Although accumulating evidence suggests that arousal pathways in the brain play important roles emergence from general anesthesia, of monoaminergic circuits are unclear. In this study, authors tested hypothesis methylphenidate (an inhibitor dopamine and norepinephrine transporters) induces isoflurane anesthesia.Using adult rats, effect intravenous on time to anesthesia. They then performed experiments test separately for methylphenidate-induced changes minute ventilation. A dose-response...

Background Etomidate is a rapidly acting sedative-hypnotic that provides hemodynamic stability. It causes prolonged suppression of adrenocortical steroid synthesis; therefore, its clinical utility and safety are limited. The authors describe the results studies to define pharmacology (R)-3-methoxy-3-oxopropyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MOC-etomidate), first etomidate analogue designed be susceptible ultra-rapid metabolism. Methods gamma-aminobutyric acid type A receptor...

Etomidate is a sedative hypnotic that often used in critically ill patients because it provides superior hemodynamic stability. However, also binds with high affinity to 11beta-hydroxylase, potently suppressing the synthesis of steroids by adrenal gland are necessary for survival. The authors report results studies define pharmacology (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), pyrrole analog etomidate specifically designed not bind 11beta-hydroxylase.The potency...

Arginine 347 in the sixth transmembrane domain of cystic fibrosis conductance regulator (CFTR) is a site four fibrosis-associated mutations. To better understand function Arg-347 and to learn how mutations at this disrupt channel activity, we mutated Asp, Cys, Glu, His, Leu, or Lys examined single-channel function. Every mutation examined, except R347K, had destabilizing effect on pore, causing flutter between two states. Chloride flow through larger state was similar that wild-type CFTR,...

The tandem pore domain K channel family mediates background currents present in excitable cells. Currents passed by certain members of the are enhanced volatile anesthetics, thus suggesting a novel mechanism anesthesia. newest member family, termed TRESK (TWIK [tandem weak inward rectifying channel]-related spinal cord channel), has not been studied for anesthetic sensitivity. We isolated coding sequence from human RNA and functionally expressed it Xenopus oocytes transfected COS-7 With both...

The cystic fibrosis transmembrane conductance regulator (CFTR) contains multiple membrane spanning sequences that form a Cl− channel pore and cytosolic domains control the opening closing of channel. fourth intracellular loop (ICL4), which connects tenth eleventh spans, has primary sequence is highly conserved across species, site preserved motif in ABC transporter family, relatively large number missense mutations associated with (CF). To investigate role ICL4 CFTR function to learn how CF...

In Brief TWIK-related acid-sensitive K+-1 (TASK-1 [KCNK3]) and TASK-3 (KCNK9) are tandem pore (K2P) potassium (K) channel subunits expressed in carotid bodies the brainstem. Acidic pH values hypoxia inhibit TASK-1 function, halothane enhances this function. These channels have putative roles ventilatory regulation volatile anesthetic mechanisms. Doxapram stimulates ventilation through an effect on bodies, we hypothesized that stimulation might result from inhibition of or K To address this,...

TASK-1 and TASK-3 tandem pore potassium channel subunits provide a constitutive acidic pH- hypoxia-inhibited conductance. TASK channels are expressed in number of tissues involved regulation breathing, the TASK-1/TASK-3 heterodimer provides predominant hypoxia-sensitive conductance carotid body type 1 glomus chemosensing cells. The bodies have an important role breathing. Doxapram is potent antagonist breathing stimulant. PK-THPP A1899 selective antagonists. I hypothesized are, like...

Summary Objective The DBA/1 mouse is a relevant animal model of sudden unexpected death in epilepsy (SUDEP), as it exhibits seizure‐induced respiratory arrest (S‐IRA) evoked by acoustic stimulation, followed cardiac arrhythmia and death. Defects serotonergic neurotransmission may contribute to S‐IRA. tryptophan hydroxylase‐2 (TPH2) enzyme converts L‐tryptophan 5‐hydroxytryptophan (5‐HTP), precursor for central nervous system (CNS) serotonin (5‐HT) synthesis; mice have polymorphism that...

Nondepolarizing neuromuscular blocking drugs (NMBDs) such as rocuronium and vecuronium are essential to anesthesia clinical practice, causing profound muscle relaxation assured patient immobility. Recovery from NMBDs, however, is important for normal breathing movement on emergence. Sugammadex, a ɣ-cyclodextrin drug that selectively binds inactivates vecuronium, has transformed practice by enabling rapid pharmacologic reversal of even "deep" levels rocuronium- vecuronium-mediated blockade....

