Administration Of Catecholamines Research Articles

On the Failure of Insulin to Affect Hyperglycemia During Cardiac Surgery

In Response: We greatly appreciate Dr. Schricker’s comments concerning our study (1) and the interesting topic of control of intraoperative hyperglycemia during cardiac surgery with cardiopulmonary bypass (CPB). His questions centered on our methodology and the observations that our protocol did not affect intraoperative glucose, although postoperative glucose was lower in the group that received insulin. As Dr. Schricker surmised, the duration of insulin administration was limited to time on CPB. Insulin was administered centrally through tubing that was not preconditioned to decrease binding. The patients were comparable with regards to preoperative medications, intraoperative fluid replacement, blood product transfusions, amount of cell saver blood replaced, and catecholamine administration. Five patients in the control group and three patients in the insulin group received catecholamine infusions during the time of separation from CPB, for an average time duration of 30 and 45 min, respectively. The anesthetic agents were comparable between groups. The initial heparin dose that was administered was indeed weight-based, but the two groups received similar doses overall (32,439 U and 33,071 U on average for the control and insulin groups, respectively, P = 0.869). This likely reflects the subsequent doses administered in response to activated clotting times, as it is well known that the response to heparin dosing is highly variable. While the group receiving insulin did indeed have a greater body mass index (BMI), upon multivariate analysis this factor did not affect glucose levels. Our study is in agreement with previously published observations by Chaney et al. that an intraoperative insulin infusion leads to lower postoperative glucose levels but unchanged intraoperative levels (2). As Dr. Schricker observes, Chaney et al. continued their insulin protocol through the period of sternal closure (2) and our protocol ceased insulin at the time of separation from CPB. It should be noted that the primary stimulus for hyperglycemia during cardiac surgery is CPB (3). Hence, once this profound stimulus ceases, it is not surprising that normal glucose control returns quickly, and the exogenous insulin administered will have an additive effect. This would be expected to lead to lower postoperative glucose levels. We strongly agree with Dr. Schricker’s concerns against allowing patients to remain hyperglycemic, especially given the recent exciting findings of Van den Berghe et al. (4). It must be noted that CPB is a potent stimulus for hyperglycemia (3), as well as an activator of the inflammatory response (5). While the hyperglycemia associated with CPB has been recognized for many years, the impact of this transient alteration in glucose control in the face of the activation of the systemic inflammatory response is poorly understood. We previously found that diabetic patients undergoing CPB have improved neutrophil phagocytosis and improved intraoperative glycemic control with an aggressive insulin infusion (6). However, the issue of hyperglycemia associated with CPB and nondiabetic patients is incompletely understood. Indeed, we were prompted to study this issue in light of the lack of consensus as to the importance of hyperglycemia during CPB in this patient population. Athos J. Rassias, MD Mark P. Yeager, MD

Is electrical stimulation during administration of catecholamines required for the evaluation of success after ablation of atrioventricular node re-entrant tachycardias?

Is electrical stimulation during administration of catecholamines required for the evaluation of success after ablation of atrioventricular node re-entrant tachycardias?

Extrabranchial chemoreceptors involved in respiratory reflexes in the neotropical fish Colossoma macropomum (the tambaqui).

In a previous study, complete denervation of the gills in the tambaqui Colossoma macropomum did not eliminate the increase in breathing amplitude seen during exposure of this species to hypoxia. The present study was designed to examine other sites of putative O(2)-sensitive receptors that could be involved in this reflex action. Superfusion of the exposed brain of decerebrate, spinalectomized fish did not reveal the presence of central chemoreceptors responsive to hyperoxic, hypoxic, hypercarbic, acidic or alkaline solutions. Subsequent central transection of cranial nerve IX and X, removing not only all innervation of the gills but also sensory input from the lateral-line, cardiac and visceral branches of the vagus nerve, did not eliminate the increase in breathing amplitude that remained following peripheral gill denervation alone. Administration of exogenous catecholamines (10 and 100 nmol kg(-1) adrenaline) to fish with intact brains and minimal surgical preparation reduced both respiratory frequency and amplitude, suggesting that humoral release of adrenaline also could not be responsible for the increase in breathing amplitude that remained following gill denervation. Denervation of the mandibular branches of cranial nerve V and the opercular and palatine branches of cranial nerve VII in gill-denervated fish (either peripheral gill denervation or central section of cranial nerves IX and X), however, did eliminate the response. Thus, our data suggest that hypoxic and hyperoxic ventilatory responses as well as ventilatory responses to internal and external injections of NaCN in the tambaqui arise from O(2)-sensitive receptors in the orobranchial cavity innervated by cranial nerves V and VII and O(2)-sensitive receptors on the gills innervated by cranial nerves IX and X. Our results also revealed the presence of receptors in the gills that account for all of the increase in ventilation amplitude and part of the increase in ventilation frequency during hyperoxic hypercarbia, a group or groups of receptors, which may be external to the orobranchial cavity (but not in the central nervous system), that contribute to the increase in ventilation frequency seen in response to hyperoxic hypercarbia and the possible presence of CO(2)-sensitive receptors that inhibit ventilation frequency, possibly in the olfactory epithelium.

