title: Salvinorin A pretreatment preserves cerebrovascular autoregulation after brain hypoxic/ischemic injury via extracellular signal-regulated kinase/mitogen-activated protein kinase in piglets.
abstract: BACKGROUND
  Cerebral hypoxia/ischemia during infant congenital heart surgery is not uncommon and may induce devastating neurologic disabilities persistent over the lifespan. Hypoxia/ischemia-induced cerebrovascular dysfunction is thought to be an important contributor to neurological damage. No pharmacological agents have been found to prevent this. Mitogen activated protein kinase (MAPK), including extracellular signal regulated kinase (ERK), c-Jun-N-terminal kinase, and p38, is thought to contribute to ischemic preconditioning. We investigated whether pretreatment with salvinorin A, the only natural nonopioid κ receptor agonist, could preserve autoregulation of the pial artery via MAPK.
  
  
  METHODS
  The response of the pial artery to hypotension and hypercapnia was monitored in piglets equipped with a closed cranial window before and after hypoxia and ischemia in the presence or absence of U0126, an inhibitor for the protein kinase upstream of ERK, sp600125, an inhibitor of c-Jun-N-terminal kinase or sb203580, an inhibitor of p38. Salvinorin A (10 μg/kg IV) was administered 30 minutes before hypoxia/ischemia in salvinorin-treated animals. Cerebrospinal fluid samples were collected before and 30 minutes after salvinorin A administration for the measurement of MAPK. Data (n = 5) were analyzed by repeated-measures analysis of variance.
  
  
  RESULTS
  Pial artery dilation to hypercapnia and hypotension was blunted after hypoxia/ ischemia but preserved well by pretreatment with salvinorin A. U0126, but not sp600125 or sb203580, abolished the preservative effects of salvinorin A on cerebral vascular autoregulation to hypotension and hypercapnia. The ratio of pERK/ERK in cerebrospinal fluid increased significantly in salvinorin-treated animals, which was inhibited by U0126.
  
  
  CONCLUSIONS
  Salvinorin A pretreatment preserves autoregulation of the pial artery to hypotension and hypercapnia after hypoxia/ischemia via ERK in a piglet model.
authors.affiliation: Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, USA. liur@uphs.upenn.ed
authors.forename: Diansan
authors.initials: D
authors.lastname: Su
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: Renyu
authors.initials: R
authors.lastname: Liu
mesh_terms: D000818:Animals; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D045785:Diterpenes, Clerodane / Q000494:pharmacology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid / Q000378:metabolism*; D006706:Homeostasis; D006935:Hypercapnia / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D007022:Hypotension / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D010841:Pia Mater / Q000098:blood supply*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D013552:Swine; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D045785:Diterpenes, Clerodane; D047428:Protein Kinase Inhibitors; D017473:Receptors, Opioid, kappa; D014665:Vasodilator Agents; D048049:Extracellular Signal-Regulated MAP Kinases; C090499:salvinorin A
references.citation: Nat Med. 1998 Feb;4(2):228-31
references.pmid: 9461198
references.citation: Stroke. 2001 Jun;32(6):1408-14
references.pmid: 11387506
references.citation: Semin Pediatr Neurol. 1998 Sep;5(3):135-51
references.pmid: 9777673
references.citation: Mol Neurobiol. 2001 Feb;23(1):1-19
references.pmid: 11642541
references.citation: Brain Res. 1998 Jul 13;799(1):44-8
references.pmid: 9666071
references.citation: Semin Cardiothorac Vasc Anesth. 2007 Mar;11(1):59-65
references.pmid: 17484174
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11934-9
references.pmid: 12192085
references.citation: Anesthesiology. 2011 Feb;114(2):374-9
references.pmid: 21245734
references.citation: Pediatr Res. 2002 May;51(5):586-91
references.pmid: 11978881
references.citation: Methods Mol Biol. 2011;717:197-219
references.pmid: 21370032
references.citation: Life Sci. 2004 Oct 15;75(22):2615-9
references.pmid: 15369697
references.citation: Science. 1999 Apr 23;284(5414):647-50
references.pmid: 10213688
references.citation: Pediatr Res. 2010 Jul;68(1):1-9
references.pmid: 20351657
references.citation: Stroke. 2008 Jan;39(1):205-12
references.pmid: 18048856
references.citation: Ment Retard Dev Disabil Res Rev. 2002;8(1):30-8
references.pmid: 11921384
references.citation: J Neurochem. 2010 Mar;112(6):1431-41
references.pmid: 19895666
references.citation: Am J Physiol Renal Physiol. 2006 Jul;291(1):F67-78
references.pmid: 16478975
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):436-41
references.pmid: 10618436
references.citation: Brain Res. 2000 Nov 24;884(1--2):51-8
references.pmid: 11082486
references.citation: Nature. 1984 Dec 6-12;312(5994):551-2
references.pmid: 6150441
references.citation: Anesthesiology. 2005 Sep;103(3):532-9
references.pmid: 16129978
references.citation: Brain Res. 1992 Mar 27;576(1):147-51
references.pmid: 1325235
references.citation: Brain Res. 2000 Mar 17;859(1):104-12
references.pmid: 10720619
references.citation: J Cereb Blood Flow Metab. 2009 Aug;29(8):1463-74
references.pmid: 19436314
references.citation: Early Hum Dev. 2001 Jan;60(3):159-170
references.pmid: 11146235
references.citation: Neurosci Lett. 2006 Dec 6;409(3):187-91
references.pmid: 17029782
references.citation: Stroke. 2005 Oct;36(10):2265-9
references.pmid: 16141421
references.citation: Neuroscience. 1999;93(1):81-8
references.pmid: 10430472
references.citation: Br J Pharmacol. 2009 Jul;157(5):844-53
references.pmid: 19422370
references.citation: Neuroreport. 2001 Nov 16;12(16):3487-91
references.pmid: 11733697
references.citation: Neuroscience. 2010 Apr 14;166(4):1091-100
references.pmid: 20083167
references.citation: Mol Interv. 2006 Oct;6(5):257-65
references.pmid: 17035666