist). At higher frequencies of EFS, 60% of preparations also produced a residual non-nitrergic, non-adrenergic, apamin-sensitive relaxation which was unaffected by vasoactive intestinal polypeptide (VIP) and inhibitors of purinergic responses [suramin, pyridoxal-phosphate-6-azophenyl 2',4' disulfonic acid (PPADS) and alpha,beta-methylene adenosine triphosphate (ATP)]. However, MRS2179 (P2Y(1) receptor antagonist) showed a modest inhibitory effect. We conclude that endogenous noradrenaline acts via postjunctional alpha(1)-adrenoceptors to antagonize neurogenic relaxations that are largely mediated by nitric oxide. Our results indicate the involvement of a non-nitrergic, non-adrenergic, apamin-sensitive transmitter which is inhibited by MRS2179, suggesting a possible role for purines.

Nervous and humoral control of cardiac performance in the winter flounder (Pleuronectes americanus).

Previous studies have suggested that flatfish lack adrenergic cardiac innervation and have a limited humoral adrenergic stress response. However, data on neurohormonal control of flatfish cardiac function is scarce, and has never been directly studied in vivo. Hence, we (1) injected neural and humoral antagonists into flounder (Pleuronectes americanus) in vivo to determine the contribution of autonomic innervation and circulating catecholamines to the control of resting cardiac function; (2) measured pre- and post-stress (90 s chase) catecholamine levels in this species; and (3) constructed in vivo catecholamine dose-response curves for cardiovascular function based on the results of the second experiment. In addition, we quantified the density (B(max)) and ligand-binding affinity (Kd) of flounder ventricular cell-surface beta-adrenoreceptors, and established whether they were of beta1 or beta2 subtype using pharmacological antagonists. The cholinergic contribution to resting flounder heart rate was comparable to other teleosts (cholinergic tonus 26%). Interestingly, however, bretylium increased heart rate, resulting in a negative resting adrenergic tonus (-11.9%), and we were unable to demonstrate that catecholamines supported cardiac function at rest or at circulating concentrations approximating those following an exhaustive chase (adrenaline, 21 nmol l(-1); noradrenaline, 14 nmol l(-1)). Myocardial B(max) was very high in the flounder (252.8 fmol mg(-1) protein), and it appears that flounder ventricular beta-adrenoreceptors are predominantly of the beta2 subtype [based on the inability of atenolol to displace [3H]CGP from the beta-adrenoreceptors, and the IC(50) value for ICI 118551 (1.91 x 10(-6) mol l(-1))]. However, the extremely low affinity (Kd 1.02 nmol l(-1)) for these receptors raises the possibility that the flounder heart is also populated by beta3-adrenoreceptors.

The involvement of heating rate and vasoconstrictor nerves in the cutaneous vasodilator response to skin warming.

Slow local skin heating (LH) causes vasodilator responses, some of which are dependent on sympathetic nerve function. It is not known, however, how the rate of LH affects either the sympathetic or the nonadrenergic components of the responses to LH and whether the adrenergic effects of LH depend on tonic sympathetic activity or whether LH stimulates transmitter release. In part 1, cutaneous vascular conductance (CVC) responses to slow and fast LH (+0.1 degrees and +2 degrees C/min) from 34 degrees to 40 degrees C were compared both at control sites and at sites pretreated with bretylium tosylate (BT; blocks transmitter release from adrenergic terminals). We confirmed, as previously found, the axon reflex (AR) response to slow LH to be blocked by BT (P < 0.05). Pretreatment with BT reduced the AR only with fast LH. BT inhibited the peak vasodilation achieved with both rates of LH (P < 0.05). Longer-term LH was associated with a slow fall in CVC, the classical "die away" phenomenon, at untreated sites (P < 0.05) but not at BT-pretreated sites. Thus the LH-stimulated AR is only partially dependent on intact sympathetic function, and the "die away" phenomenon is dependent on such function. In part 2, we tested whether the conditions in part 1 (whole body and local skin temperatures of 34 degrees C) completely suppressed sympathetic nerve activity. The infusion of BT by microdialysis did not change the CVC (P > 0.05), suggesting the absence of tonic activity in those conditions and therefore that the adrenergic components of the responses in part 1 are via the stimulation of the transmitter release by LH.

Bretylium abolishes neurotransmitter release without necessarily abolishing the nerve terminal action potential in sympathetic terminals.