Calcium and Beta Receptor Antagonist Overdose: A Review and Update of Pharmacological Principles and Management

Calcium channel and beta-adrenergic receptor antagonists are common pharmaceutical agents with multiple overlapping clinical indications. When used appropriately, these agents are safe and efficacious. In overdose, however, these agents have the potential for serious morbidity. Calcium channel blockers and beta blockers share similar physiological effects on the cardiovascular system, such as hypotension and bradycardia, in overdose and occasionally at therapeutic doses. The initial management for symptomatic overdose of both drug classes consists of supportive care measures. Other therapies including administration of glucagon, calcium, catecholamines, phosphodiesterase inhibitors and insulin have been used with varying degrees of success. In addition, intra-aortic balloon pump and extracorporeal membrane oxygenation techniques have been successfully utilized in refractory cases. This article reviews beta blocker and calcium channel blocker pharmacological principles and updates current management strategies.

Is electrical stimulation during administration of catecholamines required for the evaluation of success after ablation of atrioventricular node re-entrant tachycardias?

ObjectivesThe purpose of this study was to answer the question of whether stimulation after administration of catecholamines is mandatory for identifying unsuccessful ablations of atrioventricular node re-entrant tachycardia (AVNRT). BackgroundThe success of radiofrequency (RF) catheter ablation in AVNRT is confirmed in many centers by noninducibility of tachycardias during stimulation after the administration of catecholamines. MethodsA total of 131 patients (81 women and 50 men; mean age 53.6 ± 13.7 years [range 20 to 77]) were studied. Electrical stimulation was performed without and with the beta-adrenergic amine Orciprenaline (metaproterenol) before and after RF catheter ablation. ResultsIn 100 patients (76.3%; confidence interval [CI] 68.1% to 83.3%) an AVNRT was inducible without administration of Orciprenaline. Thirty minutes after the initially successful ablation in 95 patients, tachycardia was inducible in none of these patients, not even after Orciprenaline administration. In the 31 patients (23.7%; CI 16.7% to 31.9%) in whom there was no tachycardia inducible before ablation, Orciprenaline was given, and the stimulation protocol was repeated. In only five patients (3.8%; CI 1.3% to 8.7%) was there still no tachycardia inducible. After an initially successful ablation in the 26 patients who had inducible tachycardias with Orciprenaline before ablation, no tachycardia could be re-induced. After Orciprenaline, the tachycardia was inducible again in only one patient. ConclusionsOnly patients who require catecholamines for tachycardia induction before ablation need catecholamines for control of the success of the ablation of AVNRT.

Metabolic Modulation

featured in this issue of Circulation presents data showingthat pyruvate, which dose-dependently improved perfor-mance in myocardium from failing human hearts, may be onesuch agent.A number of abnormalities in both energy metabolism andcontractile function have been identified in failing cardiacmuscle. Metabolic changes include decreases in high energyphosphorylation potential, decreases in mitochondrial oxida-tive phosphorylation capacity, and a switch to a more fetalglycolytic metabolism.