We previously developed 2 etomidate analogs that retain etomidate's favorable hemodynamic properties but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl (MOC)-etomidate is rapidly metabolized and ultrashort acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11β-hydroxylase. hypothesized MOC-etomidate's labile ester could be incorporated into carboetomidate to produce a new agent possesses...

BACKGROUND: Although emergence from general anesthesia is clinically treated as a passive process driven by the pharmacokinetics of drug clearance, agents that hasten recovery may be useful for treating delayed emergence, delirium, and postoperative cognitive dysfunction. Activation central monoaminergic neurotransmission with methylphenidate has been shown to induce reanimation (active emergence) anesthesia. Cholinergic neurons in brainstem basal forebrain are also known promote arousal....

Calabadion 2 is a new drug-encapsulating agent. In this study, the authors aim to assess its utility as an agent reverse general anesthesia with etomidate and ketamine facilitate recovery.To evaluate effect of calabadion on recovery, studied response rats after continuous bolus intravenous or intramuscular administration. The measured electroencephalographic predictors depth (burst suppression ratio total power), functional mobility impairment, blood pressure, toxicity.Calabadion...

Etomidate is a sedative-hypnotic that often given as single intravenous bolus but rarely an infusion because it suppresses adrenocortical function. Methoxycarbonyl etomidate and (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) are analogs do not produce significant suppression when bolus. However, the effects of continuous infusions on function unknown. In this study, we compared etomidate, methoxycarbonyl carboetomidate in rat model.A closed-loop system using...

Abstract Introduction Etomidate is no longer administered as a continuous infusion for anesthetic maintenance or sedation, because it results in profound and persistent suppression of adrenocortical steroid synthesis with potentially lethal consequences critically ill patients. We hypothesized that rapidly metabolized soft analogues etomidate could be developed do not produce dysfunction even after prolonged infusion. hope such agents might also provide more rapid predictable emergence. have...

Compounds PKTHPP (1-{1-[6-(biphenyl-4-ylcarbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-4-yl]piperidin-4-yl}propan-1-one), A1899 (2ʹ′-[(4-methoxybenzoylamino)methyl]biphenyl-2-carboxylic acid 2,4-difluorobenzylamide), and doxapram inhibit TASK-1 (KCNK3) TASK-3 (KCNK9) tandem pore (K_2P) potassium channel function stimulate breathing. To better understand the molecular mechanism(s) of action these drugs, we undertook studies to identify amino residues in protein that mediate...

Methoxycarbonyl etomidate is the prototypical soft analog. Because it has relatively low potency and extremely rapidly metabolized, large quantities must be infused to maintain hypnosis. Consequently with prolonged infusion, metabolite reaches sufficient concentrations delay recovery. Dimethyl-methoxycarbonyl metomidate (DMMM) cyclopropyl-methoxycarbonyl (CPMM) are methoxycarbonyl analogs higher potencies slower clearance. of these properties, we hypothesized that dosing would lower...

Carboetomidate is a pyrrole etomidate analog that 3 orders of magnitude less potent an inhibitor in vitro cortisol synthesis than (an imidazole) and does not inhibit vivo steroid production. Although carboetomidate's reduced functional effect on thought to reflect lower binding affinity 11β-hydroxylase, differential this enzyme has never been experimentally demonstrated. In the current study, we tested hypothesis carboetomidate bind with 11β-hydroxylase by comparing their abilities...

We developed a novel pyrrole analog of etomidate, (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), which retains etomidate's desirable anesthetic and hemodynamic properties but lacks its potent inhibitory affect on adrenocorticotropic hormone-stimulated steroid synthesis. The objective this study was to test the hypothesis that in contrast carboetomidate neither suppresses adrenocortical response endotoxemia nor enhances accompanying production proinflammatory...

Cyclopropyl-methoxycarbonyl metomidate (CPMM) is a "soft" etomidate analogue currently being developed as propofol alternative for anesthetic induction and maintenance.

Abstract IL2 is an immunostimulatory cytokine for key immune cells including T and natural killer (NK) cells. Systemic supplementation could enhance NK-mediated immunity in a variety of diseases ranging from neoplasms to viral infection. However, its systemic use restricted by serious side effects limited efficacy due activation regulatory (Tregs). signaling mediated through interactions with multi-subunit receptor complex containing IL2Rα, IL2Rβ, IL2Rγ. Adult express only IL2Rβ IL2Rγ...

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel is regulated by three cytosolic domains, the regulatory domain (R domain) and two nucleotide binding domains. To learn more about how domains regulate activity, we used chemical modification to probe their structure. When applied sulfhydryl-modifying reagent N-ethylmaleimide (NEM) other N-substituted maleimides found that they rapidly irreversibly stimulated activity. CFTR contains 14 intracellular cysteine residues...