七氟醚抑制脑干吸气前运动神经元的作用机制

研究背景:位于延髓尾部腹侧髓质的神经元是与吸气相关的前运动神经元,它们是支配呼吸肌如膈肌、肋间外肌、肋间内肌等运动神经元的上一级神经元。这些神经元的兴奋状态由NMDA受体,AM PA受体调控,也受抑制性AGBAA能神经调节。作者在去大脑狗的模型上探讨七氟醚对这些突触机制的影响。方法:实验在去大脑狗上进行,并应用迷走神经切断术使其处于瘫痪状态,通过机械通气维持高氧、高碳酸血症。局部微量注射AGBAA受体阻断剂荷包牡丹碱及谷氨酸受体激动剂AMPA、NMDA后,用细胞外记录技术,观测1MAC七氟醚对单个神经元活性的影响。用神经元…     

七氟醚抑制脑干吸气前运动神经元的作用机制

研究背景：位于延髓尾部腹侧髓质的神经元是与吸气相关的前运动神经元，它们是支配呼吸肌如膈肌、肋间外肌、肋间内肌等运动神经元的上一级神经元。这些神经元的兴奋状态由NMDA受体，AM-PA受体调控，也受抑制性AGBA。能神经调节。作者在去大脑狗的模型上探讨七氟醚对这些突触机制的影响。     

Halothane Depresses Glutamatergic Neurotransmission to Brain Stem Inspiratory Premotor Neurons in a Decerebrate Dog Model

Background: Inspiratory bulbospinal neurons in the caudal ventral medulla are premotor neurons that drive phrenic motoneurons and ultimately the diaphragm. Excitatory drive to these neurons is mediated by N-methyl-d-aspartate (NMDA) receptors and [alpha]-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and modulated by an inhibitory [gamma]-aminobutyric acidA (GABAA)ergic input. The authors investigated the effect of halothane on these synaptic mechanisms in decerebrate dogs.

Methods: Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor blocker bicuculline and the glutamate agonists AMPA and NMDA. Complete blockade of the GABAAergic mechanism by bicuculline allowed differentiation between the effects of halothane on overall GABAAergic inhibition and on overall glutamatergic excitation. The neuronal responses to exogenous AMPA and NMDA were used to estimate the anesthetic effect on postsynaptic glutamatergic neurotransmission.

Results: Halothane, 1 MAC, depressed the spontaneous activity of 21 inspiratory neurons by 20.6 +/- 18.0% (mean +/- SD;P = 0.012). Overall glutamatergic excitation was depressed 15.4 +/- 20.2% (P = 0.001), while overall GABAAergic inhibition did not change. The postsynaptic responses to exogenous AMPA and NMDA were also depressed by 18.6 +/- 35.7% (P = 0.03) and 22.2 +/- 26.2% (P = 0.004), respectively.     

Sevoflurane Enhances γ-Aminobutyric Acid Type A Receptor Function and Overall Inhibition of Inspiratory Premotor Neurons in a Decerebrate Dog Model

Background: Inspiratory premotor neurons in the caudal ventral medulla relay excitatory drive to phrenic and inspiratory intercostal motoneurons in the spinal cord. These neurons are subject to tonic [gamma]-aminobutyric acid type A (GABAA)ergic inhibition. In a previous study, 1 minimum alveolar concentration (MAC) sevoflurane depressed overall glutamatergic excitatory drive and enhanced overall GABAAergic inhibitory drive to the neurons. This study investigated in further detail the effects of sevoflurane on GABAAergic inhibition by examining postsynaptic GABAA receptor activity in these neurons.

Methods: Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor antagonist bicuculline and the GABAA agonist muscimol. Complete blockade of GABAAergic inhibition by bicuculline allowed estimation of the prevailing overall inhibition of the neuron. The neuronal response to muscimol was used to assess the anesthetic effect on the postsynaptic GABAA receptor function.

Results: One MAC sevoflurane depressed the spontaneous activity of 21 inspiratory premotor neurons by (mean +/- SD) 32.6 +/- 20.5% (P < 0.001). Overall excitatory drive was depressed 17.9 +/- 19.8% (P < 0.01). Overall GABAAergic inhibition was enhanced by 18.5 +/- 18.2% (P < 0.001), and the postsynaptic GABAA receptor function was increased by 184.4 +/- 121.8% (n = 20; P < 0.001).     