Adrenergic Regulation of Lipid Mobilization in Fishes; a Possible Role in Hypoxia Survival

Lipids are for fish the major energy source. The nutritional conditions of most species vary throughout the year considerably. Thus storage and mobilization of lipids have to be tightly controlled, yet little is known about its control. Though several hormones are known to have a lipolytic effect, short term regulation of lipolysis is known for catecholamines only. Catecholamines are usually released under stress conditions, including hypoxia. In mammals these hormones have a strong lipolytic action, causing high plasma fatty acids levels during hypoxia. In contrast to mammals, several fish species show a decrease of plasma FFA-levels during hypoxia and anoxia. However, some studies gave contrasting results when catecholamines were administrated to different fish species. The reason for this may be due to opposing effects of catecholamines on lipolysis in different tissues. From catecholamine administration experiments in cannulated carp there is evidence that norepinephrine inhibits lipolysis via β1- and β3- adrenoceptors while β2-adrenoceptors are involved in stimulation of lipolysis. Thus the opposite responses of different β-adrenoceptors may explain the conflicting in-vivo results obtained with fish. In vitro studies with adipocytes from different fish species confirm that activation of β-adrenoceptors suppresses lipolysis, while the opposite occurs in hepatocytes. Inhibiting β1- and β3- adrenoceptors in adipocytes were shown to be involved. Under hypoxia β-oxidation is inhibited, resulting in accumulation of fatty acids together with intermediates of the β-oxidation. This process may cause severe cellular damage in mammalian tissues, which ‘apparently’ does not occur in fishes. Fishes encounter (environmental) hypoxia on a regular basis, while for mammals hypoxia/anoxia is a pathological phenomenon. Hence the suppression of lipolysis in fishes under hypoxia (by β1- and β3- adrenoceptors) may be considered as a survival mechanism lost in higher vertebrates.

Indocyanine green elimination rate detects hepatocellular dysfunction early in septic shock and correlates with survival.

To determine whether indocyanine green clearance is an early indicator of hepatocellular injury in septic shock and to assess its predictive value. Observational study with prospective data collection. Traumatology and critical care unit in a city hospital, staffed by traumatology and intensive care clinicians. Twelve patients in septic shock who survived at least 2 months (group S) and nine patients who died within 2 wks (group N). Routine resuscitation from septic shock (surgery, fluid loading, and administration of catecholamines and antibiotic drugs). Pulmonary artery occlusion pressure, cardiac index, oxygen delivery index, oxygen consumption index, and the indocyanine green elimination rate constant (KICG; or the slope of the loge [indocyanine green concentration] vs. time curve) 3-9 mins after injection were measured within 12 hrs of the onset of hypotension, then at 24 hrs, and every 24 hrs thereafter. Alanine aminotransferase and total bilirubin were measured on day 0 and day 1. Volume of fluid administered and duration of shock were the same in survivors and nonsurvivors. The oxygen consumption index was higher in survivors at 12 hrs, but no intergroup difference in pulmonary artery occlusion pressure, cardiac index, or oxygen delivery index was significant at any time point. KICG in nonsurvivors was lower than in survivors both initially and after 24 hrs, and it was subnormal in all patients except one survivor (p <.05). The KICG increased between 24 and 120 hrs in 11 survivors but progressively decreased and remained below 0.05 in seven nonsurvivors. The remaining two nonsurvivors died within 24 hrs of the initial measurement of KICG, which was >0.05. Alanine aminotransferase and total bilirubin were less sensitive measures of hepatic dysfunction in the first 24 hrs than the KICG. The KICG can identify reversible liver injury in septic shock, suggesting good prognosis. Either failure to increase the KICG within 120 hrs or an extremely low KICG is a poor prognostic sign.

High-frequency jet ventilation in life-threatening bilateral pulmonary contusion.

TRAUMA is the leading cause of death among young people in developed countries. 1 Because up to 80% of trauma deaths occur during the first 24 h after trauma, 1 early resuscitation and rapid assessment of trauma lesions are of paramount importance to improving the prognosis. Among traumatic lesions, pulmonary contusion is frequent but has not been recognized as an independent prognosis factor. 2-4 In very few cases, pulmonary contusion may lead to severe hypoxia and hypercarbia, which cannot be adequately controlled using conventional mechanical ventilation. Hypoxia and hypercarbia may have deleterious effects, such as enhancement of brain injury and development of circulatory shock. 5 In the most severe cases, aggressive therapeutic methods, such as extracorporeal membrane oxygenation (ECMO), have been reported. 6 At our institution, high-frequency jet ventilation (HFJV) has been used routinely for many years for the treatment of severe acute respiratory distress syndrome. 7,8 We report a series of severe trauma patients with life-threatening pulmonary contusion successfully treated with HFJV when the conventional mechanical ventilation approach failed to provide appropriate gas exchange. The current data suggest that HFJV can be a life-saving technique in severely hypoxemic patients with bilateral pulmonary contusion.

