title: L-Cysteine ethyl ester reverses the deleterious effects of morphine on, arterial blood-gas chemistry in tracheotomized rats.
abstract: This study determined whether the membrane-permeable ventilatory stimulant, L-cysteine ethylester (L-CYSee), reversed the deleterious actions of morphine on arterial blood-gas chemistry in isoflurane-anesthetized rats. Morphine (2 mg/kg, i.v.) elicited sustained decreases in arterial blood pH, pO₂ and sO₂, and increases in pCO₂ (all responses indicative of hypoventilation) and alveolar-arterial gradient (indicative of ventilation-perfusion mismatch). Injections of L-CYSee (100 μmol/kg, i.v.) reversed the effects of morphine in tracheotomized rats but were minimally active in non-tracheotomized rats. L-cysteine or L-serine ethylester (100 μmol/kg, i.v.) were without effect. It is evident that L-CYSee can reverse the negative effects of morphine on arterial blood-gas chemistry and alveolar-arterial gradient but that this positive activity is negated by increases in upper-airway resistance. Since L-cysteine and L-serine ethylester were ineffective, it is evident that cell penetrability and the sulfur moiety of L-CYSee are essential for activity. Due to its ready penetrability into the lungs, chest wall muscle and brain, the effects of L-CYSee on morphine-induced changes in arterial blood-gas chemistry are likely to involve both central and peripheral sites of action.
authors.affiliation: Pediatric Respiratory Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mendoza
authors.forename: Rachael
authors.initials: R
authors.lastname: Passafaro
authors.forename: Santhosh
authors.initials: S
authors.lastname: Baby
authors.forename: Alex P
authors.initials: AP
authors.lastname: Young
authors.forename: James N
authors.initials: JN
authors.lastname: Bates
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gaston
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lewis
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D002245:Carbon Dioxide / Q000097:blood; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008297:Male; D009020:Morphine / Q000009:adverse effects*; D009294:Narcotics / Q000009:adverse effects*; D010100:Oxygen / Q000097:blood; D011659:Pulmonary Gas Exchange / Q000187:drug effects*; D012123:Pulmonary Ventilation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014140:Tracheotomy
chemical_list: D009294:Narcotics; D002245:Carbon Dioxide; C031752:ethyl cysteine; D009020:Morphine; D003545:Cysteine; D010100:Oxygen
keywords: Arterial blood–gas chemistry; Halothane-anesthetized rats; Morphine; l-Cysteine ethylester
references.citation: JAMA. 1977 Oct 24;238(17):1833-5
references.pmid: 333133
references.citation: J Pharmacol Exp Ther. 1985 Jan;232(1):149-55
references.pmid: 2981312
references.citation: Laryngoscope. 1986 May;96(5):506-9
references.pmid: 3702565
references.citation: FASEB J. 2004 Jul;18(10):1165-7
references.pmid: 15155563
references.citation: J Appl Physiol (1985). 1986 Jan;60(1):198-203
references.pmid: 3511022
references.citation: Respir Physiol Neurobiol. 2013 May 1;186(3):255-64
references.pmid: 23473921
references.citation: Biochem Pharmacol. 1993 Apr 22;45(8):1605-12
references.pmid: 8484801
references.citation: Respir Care. 2013 Mar;58(3):482-6
references.pmid: 22781104
references.citation: Anaesth Intensive Care. 1981 Nov;9(4):326-30
references.pmid: 7316136
references.citation: FASEB J. 1993 May;7(8):678-86
references.pmid: 8500693
references.citation: Circ Res. 1980 Jul;47(1):1-9
references.pmid: 7379260
references.citation: J Pharmacol Methods. 1987 Mar;17(1):15-25