BACKGROUND AND PURPOSE: The antidysrhythmic bretylium is useful experimentally because it selectively abolishes neurotransmitter release from sympathetic peripheral nerve terminals. Its mechanism of action seemed settled, but recent results from optical monitoring of single terminals now suggests a new interpretation. EXPERIMENTAL APPROACH: Orthograde transport of a dextran-conjugated Ca(2+) indicator to monitor Ca(2+) in nerve terminals of mouse isolated vas deferens with a confocal microscope. In some experiments, local neurotransmitter release was detected by monitoring neuroeffector Ca(2+) transients (NCTs) in adjacent smooth muscles, a local measure of purinergic transmission. Sympathetic terminals were identified with catecholamine fluorescence (UV excitation) or post-experiment immunohistochemistry. KEY RESULTS: Bretylium (10 microM) abolished NCTs at 60/61 junctions over the course of 2 h, indicating effective abolition of neurotransmitter release. However, bretylium did not abolish the field stimulus-induced Ca(2+) transient in most nerve terminals, but did increase both action potential delay (by 2+/-0.4 ms) and absolute refractory period (by 4+/-2 ms). Immunohistochemistry demonstrated that 85-96% of terminals orthogradely filled with a dextran-conjugated fluorescent probe contained Neuropeptide Y (NPY). A formaldehyde-glutaraldehyde-induced catecholamine fluorescence (FAGLU) technique was modified to allow sympathetic terminals to be identified with a Ca(2+) indicator present. Most terminals contained catecholamines (based on FAGLU) or secrete ATP (as NCTs in adjacent smooth muscle cells are abolished). CONCLUSIONS AND IMPLICATIONS: Bretylium can inhibit neurotransmitter release downstream of Ca(2+) influx without abolishing the nerve terminal action potential. Bretylium-induced increases in the absolute refractory period permit living sympathetic terminals to be identified.

Cholinergic innervation of the guinea-pig isolated vas deferens.

Recently, a cholinergic neurogenic component of contraction has been characterised in the aganglionic mouse vas deferens. In this paper, a cholinergic component of contraction in the guinea-pig vas deferens is characterised pharmacologically. A residual, tetrodotoxin-sensitive (TTX, 0.3 microM), neurogenic contraction was revealed after prolonged exposure (5 h) to the adrenergic neurone blocker bretylium (20 microM) or in the presence of prazosin (100 nM) and alpha,beta-methylene ATP (1 microM), a purinergic agonist which desensitizes P2X receptors. The bretylium-resistant component was potentiated by the acetylcholinesterase (AChE) inhibitor neostigmine (10 microM) and inhibited by the muscarinic-receptor (mAChR) antagonist cyclopentolate (1 microM). Nicotine (30 microM) enhanced the bretylium-resistant component. Neostigmine increased the second component of contraction in the presence of prazosin and alpha,beta-methylene ATP, whilst yohimbine (1 microM), an alpha(2) adrenergic receptor antagonist, enhanced both the first and second components of the electrically evoked contraction. These enhanced contractions were blocked by cyclopentolate in both cases. Nicotine enhanced the cholinergic component of contraction revealed by neostigmine but failed to have any detectable effects in the presence of cyclopentolate. Neostigmine alone increased the slow component of contraction which was reversed by cyclopentolate to control levels. The M(3) receptor-antagonist 4-DAMP (10 nM) markedly inhibited the cholinergic component of contraction to a level comparable with cyclopentolate. Laser microscopy has shown that neostigmine also increased the frequency of spontaneous Ca(2+) transients remaining in smooth muscle cells after perfusion with prazosin and alpha,beta-methylene ATP, an effect blocked by 4-DAMP. These experimental data show that there is a functional cholinergic innervation in the guinea-pig vas deferens whose action is limited by acetylcholinesterase, blocked by cyclopentolate and mediated through M3 receptors. Moreover, by blocking the cholinesterase, the increased amount of ACh generates spontaneous Ca(2+) transients in smooth muscle cells.

Influence of hyperoxia on skin vasomotor control in normothermic and heat-stressed humans.

