Inhibition of glucose transport and direct interactions with type 1 facilitative glucose transporter (GLUT-1) by etomidate, ketamine, and propofol: a comparison with barbiturates.

Ketamine, etomidate, propofol, and pentobarbital were compared for effects on and interactions with the type 1 facilitative glucose transporter (GLUT-1). Fluxes of radiolabeled hexoses were used to determine the effects of anesthetics on GLUT-1 function. Hypotonic hemolysis of human erythrocytes was used to assess perturbations of membrane integrity. Quenching of intrinsic protein fluorescence was used to assess the direct interactions of anesthetics with purified GLUT-1. Pentobarbital, ketamine, etomidate, and propofol inhibited glucose transport in murine fibroblasts with IC(50) values of 0.8, 1. 6, 0.1, and 0.4 mM, respectively. Pentobarbital, ketamine, etomidate, and propofol also inhibited sugar transport in human erythrocytes. The IC(50) values for pentobarbital and ketamine exhibited substrate dependence for equilibrium exchange but not unidirectional effluxes. This was not observed for etomidate. Propofol did not inhibit equilibrium exchange but did inhibit unidirectional efflux with little substrate dependence. Pentobarbital protected against hemolysis, whereas etomidate and ketamine promoted hemolysis of erythrocytes. Propofol had no effect on membrane integrity. Pentobarbital, ketamine, and etomidate all interacted directly with GLUT-1, with apparent K(d) values of 2.2, 0.8, and 0.5 mM, respectively. Like barbiturates, ketamine, etomidate, and propofol inhibited GLUT-1 at concentrations near to those used pharmacologically. Inhibition of GLUT-1 by these intravenous general anesthetics was complex, exhibiting differential kinetic effects on equilibrium exchange versus unidirectional fluxes and contrasting substrate dependencies. Like barbiturates, ketamine and etomidate bound to GLUT-1 with affinities that paralleled inhibition of glucose transport. As a class, intravenous general anesthetics, in contrast to inhalation anesthetics, inhibit GLUT-1-mediated glucose transport.

Acute and chronic pharyngitis across the lifespan.

Although most instances of sore throat are caused by relatively benign infectious or noninfectious processes, pharyngitis may herald serious or even fatal illnesses. Viral pharyngitis is the diagnosis in most cases, but because GABHS is the most common bacterial organism requiring antimicrobial treatment, an office visit is often necessary. There is no exact constellation of signs and symptoms that is pathognomonic for GABHS; nevertheless, sudden onset of sore throat with fever and cervical lymph node tenderness, in the absence of cough and nasal symptoms, is at least suggestive in adults, and possibly in children. Physical examination and prudent use of laboratory testing will assist in the diagnosis of both acute and chronic pharyngitis. The primary care provider who promptly identifies and properly treats patients infected with S. pyogenes has reduced the number of missed school or work days, the risk of developing ARF, the likelihood of transmission to others, and inappropriate use of antibiotics for those with other causes of sore throat. Further education of patient, family, and other clinicians will reduce medical expenses, avoid unnecessary antibiotic exposure, and inform the public regarding judicious management of pharyngitis.

Effects of barbiturates on facilitative glucose transporters are pharmacologically specific and isoform selective.

Barbiturates inhibit GLUT-1-mediated glucose transport across the blood-brain barrier, in cultured mammalian cells, and in human erythrocytes. Barbiturates also interact directly with GLUT-1. The hypotheses that this inhibition of glucose transport is (i) selective, preferring barbiturates over halogenated hydrocarbon inhalation anesthetics, and (ii) specific, favoring some GLUT-# isoforms over others were tested. Several oxy- and thio-barbiturates inhibited [3H]-2-deoxyglucose uptake by GLUT-1 expressing murine fibroblasts with IC50s of 0.2-2.9 mm. Inhibition of GLUT-1 by barbiturates correlates with their overall lipid solubility and pharmacology, and requires hydrophobic side chains on the core barbiturate structure. In contrast, several halogenated hydrocarbons and ethanol (all 10 mm). Thus, barbiturates selectively inhibit glucose transport by some, but not all, facilitative glucose transporter isoforms.