references.pmid: 3031383
references.citation: Acta Anaesthesiol Scand. 1982 Oct;26(5):514-8
references.pmid: 7148367
references.citation: Am J Physiol. 1991 Nov;261(5 Pt 2):R1286-93
references.pmid: 1951777
references.citation: Hum Exp Toxicol. 1994 Nov;13(11):776-80
references.pmid: 7857697
references.citation: Pulm Pharmacol. 1992 Sep;5(3):159-65
references.pmid: 1359915
references.citation: Curr Top Cell Regul. 2000;36:151-80
references.pmid: 10842751
references.citation: J Biol Chem. 1997 Jan 31;272(5):2841-5
references.pmid: 9006926
references.citation: Life Sci. 1982 Mar 29;30(13):1121-7
references.pmid: 7078349
references.citation: Biol Chem. 2006 Oct-Nov;387(10-11):1371-6
references.pmid: 17081109
references.citation: Arch Int Pharmacodyn Ther. 1978 Jun;233(2):296-304
references.pmid: 686916
references.citation: Am J Respir Crit Care Med. 1994 Feb;149(2 Pt 1):538-51
references.pmid: 7508323
references.citation: J Nutr Biochem. 2008 Apr;19(4):207-15
references.pmid: 17707628
references.citation: Chest. 2004 Jul;126(1):159-64
references.pmid: 15249457
references.citation: J Cardiothorac Vasc Anesth. 2003 Feb;17(1):69-72
references.pmid: 12635063
references.citation: Pharmacol Res. 2009 Jan;59(1):74-9
references.pmid: 18996201
references.citation: Radiol Clin North Am. 1991 Sep;29(5):965-71
references.pmid: 1871264
references.citation: Saudi J Anaesth. 2010 Jan;4(1):2-5
references.pmid: 20668558
references.citation: J Recept Res. 1980;1(2):329-54
references.pmid: 6271956
references.citation: Respir Physiol. 1995 May;100(2):107-17
references.pmid: 7624612
references.citation: Anesth Analg. 2001 Jan;92(1):273-5
references.pmid: 11133644
references.citation: Biochem Pharmacol. 1993 Oct 5;46(7):1131-7
references.pmid: 8216362
references.citation: Chest. 2005 Sep;128(3):1348-56
references.pmid: 16162728
references.citation: Toxicol Lett. 2009 Sep 10;189(2):115-20
references.pmid: 19477250
references.citation: Am J Surg. 2005 Nov;190(5):752-6
references.pmid: 16226953
references.citation: South Med J. 1984 Apr;77(4):499-501
references.pmid: 6710206
references.citation: Nature. 1993 Aug 12;364(6438):626-32
references.pmid: 8394509
references.citation: Am J Vet Res. 1987 Nov;48(11):1626-30
references.pmid: 2449102
references.citation: Drug Saf. 1998 Sep;19(3):173-89
references.pmid: 9747665
references.citation: Eur J Pharmacol. 1982 May 7;80(1):57-63
references.pmid: 6284530
references.citation: Anaesthesist. 1983 Feb;32(2):60-6
references.pmid: 6405654
references.citation: Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 1):1525-31
references.pmid: 10556115
references.citation: Bull Tokyo Med Dent Univ. 1985 Jun;32(2):31-9
references.pmid: 3864560
references.citation: Respir Physiol Neurobiol. 2009 Sep 30;168(3):281-8
references.pmid: 19632358
references.citation: J Mol Cell Cardiol. 1994 Apr;26(4):455-61
references.pmid: 8072003
references.citation: Trends Mol Med. 2003 Apr;9(4):160-8
references.pmid: 12727142
references.citation: Biochem J. 1983 Nov 15;216(2):507-10
references.pmid: 6661213
references.citation: Anesthesiology. 1996 Apr;84(4):1011
references.pmid: 8638826
references.citation: Chemistry. 2011 Jan 17;17(3):873-9
references.pmid: 21226102
references.citation: Chest. 1999 Apr;115(4):1194-7
references.pmid: 10208229
references.citation: Br J Pharmacol. 1986 Aug;88(4):889-98
references.pmid: 2874862
references.citation: Anesthesiology. 2010 Jan;112(1):226-38
references.pmid: 20010421
references.citation: Q J Exp Physiol. 1981 Jul;66(3):273-84
references.pmid: 6166957