Norepinephrine as a growth stimulating factor in bacteria—mechanistic studies

Catecholamines (norepinephrine, epinephrine, dopamine) enhance the growth of several species of gram-negative bacteria. Since catechol rings are known siderophores in bacteria, the administration of catecholamines may enhance growth by improving iron uptake in growth-limiting media, serving as auxiliary siderophores. We have tested the iron content in bacterial growth media which are known to support rapid growth and “slow growth” media. Additionally, we have examined the uptake of 3H-norepinephrine, to determine whether the catecholamine is actually taken into the bacteria or is merely adsorbed to the outside of the bacteria. Finally, we have been examining the supernatants produced by culturing bacteria with norepinephrine. These supernatants have been shown to have the capacity to enhance growth of naive cultures of bacteria, and are suggested to contain an “autoinducer of growth”. We have found that both fast-growth and slow-growth media contain similar concentrations of iron, and that these levels do not change in most supernatants from NE-supplemented bacterial cultures. Examination of culture supernatants from NE-supplemented bacteria under different temperature conditions reveals some interesting differences. First, culture supernatant from NE-treated Escherichia coli, cultured at 37°C, when examined by HPLC, exhibits a change in the norepinephrine content over time which is not seen in supernatant from 21°C cultures or other media treatments. Second, the 37°C culture NE-supplemented E. coli supernatant was significantly more effective in enhancing growth of three bacterial species than any other culture method other than NE-supplementation itself (this includes supernatant from NE-supplemented cultures of the other two species as well as supernatants from unsupplemented cultures of all three species).

Halothane and Sevoflurane Decrease Norepinephrine-Stimulated Glucose Transport in Neonatal Cardiomyocyte

Catecholamine regulates myocardial glucose use. However, the effect of inhaled anesthetics on myocardial glucose transport stimulated by catecholamine is unclear. We studied the effect of halothane and sevoflurane on uptake of 2-deoxyglucose stimulated by norepinephrine in neonatal cardiomyocytes and the mechanism that modulates glucose transport. We studied the effects of halothane and sevoflurane on norepinephrine (NE)-stimulated glucose uptake and the effects of halothane and sevoflurane on glucose uptake stimulated by W7 (a calcium releasing agent), phorbol 12 myristate-13-acetate (a protein kinase C agonist), and LiCl. Sevoflurane decreased NE-stimulated glucose uptake from 63.7 +/- 7.0 to 41.2 +/- 3.7 pmol h(-1) mg protein(-1), and halothane also attenuated NE-stimulated glucose uptake to 37.8 +/- 5.7 pmol h(-1) mg protein(-1). W7 at 10 micromol/L increased glucose uptake from 16.4 +/- 1.4 to 41.2 +/- 3. 4 pmol h(-1) mg protein(-1). The stimulation was inhibited in the presence of 0.8 mmol/L sevoflurane and 0.58 mmol/L halothane to 23.9 +/- 3.7 and 25.6 +/- 3.6 pmol h(-1) mg protein(-1), respectively. Halothane and sevoflurane did not significantly affect the glucose uptake stimulated by 1 nmol/L insulin, 10 micromol/L PMA, or 10 mmol/L LiCl. We conclude that halothane and sevoflurane decrease NE-stimulated glucose uptake through decrease in intracellular calcium in cardiomyocytes. The effect of inhaled anesthetics on myocardial glucose uptake during administration of catecholamine is unclear. The myocardial glucose uptake is stimulated not only by catecholamine, but also by insulin, protein kinase C, and increase of intracellular calcium. We examined the effects of halothane and sevoflurane on glucose uptake.