Halothane Enhances γ-Aminobutyric Acid Receptor Type A Function but Does Not Change Overall Inhibition in Inspiratory Premotor Neurons in a Decerebrate Dog Model

Background: Inspiratory premotor neurons in the caudal ventral medulla relay excitatory drive to phrenic and inspiratory intercostal motoneurons in the spinal cord. These neurons are subject to tonic [gamma]-aminobutyric acid type A (GABAA)-mediated (GABAAergic) inhibition. In a previous study, 1 minimum alveolar concentration (MAC) halothane depressed overall glutamatergic excitatory drive but did not change overall inhibitory drive to the neurons. This study investigated in further detail the effects of halothane on GABAAergic inhibition by examining postsynaptic GABAA receptor activity in these neurons.

Methods: Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC halothane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor antagonist bicuculline and the GABAA agonist muscimol. Complete blockade of GABAergic inhibition by bicuculline allowed estimation of the prevailing overall inhibition of the neuron. The neuronal response to muscimol was used to assess the anesthetic effect on the postsynaptic GABAA receptor function.

Results: One minimum alveolar concentration halothane depressed the spontaneous activity of 19 inspiratory premotor neurons by 22.9 +/- 29.1% (mean +/- SD; P < 0.01). Overall excitatory drive was depressed 23.6 +/- 16.9% (P < 0.001). Overall GABAergic inhibition was not changed (+8.7 +/- 27.5%; P = 0.295), but the postsynaptic GABAA receptor function was increased by 110.3 +/- 97.5% (P < 0.001).     

Effects of Halothane and Sevoflurane on Inhibitory Neurotransmission to Medullary Expiratory Neurons in a Decerebrate Dog Model

Background: In canine expiratory bulbospinal neurons, 1 minimum alveolar concentration (MAC) halothane and sevoflurane reduced the glutamatergic excitatory drive at a presynaptic site and enhanced the overall [gamma]-aminobutyric acid (GABA)-mediated inhibitory input. The authors investigated if this inhibitory enhancement was mainly caused by postsynaptic effects.

Methods: Two separate anesthetic studies were performed in two sets of decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC halothane or sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor agonist muscimol and the GABAA receptor antagonist bicuculline. Complete blockade of GABAA-mediated inhibition with bicuculline was used to assess the prevailing overall inhibitory input to the neuron. The neuronal response to muscimol was used to estimate the anesthetic effect on postsynaptic GABAA receptor function.

Results: Halothane at 1 MAC depressed the spontaneous activity of 12 expiratory neurons 22.2 +/- 14.8% (mean +/- SD) and overall glutamatergic excitation 14.5 +/- 17.9%. Overall GABA-mediated inhibition was enhanced 14.1 +/- 17.9% and postsynaptic GABAA receptor function 74.2 +/- 69.2%. Sevoflurane at 1 MAC depressed the spontaneous activity of 23 neurons 20.6 +/- 19.3% and overall excitation 10.6 +/- 21.7%. Overall inhibition was enhanced 15.4 +/- 34.0% and postsynaptic GABAA receptor function 65.0 +/- 70.9%. The effects of halothane and sevoflurane were not statistically different.     

Effects of Sevoflurane on Excitatory Neurotransmission to Medullary Expiratory Neurons and on Phrenic Nerve Activity in a Decerebrate Dog Model

Background: Sevoflurane is a new volatile anesthetic with a pronounced respiratory depressant effect. Synaptic neurotransmission in canine expiratory bulbospinal neurons is mainly mediated by excitatory N-methyl-d-aspartatic acid (NMDA) receptor input and modulated by inhibitory [gamma]-aminobutyric acid type A (GABAA) receptors. The authors investigated the effect of sevoflurane on these mechanisms in decerebrate dogs.

Methods: Studies were performed in decerebrate, vagotomized, paralyzed and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC; 2.4%) sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the glutamate agonist NMDA and the GABAA receptor blocker bicuculline in a two-part protocol. First, complete blockade of the GABAAergic mechanism by bicuculline allowed differentiation between the effects of sevoflurane on overall GABAAergic inhibition and on overall glutamatergic excitation. In a second step, the neuronal response to exogenous NMDA was used to estimate sevoflurane's effect on postsynaptic glutamatergic neurotransmission.