references.citation: Drug Intell Clin Pharm. 1983 Jun;17(6):411-7
references.pmid: 6861632
references.citation: Respir Care. 2005 Apr;50(4):526-33
references.pmid: 15807916
references.citation: Clin Pharmacol Ther. 1978 Mar;23(3):281-7
references.pmid: 627133
references.citation: J Biol Chem. 1995 Nov 24;270(47):28158-64
references.pmid: 7499306
references.citation: Biomed Khim. 2011 Nov-Dec;57(6):615-23
references.pmid: 22359917
references.citation: Xenobiotica. 1988 Jul;18(7):839-47
references.pmid: 3176522
references.citation: Acta Anaesthesiol Scand. 1989 Jan;33(1):1-5
references.pmid: 2644747
references.citation: Br J Anaesth. 2004 Aug;93(2):212-23
references.pmid: 15169738
references.citation: Can J Anaesth. 1990 Mar;37(2):210-8
references.pmid: 2178789
references.citation: Pediatr Emerg Care. 2005 Nov;21(11):751-4
references.pmid: 16280950
references.citation: Nature. 2001 Sep 13;413(6852):171-4
references.pmid: 11557982
references.citation: Cell Calcium. 1997 Jan;21(1):19-29
references.pmid: 9056074
references.citation: Br J Pharmacol. 1980;71(1):297-305
references.pmid: 6781573
references.citation: Eur J Pharmacol. 1983 Jul 22;91(2-3):181-8
references.pmid: 6311577
references.citation: Pharmacol Res Commun. 1981 Jun;13(6):535-40
references.pmid: 7291282
references.citation: IUBMB Life. 2007 Jan;59(1):21-6
references.pmid: 17365176
references.citation: Anesth Analg. 1989 Dec;69(6):756-62
references.pmid: 2589656
references.citation: Am J Respir Crit Care Med. 2006 Jun 1;173(11):1186-93
references.pmid: 16528016
references.citation: Chest. 1980 Dec;78(6):819-21
references.pmid: 7449459
references.citation: Chest. 2001 Dec;120(6 Suppl):477S-81S
references.pmid: 11742969
references.citation: Free Radic Biol Med. 2010 Jan 1;48(1):55-64
references.pmid: 19819329
references.citation: J Physiol Pharmacol. 2005 Jun;56(2):195-203
references.pmid: 15985702
references.citation: Pain Physician. 2008 Mar;11(2 Suppl):S133-53
references.pmid: 18443637
references.citation: Alcohol. 2009 Dec;43(8):649-56
references.pmid: 20004343
references.citation: Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10719-24
references.pmid: 20556885
references.citation: Intensive Care Med. 2002 Jun;28(6):726-30
references.pmid: 12107678
references.citation: Int J Immunopharmacol. 1999 Mar;21(3):185-93
references.pmid: 10348368
references.citation: Clin Pharmacol Ther. 2003 Aug;74(2):102-12
references.pmid: 12891220
references.citation: Vascul Pharmacol. 2006 Jun;44(6):476-90
references.pmid: 16697269
references.citation: Antioxid Redox Signal. 2010 May 1;12(9):1111-23
references.pmid: 19803743
references.citation: Ger Med Sci. 2010 Jun 07;8:Doc10
references.pmid: 20577645
references.citation: J Pharmacol Exp Ther. 1986 Jul;238(1):192-7
references.pmid: 3723397
references.citation: Tohoku J Exp Med. 1991 Jun;164(2):157-67
references.pmid: 1750036
references.citation: Life Sci. 1975 May 1;16(9):1477-82
references.pmid: 1134206
references.citation: Free Radic Biol Med. 2008 Sep 1;45(5):549-61
references.pmid: 18544350
references.citation: J Med Chem. 2001 Jun 7;44(12):2035-8
references.pmid: 11384248
references.citation: Anesthesiology. 1997 Nov;87(5):1070-4
references.pmid: 9366458
references.citation: Clin Pharmacokinet. 2006;45(11):1051-60
references.pmid: 17048971
references.citation: Exp Clin Endocrinol. 1988 Aug;91(3):350-4
references.pmid: 3075186
references.citation: Vet Anaesth Analg. 2008 Jul;35(4):326-32
references.pmid: 18282250
references.citation: Biochem Biophys Res Commun. 2011 Jan 21;404(3):785-9
references.pmid: 21168387