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Biomedical subjects

Andrew T Gray

Publications and source records attributed to Andrew T Gray.

At least 19 recordsLinked to original sources
PubMed2003

Amide local anesthetics potently inhibit the human tandem pore domain background K+ channel TASK-2 (KCNK5).

Blockade of voltage-gated sodium (Na+) channels by local anesthetics represents the main mechanism for inhibition of impulse propagation. Local anesthetic-induced potassium (K+) channel inhibition is also known to influence transmission of sensory impulses and to potentiate inhibition. K+ channels involved in this mechanism may belong to the emerging family of background tandem pore domain K+ channels (2P K+ channels). To determine more precisely the effects of local anesthetics on members of this ion channel family, we heterologously expressed the 2P K+ channels TASK-2 (KCNK5), TASK-1 (KCNK3), and chimeric TASK-1/TASK-2 channels in oocytes of Xenopus laevis. TASK-2 cDNA-transfected HEK 293 cells were used for single-channel recordings. Local anesthetic inhibition of TASK-2 was dose-dependent, agent-specific, and stereoselective. The IC50 values for R-(+)-bupivacaine and S-(-)-bupivacaine were 17 and 43 micro M and for R-(+)-ropivacaine and S-(-)-ropivacaine, 85 and 236 micro M. Lidocaine (1 mM) inhibited TASK-2 currents by 55 +/- 4%, whereas its quaternary positively charged analog N-ethyl lidocaine (QX314) had no effect. Bupivacaine (100 micro M) decreased channel open probability from 20.8 +/- 1.6% to 5.6 +/- 2.2%. Local anesthetics [300 micro M R-(+)-bupivacaine] caused significantly greater depolarization of the resting membrane potential of TASK-2-expressing oocytes compared with water-injected control oocytes (15.8 +/- 2.5 mV versus 0.1 +/- 0.05 mV; p < 0.001). Chimeric TASK-1/TASK-2 2P K+ channel subunits that retained pH sensitivity demonstrated that the carboxy domain of TASK-2 mediates the greater local anesthetic sensitivity of TASK-2. These results show that clinically achievable concentrations of local anesthetics inhibit background K+ channel function and may thereby enhance conduction blockade.

Amides↗
PubMed2003

Mutation of KCNK5 or Kir3.2 potassium channels in mice does not change minimum alveolar anesthetic concentration.

UNLABELLED: Several reports suggest that clinically used concentrations of inhaled anesthetics can increase conductance through noninactivating potassium channels and that the resulting hyperpolarization might decrease excitability, thereby leading to the anesthetic state. We speculated that animals deficient in such potassium channels might be resistant to the effects of anesthetics. Thus, in the present study, we measured the minimum alveolar anesthetic concentration (MAC) needed to prevent movement in response to a noxious stimulus in 50% of adult mice lacking functional KCNK5 potassium channel subunits and compared these results with those for heterozygous and wild-type mice. We also measured MAC in weaver mice that had a mutation in the potassium channel Kir3.2 and compared the resulting values with those for wild-type mice. MAC values for desflurane, halothane, and isoflurane for KCNK5-deficient mice and isoflurane MAC values for weaver mice did not differ from MAC values found in control mice. Our results do not support the notion that these potassium channels mediate the capacity of inhaled anesthetics to produce immobility. In addition, we found that the weaver mice did not differ from control mice in their susceptibility to convulsions from the nonimmobilizers flurothyl [di-(2,2,2,-trifluoroethyl)ether] or 2N (1,2-dichlorohexafluorocyclobutane). IMPLICATIONS: Mice harboring mutations in either of two different potassium channels have minimum alveolar anesthetic concentration (MAC) values that do not differ from MAC values found in control mice. Such findings do not support the notion that these potassium channels mediate the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation.

Anesthetics, Inhalation↗
PubMed2003

The use of the potassium channel activator riluzole to test whether potassium channels mediate the capacity of isoflurane to produce immobility.

UNLABELLED: Inhaled anesthetics produce immobility during noxious stimulation, primarily by actions on the spinal cord. In this study, we examined whether activation of potassium channels of the KCNK subfamily alters volatile anesthetic potency. We measured the change in isoflurane minimum alveolar anesthetic concentration (MAC) during 4-h intrathecal or IV infusions of the nonspecific KCNK activator riluzole in 54 Sprague-Dawley rats. IV or intrathecal infusions of riluzole doses that did not result in permanent injury or death equally decreased isoflurane MAC. We conclude that although riluzole exhibited anesthetic effects, the similar dose response from IV or intrathecal infusion suggests systemic absorption and actions in the brain rather than the spinal cord. IMPLICATIONS: Riluzole, a drug that activates potassium channels and decreases glutamatergic neurotransmission, primarily acts on supraspinal sites to produce immobility in response to noxious stimuli. This finding does not support the hypothesis that potassium channels mediate the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation.

Anesthetics, Inhalation↗
PubMed2003

Inhaled anesthetics and immobility: mechanisms, mysteries, and minimum alveolar anesthetic concentration.

Studies using molecular modeling, genetic engineering, neurophysiology/pharmacology, and whole animals have advanced our understanding of where and how inhaled anesthetics act to produce immobility (minimum alveolar anesthetic concentration; MAC) by actions on the spinal cord. Numerous ligand- and voltage-gated channels might plausibly mediate MAC, and specific amino acid sites in certain receptors present likely candidates for mediation. However, in vivo studies to date suggest that several channels or receptors may not be mediators (e.g., gamma-aminobutyric acid A, acetylcholine, potassium, 5-hydroxytryptamine-3, opioids, and alpha(2)-adrenergic), whereas other receptors/channels (e.g., glycine, N-methyl-D-aspartate, and sodium) remain credible candidates.

