Salvinorin A pretreatment preserves cerebrovascular autoregulation after brain hypoxic/ischemic injury via extracellular signal-regulated kinase/mitogen-activated protein kinase in piglets

Anesth Analg. 2012 Jan;114(1):200-4. doi: 10.1213/ANE.0b013e31823a5d36. Epub 2011 Nov 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebrovascular Circulation / drug effects*
  • Disease Models, Animal
  • Diterpenes, Clerodane / pharmacology*
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / cerebrospinal fluid
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Homeostasis
  • Hypercapnia / drug therapy
  • Hypercapnia / enzymology
  • Hypercapnia / physiopathology
  • Hypotension / drug therapy
  • Hypotension / enzymology
  • Hypotension / physiopathology
  • Hypoxia-Ischemia, Brain / cerebrospinal fluid
  • Hypoxia-Ischemia, Brain / drug therapy*
  • Hypoxia-Ischemia, Brain / enzymology
  • Hypoxia-Ischemia, Brain / physiopathology
  • Pia Mater / blood supply*
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / metabolism
  • Swine
  • Vasodilation / drug effects
  • Vasodilator Agents / pharmacology*


  • Diterpenes, Clerodane
  • Protein Kinase Inhibitors
  • Receptors, Opioid, kappa
  • Vasodilator Agents
  • Extracellular Signal-Regulated MAP Kinases
  • salvinorin A