Effects of angiotensin II on LHRH release, as measured by in vivo microdialysis of the anterior pituitary gland of conscious female rats.

The present experiments assessed the effects of central administration of angiotensin II (Ang II) on mean levels of luteinizing hormone-releasing hormone (LHRH) in the extracellular fluid of the anterior pituitary gland, monitored by in vivo microdialysis. Ovariectomized rats were tested under two conditions: (1) nonhormone-treated where Ang II infusion inhibits luteinizing hormone (LH) release, and (2) ovarian hormone-treated where Ang II stimulates LH secretion. Animals were ovariectomized and chronic guide cannulae were implanted, one into the lateral cerebral ventricle for infusion of Ang II and one directed toward the anterior pituitary gland for the insertion of the microdialysis probe. Approximately 1 week later, the dialysis probe was inserted and cemented into place. The length of the dialysis probe transected the pituitary gland from its dorsal to ventral aspects. Dialysis samples were collected at 15-min intervals. Levels of LHRH were continuously monitored in nonhormone-treated animals, prior to and during intracerebroventricular (i.c.v.) infusion of Ang II. The dialysis probe was removed at the end of the experiment. One week later, the same animals were treated with estrogen and progesterone and dialysis of the anterior pituitary gland was performed 3 days later using a protocol identical to the first dialysis sampling session. A separate group of animals was tested to confirm the effects of lateral ventricle infusion of this dose of Ang II on LH release. There were no detectable values of LHRH in dialysis samples from non-hormone-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Angiotensin II Receptor Subtypes and the Control of Luteinizing Hormone and Prolactin Secretion in Female Rats.

The present experiments examined the role of the two recently identified angiotensin II (Ang II) receptor subtypes, AT, and AT(2) , in the central nervous system regulation of luteinizing hormone (LH) and prolactin secretion in estrogen- and progesterone-treated ovariectomized rats. In this animal model, intracerebroventricular (icv) injection of Ang II stimulates LH and inhibits prolactin release. The specific Ang II receptor subtype antagonists losartan (AT(1) ) or PD123177 (AT(2) ) were administered (icv) in various doses (10 ng to 1,000 ng) 10 min prior to icv injection of Ang II (100 ng). Control animals were pretreated with artificial cerebrospinal fluid prior to Ang II administration. Blood samples for LH and prolactin determinations were taken from conscious, freely-moving rats prior to and following injection of the antagonists and Ang II. Water intake was measured. Ang ll-induced water intake was attenuated 62% by 1,000 ng losartan; water intake was not affected by lower doses of losartan or by any dose of PD123177. Ang ll-induced stimulation of LH release was abolished by the 1,000 ng doses of losartan and PD123177 and attenuated by the 500 ng doses of both drugs. Lower doses did not affect Ang ll-induced LH secretion. Ang ll-induced inhibition of prolactin release was significantly reduced by the 1,000 ng doses of both losartan and PD123177. Lower doses of either drug did not affect the Ang II inhibition of prolactin release. Previous studies had shown that Ang II administration into the anterior hypothalamus-medial preoptic (AHPO) area stimulated LH release. This brain area contains AT(1) receptors. To investigate the potential brain site where the AT(2) receptor may influence LH release, Ang II was injected into the locus ceruleus, a brain nucleus which contains predominately the AT(2) receptor subtype. Ang II administration into the locus ceruleus was paired with an injection of artificial cerebrospinal fluid or Ang II into the AHPO area. Injection of Ang II into the AHPO area stimulated LH release. Injection into the locus ceruleus did not affect LH secretion, nor did it modify the rise in LH elicited by administration of Ang II into the AHPO area. Plasma levels of prolactin were not altered by any of these injections. Taken together, these data demonstrate that, in estrogen- and progesterone-treated female rats, icv Ang ll-induced water intake is mediated by the AT, receptor subtype, while Ang ll-induced changes in LH and prolactin secretion appear to be mediated by both the AT(2) and AT(2) receptor subtypes. The latter observations are one of the first suggesting a potential function for the AT(2) subtype in vivo, although the physiological relevance of this observation, as well as the site of action for the effects on LH and prolactin, remain to be established.