Results: One minimum alveolar concentration sevoflurane depressed the spontaneous activity of 16 expiratory neurons by 36.7 +/- 22.4% (mean +/- SD). Overall glutamatergic excitation was depressed 19.5 +/- 16.2%, and GABAAergic inhibition was enhanced 18.7 +/- 20.6%. However, the postsynaptic response to exogenous NMDA was not significantly altered. In addition, 1 MAC sevoflurane depressed peak phrenic nerve activity by 61.8 +/- 17.7%.     

Effects of Halothane on Excitatory Neurotransmission to Medullary Expiratory Neurons in a Decerebrate Dog Model

Background: The activity of canine expiratory (E) neurons in the caudal ventral respiratory group is primarily dependent on N-methyl-d-aspartic acid (NMDA) receptor-mediated excitatory chemodrive inputs and modulated by an inhibitory mechanism mediated via [gamma]-aminobutyric acidA (GABAA) receptors. In an intact canine preparation, halothane depressed the activity of these neurons mainly by reduction in overall glutamatergic excitation. A new decerebrate preparation allows comparison of the effects of halothane on these synaptic mechanisms with an anesthetic-free baseline state.

Methods: Two separate studies were performed in decerebrate, vagotomized, paralyzed, mechanically ventilated dogs during hypercapnic hyperoxia. In study 1, the effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded E neuronal activity was studied before and during complete GABAA receptor blockade by localized pressure ejection of bicuculline. Complete blockade of the inhibitory mechanism allowed differentiation between the effects of halothane on overall GABAA-mediated inhibition and on overall NMDA receptor-mediated excitation. In study 2, the effect of 1 MAC halothane on the dose response of neurons to localized picoejection of the glutamate agonist NMDA was used to estimate halothane effect on postsynaptic glutamatergic excitatory neurotransmission.

Results: In study 1, the spontaneous activity of 14 E neurons was depressed 38.6 +/- 20.6% (mean +/- SD) by 1 MAC halothane. Overall excitation was depressed 31.5 +/- 15.5%. The GABAergic inhibition showed a 11.7 +/- 18.3% enhancement during halothane. In study 2, the spontaneous activity of 13 E neurons was again significantly depressed by 1 MAC halothane (27.9 +/- 10.6%), but the postsynaptic response of the neurons to exogenous NMDA was not significantly depressed by halothane (3.3 +/- 38.4%).     

Sevoflurane but Not Propofol Preserves Myocardial Function in Coronary Surgery Patients

Background: Sevoflurane has been shown to protect against myocardial ischemia and reperfusion injury in animals. The present study investigated whether these effects were clinically relevant and would protect left ventricular (LV) function during coronary surgery.

Methods: Twenty coronary surgery patients were randomly assigned to receive either target-controlled infusion of propofol or inhalational anesthesia with sevoflurane. Except for this, anesthetic and surgical management was the same in all patients. A high-fidelity pressure catheter was positioned in the left ventricle and the left atrium. LV response to increased cardiac load, obtained by leg elevation, was assessed before and after cardiopulmonary bypass (CPB). Effects on contraction were evaluated by analysis of changes in dP/dtmax. Effects on relaxation were assessed by analysis of the load dependence of myocardial relaxation (R = slope of the relation between time constant [tau] of isovolumic relaxation and end-systolic pressure). Postoperative concentrations of cardiac troponin I were followed during 36 h.

Results: Before CPB, leg elevation slightly increased dP/dtmax in the sevoflurane group (5 +/- 3%), whereas it remained unchanged in the propofol group (1 +/- 6%). After CPB, leg elevation resulted in a decrease in dP/dtmax in the propofol group (-5 +/- 4%), whereas the response in the sevoflurane group was comparable to the response before CPB (5 +/- 4%). Load dependence of LV pressure fall (R) was similar in both groups before CPB. After CPB, R was increased in the propofol group but not in the sevoflurane group. Troponin I concentrations were significantly lower in the sevoflurane than in the propofol group.     