Anesthetics, Inhalation↗
PubMed2003

Sciatic nerve block in a child: a sonographic approach.

UNLABELLED: Ultrasound technology can facilitate peripheral nerve blocks in clinical practice. In this case report, ultrasound imaging was used to identify the sciatic nerve and guide local anesthetic injection in the subgluteal region of a child undergoing Achilles tendon lengthening. Sonographic guidance may be especially useful for peripheral nerve blocks in children because the neural imaging is often excellent and reference landmarks are variable. IMPLICATIONS: In this case report, ultrasound was used to identify the sciatic nerve and guide local anesthetic injection in the subgluteal region of a child. Sonographic guidance may be especially useful for peripheral nerve blocks in children because the neural imaging is often excellent and reference landmarks are variable.

Achilles Tendon↗
PubMed2002

Glutamine uptake by neurons: interaction of protons with system a transporters.

Astrocytes provide the glutamine required by neurons to synthesize glutamate and GABA. However, the mechanisms involved in glutamine transfer from glia to neurons have remained poorly understood. Recent work has implicated the System N transporter SN1 in the efflux of glutamine from astrocytes and the very closely related System A transporters SA1 and SA2 in glutamine uptake by neurons. To understand how these closely related proteins mediate flux in different directions, we have examined their ionic coupling. In contrast to the electroneutral exchange of H+ for Na+ and neutral amino acid catalyzed by SN1, we now show that SA1 and SA2 do not couple H+ movement to amino acid flux. As a result, SA1 and SA2 are electrogenic and do not mediate flux reversal as readily as SN1. Differences between System N and A transporters in coupling to H+ thus contribute to the delivery of glutamine from glia to neurons. Nonetheless, although they are not transported, H+ inhibit SA1 and SA2 by competing with Na+.

Amino Acid Transport System A↗
PubMedDate not supplied

The musculocutaneous nerve: ultrasound appearance for peripheral nerve block.

BACKGROUND AND OBJECTIVES: To gain complete anesthesia of the forearm, block of the musculocutaneous nerve is necessary. Variations in its course and position make localization of the musculocutaneous nerve problematic. The aim of the study is to describe the ultrasound appearance of the musculocutaneous nerve in the axilla and to suggest potential areas to target neural block. METHODS: We scanned the axillary regions of 19 volunteers and assessed the size and shape of 34 musculocutaneous nerves at entry into, exit from, and in the center of the coracobrachialis muscle. Furthermore, we measured the depth of the musculocutaneous nerve under the skin surface and its distance from the axillary artery at those 3 measurement points. RESULTS: As it travels through the coracobrachialis muscle, the musculocutaneous nerve changes in shape from oval to flat-oval to triangular. During this course, the musculocutaneous nerve also separates from the axillary artery and becomes more lateral while changing its depth from the surface. The musculocutaneous nerve increases its transverse area along this nerve path. In 2 subjects, the musculocutaneous nerve could not be visualized unilaterally within the course of the coracobrachialis muscle. CONCLUSIONS: Knowledge of its ultrasound appearance facilitates localization and successful block of the musculocutaneous nerve. Because the distance between the musculocutaneous nerve and brachial plexus varies, different locations of musculocutaneous nerve puncture during ultrasound-guided regional anesthesia can be chosen.

Axillary Artery↗
PubMedDate not supplied

Ultrasound guidance for ulnar nerve block in the forearm.

OBJECTIVE: The objective of this study was to establish the feasibility of ulnar nerve block under direct imaging. CASE REPORTS: Two patients undergoing surgery on the fifth digit or medial hand received ulnar nerve blocks in the mid-forearm (approximately 15 cm proximal to the styloid process of the ulna). Ultrasound imaging was used to identify the ulnar nerve in the forearm and guide local anesthetic infiltration. Both patients had successful blocks, including sensory anesthesia of the dorsomedial hand. CONCLUSIONS: Ultrasound guidance for ulnar nerve block in the forearm is a promising technique that includes block of the dorsal cutaneous branch. Anatomic and sonographic considerations are discussed.

Adult↗
PubMedDate not supplied

Ultrasound visibility of needles used for regional nerve block: an in vitro study.

BACKGROUND AND OBJECTIVES: Ultrasound visibility of regional block needles is a critical component for safety and success of regional anesthetic procedures. The aim of the study was to formally assess factors that influence ultrasound visibility of needles used in regional anesthesia. METHODS: Regional block needles between 17- and 22-G diameter were inserted in a tissue equivalent phantom at angles from 0 degrees to 65 degrees relative to the phantom surface. For visibility enhancement, the needles were primed with air or water in combination with stylets and different size guide wires. Ultrasound measurements of needle tips and shafts were performed using transversal and longitudinal imaging with a linear 15-MHz transducer. Univariate and multivariate statistical analyses were performed on 719 visibility measurements. RESULTS: Hustead tip needles exhibited best ultrasound visibility. Ultrasound visibility of the needle tip was increased by insertion of a medium size guide wire. Water or air priming of the needle, insulation, and the insertion of a stylet did not influence needle visibility. Long axis imaging of the needle for shallow insertion angles (<30 degrees in relation to the phantom surface) and short-axis imaging for steep angles (>60 degrees ) provided the best ultrasound visibility of the needle tips. Needle visibility decreased linearly with steeper insertion angles ( P <.001) and smaller needle diameters ( P <.001). CONCLUSIONS: The results of our in-vitro study suggest a number of factors enhancing ultrasound visibility of regional block needles. The use of needles in the largest possible size inserted with a medium-size guide wire provides the best ultrasound visibility. Analysis of the approach angle favors needle insertion parallel to the transducer. The consideration of these factors may improve safety and success of ultrasound-guided regional blocks.

Equipment Design↗