Hyperoxia induces skin vasoconstriction in humans, but the mechanism is still unclear. In the present study we examined whether the vasoconstrictor response to hyperoxia is through activated adrenergic function (protocol 1) or through inhibitory effects on nitric oxide synthase (NOS) and/or cyclooxygenase (COX) (protocol 2). We also tested whether any such vasoconstrictor effect is altered by body heating. In protocol 1 (n = 11 male subjects), release of norepinephrine from adrenergic terminals in the forearm skin was blocked locally by iontophoresis of bretylium (BT). In protocol 2, the NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) and the nonselective COX antagonist ketorolac (Keto) were separately administered by intradermal microdialysis in 11 male subjects. In the two protocols, subjects breathed 21% (room air) or 100% O(2) in both normothermia and hyperthermia. Skin blood flow (SkBF) was monitored by laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as the ratio of SkBF to blood pressure measured by Finapres. In protocol 1, breathing 100% O(2) decreased (P < 0.05) CVC at the BT-treated and at untreated sites from the levels of CVC during 21% O(2) breathing both in normothermia and hyperthermia. In protocol 2, the administration of l-NAME inhibited (P < 0.05) the reduction of CVC during 100% O(2) breathing in both thermal conditions. The administration of Keto inhibited (P < 0.05) the reduction of CVC during 100% O(2) breathing in hyperthermia but not in normothermia. These results suggest that skin vasoconstriction with hyperoxia is partly due to the decreased activity of functional NOS in normothermia and hyperthermia. We found no significant role for adrenergic mechanisms in hyperoxic vasoconstriction. Decreased production of vasodilator prostaglandins may play a role in hyperoxia-induced cutaneous vasoconstriction in heat-stressed humans.

The effect of the sympathetic and sensory nervous system on active eustachian tube function in the rat.

CONCLUSION: We propose that simultaneous activation of the sensory and sympathetic nervous system may adversely affect eustachian tube function, which may have a role in the genesis of Ménière's disease. OBJECTIVE: We have determined the distribution of sympathetic and nociceptive sensory axons in the mucosa of the rat eustachian tube and investigated whether sympathetic or nociceptive neurons influence the function of the eustachian tube. MATERIALS AND METHODS: We tested whether the ability of a rat to equalize air pressure in the middle ear during evoked swallowing was altered by activation or blockade of the local sympathetic nervous system, or by stimulation of nociceptive neurons with capsaicin. RESULTS: Sympathetic axons were sparse, but CGRP-immunoreactive, nociceptive axons formed a dense subepithelial plexus beneath the eustachian tube epithelium. Neither the adrenergic blocking drug, bretylium, nor electrical stimulation of the superior cervical ganglion significantly altered eustachian tube function. Capsaicin alone did not affect eustachian tube function but capsaicin applied with an alpha adrenoceptor agonist impaired the function of the eustachian tube. Capsaicin applied to the bulla also increased spontaneous swallowing in anaesthetized rats and this effect was enhanced by addition of an alpha adrenoceptor agonist and by stimulation of the superior cervical ganglion.

Adrenergic control of venous capacitance during moderate hypoxia in the rainbow trout (Oncorhynchus mykiss): role of neural and circulating catecholamines.

Central venous blood pressure (P(ven)) increases in response to hypoxia in rainbow trout (Oncorhynchus mykiss), but details on the control mechanisms of the venous vasculature during hypoxia have not been studied in fish. Basic cardiovascular variables including P(ven), dorsal aortic blood pressure, cardiac output, and heart rate were monitored in vivo during normoxia and moderate hypoxia (P(W)O(2) = approximately 9 kPa), where P(W)O(2) is water oxygen partial pressure. Venous capacitance curves for normoxia and hypoxia were constructed at 80-100, 90-110, and 100-120% of total blood volume by transiently (8 s) occluding the ventral aorta and measure P(ven) during circulatory arrest to estimate the mean circulatory filling pressure (MCFP). This allowed for estimates of hypoxia-induced changes in unstressed blood volume (USBV) and venous compliance. MCFP increased due to a decreased USBV at all blood volumes during hypoxia. These venous responses were blocked by alpha-adrenoceptor blockade with prazosin (1 mg/kg body mass). MCFP still increased during hypoxia after pretreatment with the adrenergic nerve-blocking agent bretylium (10 mg/kg body mass), but the decrease in USBV only persisted at 80-100% blood volume, whereas vascular capacitance decreased significantly at 90-110% blood volume. In all treatments, hypoxia typically reduced heart rate while cardiac output was maintained through a compensatory increase in stroke volume. Despite the markedly reduced response in venous capacitance after adrenergic blockade, P(ven) always increased in response to hypoxia. This study reveals that venous capacitance in rainbow trout is actively modulated in response to hypoxia by an alpha-adrenergic mechanism with both humoral and neural components.