Vasopressin as an alternative to norepinephrine in the treatment of milrinone-induced hypotension

To determine whether vasopressin could be effective in treating the hypotension associated with phosphodiesterase III inhibition. Phosphodiesterase III inhibitors are cardiotonic agents that increase myocardial contractility and decrease vascular smooth muscle tone. The vasodilatory effect can be profound, and the resulting hypotension frequently requires the administration of catecholamine pressors. Retrospective analysis of existing data. The medical or surgical intensive care unit of Columbia-Presbyterian Medical Center. Three consecutive patients receiving milrinone and requiring catecholamine pressors to maintain systolic arterial pressure of > or =90 mm Hg. Vasopressin was administered to the three patients. Vasopressin (0.03-0.07 units/min) increased systolic arterial pressure from 90+/-4.7 to 130+/-2.3 mm Hg while reducing the administration of catecholamine pressors. Vasopressin at very low doses appears to be an effective vasopressor for milrinone-induced hypotension.

Metformin inhibits catecholamine-stimulated lipolysis in obese, hyperinsulinemic, hypertensive subjects in subcutaneous adipose tissue: an in situ microdialysis study.

Metformin has been reported to decrease the plasma concentrations of non-esterified fatty acids in Type 2 diabetic subjects. This study investigated the effects of metformin on basal and catecholamine-stimulated lipolysis in abdominal subcutaneous adipose tissue of obese, hyperinsulinaemic, hypertensive subjects. Fourteen subjects with severe obesity (12 female, twomale, age 35.4 +/- 4 years, body mass index 48.2 +/- 2 kg/m2, body fat mass 63.3 +/- 5 kg) were recruited. Glycerol and lactate concentrations were determined in the presence of metformin and after administration of catecholamines using microdialysis. Simultaneously, blood flow was assessed with the ethanol escape method. Glycerol release was lowered by metformin during the 3-h experiment (P<0.01). The lipolytic activity of catecholamines was suppressed when adipose tissue was pre-treated with metformin (P<0.001). Lactate concentration increased after application of metformin (P<0.01) and catecholamines (P<0.001). Blood flow was decreased in the presence of adrenaline (P < 0.01), but this effect was abolished by metformin. The present data demonstrate the effects of metformin on lipolysis in subcutaneous adipose tissue in vivo. In the large body fat mass of obese subjects, a reduction of lipolysis in adipose tissue may contribute to a decrease of VLDL synthesis in the liver resulting in a lowered plasma triglyceride concentration.

Vasopressin Deficiency and Pressor Hypersensitivity In Hemodynamically Unstable Organ Donors

Background —Solid organ donors often develop hypotension due to vasodilation, and recently we observed that a variety of vasodilatory states are characterized by vasopressin deficiency and hypersensitivity. Thus, we investigated the prevalence of vasopressin deficiency in hypotensive solid organ donors without clinical evidence of diabetes insipidus; we also investigated the vasopressor effect of vasopressin replacement in hypotensive donors. Methods and Results —Fifty organ donors were evaluated for hemodynamic instability, (mean arterial pressure [MAP]≤ 70 mm Hg despite the use of catecholamine vasopressors), and in those unstable donors who were not already receiving exogenous vasopressin, low-dose vasopressin was administered as a continuous infusion (0.04 to 0.1 U/min). MAP, catecholamine requirements, serum vasopressin, and serum osmolality were obtained before and after vasopressin administration. Ten patients meeting the enrollment criteria received vasopressin and MAP increased from 72.2±3.5 to 89.8±4.2 mm Hg, ( P &lt;0.05), allowing for complete discontinuation of catecholamine pressors in 4 (40%) patients and a decrement in pressor dose in 4 (40%). Plasma vasopressin levels (2.9±0.8 pg/mL) were low for the degree of hypotension. Conclusions —Hemodynamically unstable organ donors without clinically apparent diabetes insipidus display a defect in the baroreflex-mediated secretion of vasopressin. In these patients, low-dose vasopressin significantly increases blood pressure with a pressor response sufficient to reduce catecholamine administration.

Vasopressin deficiency and pressor hypersensitivity in hemodynamically unstable organ donors.

Solid organ donors often develop hypotension due to vasodilation, and recently we observed that a variety of vasodilatory states are characterized by vasopressin deficiency and hypersensitivity. Thus, we investigated the prevalence of vasopressin deficiency in hypotensive solid organ donors without clinical evidence of diabetes insipidus; we also investigated the vasopressor effect of vasopressin replacement in hypotensive donors. Fifty organ donors were evaluated for hemodynamic instability, (mean arterial pressure [MAP]</= 70 mm Hg despite the use of catecholamine vasopressors), and in those unstable donors who were not already receiving exogenous vasopressin, low-dose vasopressin was administered as a continuous infusion (0. 04 to 0.1 U/min). MAP, catecholamine requirements, serum vasopressin, and serum osmolality were obtained before and after vasopressin administration. Ten patients meeting the enrollment criteria received vasopressin and MAP increased from 72.2+/-3.5 to 89.8+/-4.2 mm Hg, (P<0.05), allowing for complete discontinuation of catecholamine pressors in 4 (40%) patients and a decrement in pressor dose in 4 (40%). Plasma vasopressin levels (2.9+/-0.8 pg/mL) were low for the degree of hypotension. Hemodynamically unstable organ donors without clinically apparent diabetes insipidus display a defect in the baroreflex-mediated secretion of vasopressin. In these patients, low-dose vasopressin significantly increases blood pressure with a pressor response sufficient to reduce catecholamine administration.

Alpha-adrenergic blockade restores normal fluid transport capacity of alveolar epithelium after hemorrhagic shock.

Activation of beta-adrenergic receptors in the lung is an important mechanism that can prevent alveolar flooding after brief but severe hemorrhagic shock. However, a neutrophil-dependent oxidant injury to the alveolar epithelium prevents the normal upregulation of alveolar fluid clearance by catecholamines after prolonged hemorrhagic shock. Because hemorrhage increases proinflammatory cytokine expression in the lung partly through the activation of alpha-adrenergic receptors, the objective of this study was to determine whether alpha-adrenergic blockade would restore the normal fluid transport capacity of the alveolar epithelium after hemorrhagic shock. Hemorrhagic shock was associated with a significant increase of interleukin-1beta (IL-1beta) concentration in the lung and a failure of the alveolar epithelium to respond to beta-adrenergic agonists, with the upregulation of vectorial fluid transport despite intra-alveolar administration of exogenous catecholamines. In contrast, catecholamine-mediated upregulation of alveolar liquid clearance was restored by pretreatment with phentolamine, an alpha-adrenergic-receptor antagonist. Phentolamine pretreatment also significantly attenuated the shock-mediated increase of IL-1beta concentration in the lung. Additional experiments demonstrated that the inhibition of IL-1beta binding to its receptor by the administration of IL-1-receptor antagonist restored the normal fluid transport capacity of the alveolar epithelium after hemorrhagic shock. In summary, the results of these studies indicate that the activation of alpha-adrenergic receptors after hemorrhagic shock prevents the beta-adrenergic-dependent upregulation of alveolar fluid clearance by modulating the severity of the pulmonary inflammatory response.

Mechanisms Underlying Immunologic States during Pregnancy: Possible Association of the Sympathetic Nervous System

NK and extrathymic T cells are abundant in the decidua of the pregnant uterus. To determine how this unique pattern is induced, overall populations of leukocytes were examined in the blood and other tissues in pregnant women. Time-kinetic studies showed that a basal change of leukocytes during pregnancy was granulocytosis and lymphocytopenia in the blood. This change might be due to sympathetic nerve activation during pregnancy, because the administration of catecholamine is known to activate myelopoiesis in the bone marrow. In addition to the numerical change, the functional activation of NK and extrathymic T cells also seemed to be present. This might be due to NK cells and extrathymic T cells (as well as granulocytes), which carry a high density of surface adrenergic receptors. Such functional activation of NK and extrathymic T cells was more prominent in the blood and urine in patients with preeclampsia and hyperemesis gravidarum than in normal pregnant women. The present results suggest that the activation of granulocytes, NK cells, and extrathymic T cells is essential for the maintenance of pregnancy but that overactivation thereof may be responsible for the onset of pregnancy disorders.

Inhibition of beta-adrenergic-dependent alveolar epithelial clearance by oxidant mechanisms after hemorrhagic shock.