Deciding Not to GO: Neuronal Correlates of Response Selection in a GO/NOGO Task in Primate Premotor and Parietal Cortex

Monkeys performed reaching movements in two opposite directionsin a symmetrically rewarded GO/NOGO task with an instmcted-delayperiod. Instructional cues were presented at the target locations.The decision not to move was clearly reflected in cell activityin dorsal premotor cortex, but not in parietal cortex area 5.In premotor cortex, the initial response (<250 msec) of mostcells to the appearance of the instructional cues in GO andNOGO trials was similar. However, by the end of the delay period,the responses of most cells were statistically different betweenthe two trial types, and the population signals were much lessdirectional in the NOGO trials than in the GO trials. In area5, in contrast single-cell and population signals were generallysimilar and strongly directional in both GO and NOGO trials.This result suggests a role for area 5 in visuomotor analysisfor the guidance of limb movements. It further suggests thatseparate representations of potential motor responses to externalinputs and of the intended response to that input can coexistin parietal and premotor cortex, respectively.     

Renalase, a Novel Enzyme Involved in Blood Pressure Regulation, Is Related to Kidney Function but Not to Blood Pressure in Hemodialysis Patients

Renalase, secreted by the kidney, degrades catecholamines and may play a role in the regulation of sympathetic tone and blood pressure. The aim of this study was to assess serum renalase levels in hemodialysis patients and their relationship to blood pressure control, type of antihypertensive therapy and the presence of residual renal function. Results: The mean serum renalase in the study cohort was significantly higher than in the control group (27.53 ± 7.18 vs. 3.86 ± 0.73 μg/ml, p < 0.001). The serum renalase concentration was significantly lower in patients with residual renal function when compared to the anuric patients. The type of hypotensive treatment (β-blockers, ACE inhibitors or AT1 receptor blockers) did not affect renalase levels. There was a significant inverse correlation between the serum renalase and age (r = -0.28, p = 0.023) and residual renal function (r = -0.327, p = 0.001). Renalase was not related to blood pressure, heart rate or hemodialysis vintage. Conclusion: Elevated renalase levels in HD patients may be due to impaired kidney function. Further studies are needed to prove or disprove the possible role of renalase in the pathogenesis of hypertension in patients with kidney diseases.     

The Midlatency Auditory Evoked Potentials Predict Responsiveness to Verbal Commands in Patients Emerging from Anesthesia with Xenon, Isoflurane, and Sevoflurane but Not with Nitrous Oxide

Background: It has recently been demonstrated that the approximately 40-Hz spectral power of the midlatency auditory evoked potential (MLAEP) correlates well with wakefulness during desflurane or propofol anesthesia. The aim of this study was to characterize how other inhalational anesthetics affects the MLAEP as the patients regain responsiveness to simple verbal command during emergence from anesthesia.

Methods: Sixty patients were randomly assigned to receive xenon, isoflurane, sevoflurane, or nitrous oxide (N2O) supplemented with epidural anesthesia. During emergence, the concentration of an anesthetic was decreased in 0.1-minimum alveolar concentration (MAC) decrements from 0.8 MAC or from 70% in the case of N2O, and each new concentration was maintained for 15 min. Every 5 min during each equilibration period, the MLAEP was recorded and the patients were asked to open their eyes and squeeze and release the investigator's hand. This process was repeated until the first response to either of these commands was observed.

Results: Thirteen patients were excluded because of technical reasons. The preanesthetic MLAEP showed a periodic waveform, where the Na-Pa-Nb complex was the most prominent component contributing to the high energy around 29-39 Hz in the power spectrum. Emergence from xenon, isoflurane, and sevoflurane anesthesia produced similar changes in the MLAEP. The spectral power for the frequency 29 Hz or greater was severely suppressed at 0.8 MAC but significantly recovered between the concentration only 0.1 MAC higher that permitting the first response to command and that associated with the first response. In contrast, N2O hardly affected the MLAEPs, even at the concentrations producing unresponsiveness. Two patients did not lose responsiveness even at the highest concentration tested (70%).     

Sevoflurane depresses glutamatergic neurotransmission to brainstem inspiratory premotor neurons but not postsynaptic receptor function in a decerebrate dog model

BACKGROUND: Inspiratory bulbospinal neurons in the caudal ventral medulla are premotor neurons that drive motoneurons, which innervate pump muscles such as the diaphragm and external intercostals. Excitatory drive to these neurons is mediated by N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and is modulated by an inhibitory gamma-aminobutyric acid type A (GABAA)ergic input. The authors investigated the effect of sevoflurane on these synaptic mechanisms in decerebrate dogs. METHODS: Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration sevoflurane on extracellularly recorded activity of single neurons was measured during localized picoejection of the GABAA receptor blocker bicuculline and the glutamate agonists AMPA and NMDA. Complete blockade of the GABAAergic mechanism by bicuculline allowed differentiation between the effects of sevoflurane on overall GABAAergic inhibition and on overall glutamatergic excitation. The neuronal responses to exogenous AMPA and NMDA were used to estimate the anesthetic effect on postsynaptic glutamatergic neurotransmission. RESULTS: One minimum alveolar concentration sevoflurane depressed the spontaneous activity of 23 inspiratory premotor neurons by (mean +/- SD) 30.0 +/- 21.0% (P < 0.001). Overall glutamatergic excitation was depressed 19.2 +/- 18.5% (P < 0.001), whereas overall GABAAergic inhibition was enhanced by 11.9 +/- 25.1% (P < 0.05). The postsynaptic responses to exogenous AMPA and NMDA did not change. CONCLUSION: One minimum alveolar concentration depressed the activity of inspiratory premotor neurons by a reduction of glutamatergic excitation and an increase in overall inhibition. The postsynaptic AMPA and NMDA receptor response was unchanged. These findings contrast with studies in inspiratory premotor neurons where halothane did not change overall inhibition but significantly reduced the postsynaptic glutamate receptor response.     

Mineralocorticoid Receptor Antagonism and Aldosterone Synthesis Inhibition Do Not Improve Glomerulosclerosis and Renal Interstitial Fibrosis in a Model of Chronic Kidney Allograft Injury

Chronic allograft injury (CAI) is a major cause of late graft failure with a multifactorial pathogenesis; however, in different experiments an inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers ameliorated the progression of chronic renal disease. Different concepts supposed that aldosterone is involved in development and/or progression of renal diseases via interaction with a non-epithelial mineralocorticoid receptor (MR), e.g. reducing neointima formation. Our examinations therefore targeted on the effects of the aldosterone synthase inhibitor fadrozole and the MR antagonist spironolactone compared to vehicle in an established rat model of CAI. In our model of CAI, neither the aldosterone biosynthesis inhibitor nor a direct MR blockade had a positive effect on renal CAI in rats. Fadrozole- and spironolactone-treated animals demonstrated a higher proteinuria value, pathologically elevated potassium values, higher tubulointerstitial damage and markedly increased heart weight/body weight as compared to vehicle. Our observations also suggest that inhibition of the MR or the biosynthesis itself had a bad influence on the amount of sclerotic glomeruli and tubulointerstitial damage. The positive effects of inhibition of aldosterone as described in cardiac models could not yet be detected in kidney recipients.     

Vasopressin, but Not Fluid Resuscitation, Enhances Survival in a Liver Trauma Model with Uncontrolled and Otherwise Lethal Hemorrhagic Shock in Pigs

Background: The authors compared the effects of vasopressin versus fluid resuscitation on survival in a liver trauma model with uncontrolled and otherwise lethal hemorrhagic shock in pigs.

Methods: A midline laparotomy was performed on 23 domestic pigs, followed by an incision, and subsequent finger fraction across the right medial liver lobe. During hemorrhagic shock, animals were randomly assigned to receive either 0.4 U/kg vasopressin (n = 9), or fluid resuscitation (n = 7), or saline placebo (n = 7), respectively. A continuous infusion of 0.08 U [middle dot] kg-1 [middle dot] min-1 vasopressin in the vasopressin group, or normal saline was subsequently administered in the fluid resuscitation and saline placebo group, respectively. After 30 min of experimental therapy, bleeding was controlled by surgical intervention, and blood transfusion and rapid fluid infusion were subsequently performed.