Endogenous release of catecholamines is an important mechanism that can prevent alveolar flooding after brief but severe hemorrhagic shock. The objective of this study was to determine whether this catecholamine-dependent mechanism upregulates alveolar liquid clearance after prolonged hemorrhagic shock. Rats were hemorrhaged to a mean arterial pressure of 30-35 mmHg for 60 min and then resuscitated with a 4% albumin solution. Alveolar liquid clearance was measured 5 h later as the concentration of protein in the distal air spaces over 1 h after instillation of a 5% albumin solution into one lung. There was no upregulation of alveolar liquid clearance after prolonged hemorrhagic shock and fluid resuscitation despite a significant increase in plasma epinephrine levels. The intravenous or intra-alveolar administration of exogenous catecholamines did not upregulate alveolar liquid clearance. In contrast, catecholamine-mediated upregulation of alveolar liquid clearance was restored either by depletion of neutrophils with vinblastine, by the normalization of the concentration of reduced glutathione in the alveolar epithelial lining fluid by N-acetylcysteine, or by the inhibition of the conversion from xanthine dehydrogenase to xanthine oxidase. These experiments provide the first in vivo evidence that a neutrophil-dependent oxidant injury to the alveolar epithelium prevents the upregulation of alveolar fluid clearance by catecholamines in the absence of a major alteration in paracellular permeability to protein after prolonged hemorrhagic shock.

Catecholamine enhancement ofAeromonas hydrophilagrowth

Several species of bacteria have been shown to respond to the administration of norepinephrine and other catecholamines with increased growth (in culture) and virulence. In this study, we examined the effects of catecholamines on the growth of cultures ofAeromonas hydrophila, a Gram-negative bacillus found in brackish water. Bacterial cultures were maintained in tryptic soy both, then washed free of medium and transferred to a bovine serum-supplemented minimal salts medium. Treatment ofA. hydrophilacultures with 10−3to 10−5M norepinephrine resulted in dramatic increases in growth at 24 h and longer, as assessed by spot plate analysis on tryptic soy agar plates. Norepinephrine-treated cultures had 4.5 log greater bacterial numbers than control cultures. Epinephrine, dopamine and isoproterenol were shown to be similarly effective in enhancing growth ofA. hydrophila, over narrower concentration ranges. Acetylcholine supplementation of cultures did not alter the growth ofA. hydrophila.Serotonin slightly enhancedAeromonasgrowth when administered at very high concentrations (10−3M). The increased growth observed after catecholamine administration may alter the capacity to infect an animal under stressful conditions, and is another potential mechanism by which a stress response can affect susceptibility to disease.

The uncoupling proteins, a review.

The uncoupling protein-1 (UCP1), cloned in 1985 (1– 4) and called UCP until 1997, is an inner mitochondrial membrane protein (5) expressed exclusively in the brown adipocyte (6–8). It dissipates the mitochondrial proton (H) gradient generated by the respiratory chain, producing heat instead of ATP (8, 9). In rodents the brown adipose tissue (BAT) contributes to both the maintenance of body temperature in a cold environment through nonshivering thermogenesis and the control of body weight through the regulatory (or facultative) part of diet-induced thermogenesis (10, 11). It has been shown that during cold acclimation the capacity of brown adipocytes to produce heat is determined by the UCP1 content of their mitochondria (12–14). Several observations led to the hypothesis that there could exist uncoupling proteins in tissues other than BAT. First, adult humans, who possess very little active BAT (15, 16), produce heat in their skeletal muscle in response to glucose or catecholamine administration (17–20). Secondly, mitochondrial H leaks have been observed in tissues devoid of UCP1 (21–23). They may account for up to 50% of the oxygen consumption of some tissues (24, 25), and up to 30% of whole body metabolic rate in the rat (24–26). It was suggested that the H leak was related to resting metabolic rate (27, 28). Supporting the previous observations, several groups independently cloned novel UCPs, i.e. UCP2 (29–31) and UCP3 (31, 32). UCP2 is expressed in most tissues studied in humans and rodents, and UCP3 mainly in skeletal muscle in humans, and BAT and skeletal muscle in rodents (31). UCP1, which was thought to be a protein unique to BAT, is in fact a member of an emerging family of uncoupling proteins expressed in humans and animals, and even in plants (33, 34).