Results: Maximum mean arterial blood pressure during experimental therapy in the vasopressin-treated animals was significantly higher than in the fluid resuscitation and saline placebo groups (mean +/- SD, 72 +/- 26 vs. 38 +/- 16 vs. 11 +/- 7 mmHg, respectively;P < 0.05). Subsequently, mean arterial blood pressure remained at approximately 40 mmHg in all vasopressin-treated animals, whereas mean arterial blood pressure in all fluid resuscitation and saline placebo pigs was close to aortic hydrostatic pressure (~15 mmHg) within approximately 20 min of experimental therapy initiation. Total blood loss was significantly higher in the fluid resuscitation pigs compared with vasopressin or saline placebo after 10 min of experimental therapy (65 +/- 6 vs. 42 +/- 4 vs. 43 +/- 6 ml/kg, respectively;P < 0.05). Seven of seven fluid resuscitation, and seven of seven saline placebo pigs died within approximately 20 min of experimental therapy, while 8 of 9 vasopressin animals survived more than 7 days (P < 0.05).     

Electroencephalographic Burst Suppression Is Not Required to Elicit Maximal Neuroprotection from Pentobarbital in a Rat Model of Focal Cerebral Ischemia

Background: Barbiturates have previously been demonstrated to reduce focal cerebral ischemic brain damage. However, the dose of drug required to elicit maximal neuroprotection has not been defined. The authors' hypothesized that doses of pentobarbital substantially lower than those required to cause electroencephalographic burst suppression would result in maximal magnitudes of reduction of cerebral infarct volume.

Methods: Wistar rats underwent 90 min of filament occlusion of the middle cerebral artery while either awake (control), or anesthetized with intravenous sodium pentobarbital administered to preserve an active electroencephalogram (15-23 mg *symbol* kg sup -1 *symbol* h sup -1) or a pattern of burst suppression (45-60 mg *symbol* kg sup -1 *symbol* h sup -1; n = 17). During ischemia and for the first 6 h of recirculation, brain temperature was rigorously controlled at 38.0+/-0.2 degree Celsius. Rats were allowed a recovery interval of 7 days after which neurologic function and cerebral infarct volume were assessed. In nonischemic rats undergoing a similar anesthetic protocol, the cerebral metabolic rate of glucose utilization was measured at each anesthetic depth.

Results: Relevant physiologic values were similar between groups. Total infarct volume (mean+/-SD) was smaller in the active electroencephalogram group than in the control group (124+/-68 mm sup 3 versus 163+/-66 mm3; P < 0.05). Increasing the dose of pentobarbital (burst suppression) did not further decrease infarct volume (128+/-54 mm3). Neurologic score and infarct volume were positively correlated (P < 0.001). Cerebral metabolic rate of glucose utilization was reduced by 56% in the burst suppression group versus 43% in the active electroencephalogram pentobarbital group (P < 0.001).     

Esmolol Improves Left Ventricular Function via Enhanced β-Adrenergic Receptor Signaling in a Canine Model of Coronary Revascularization

Background: Recent American Heart Association guidelines highlight the paucity of data on effectiveness and/or mechanisms underlying use of [beta]-adrenergic receptor ([beta]AR) antagonists after acute coronary syndromes in patients subsequently undergoing revascularization. It is important to assess whether [beta]AR antagonists might protect the heart and improve ventricular function in this scenario. The authors therefore used esmolol (an ultra-short-acting [beta]AR antagonist) to determine whether [beta]AR antagonist treatment improves left ventricular function in a canine model of acute reversible coronary ischemia followed by coronary reperfusion during cardiopulmonary bypass (CPB). The authors also tested whether the mechanism includes preserved [beta]AR signaling.

Methods: Dogs were randomized to either esmolol or saline infusions administered during CPB (n = 29). Pre-CPB and end-CPB transmyocardial left ventricular biopsies were obtained; plasma catecholamine concentrations, myocardial [beta]AR density, and adenylyl cyclase activity were measured. In addition, left ventricular systolic shortening and postsystolic shortening were determined immediately prior to each biopsy.

Results: While [beta]AR density remained unchanged in each group, isoproterenol-stimulated adenylyl cyclase activity decreased 26 +/- 6% in the control group but increased 38 +/- 10% in the esmolol group (pre-CPB to end-CPB, mean +/- SD, P = 0.0001). Left ventricular systolic shortening improved in both groups after release of coronary (LAD) ligature; however, the esmolol group increased to 72 +/- 23% of pre-CPB values compared to 48 +/- 12% for the control group (P = 0.0008).     

Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor,Elafin, to Maintain Graft Perfusion During Acute Rejection

The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b‐9. Elafin was also found to promote angiogenesis through activation of the extracellular signal‐regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling.