ERK1/2 inhibition attenuates cerebral blood flow reduction and abolishes ET(B) and 5-HT(1B) receptor upregulation after subarachnoid hemorrhage in rat.

Abstract

Upregulation of endothelin B (ET(B)) and 5-hydroxytryptamine 1B (5-HT(1B)) receptors via transcription has been found after experimental subarachnoid hemorrhage (SAH), and this is associated with enhanced phosphorylation of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK1/2). In the present study, we hypothesized that inhibition of ERK1/2 alters the ET(B) and 5-HT(1B) receptor upregulation and at the same time prevents the sustained cerebral blood flow (CBF) reduction associated with SAH. The ERK1/2 inhibitor SB386023-b was injected intracisternally in conjunction with and after the induced SAH in rats. At 2 days after the SAH, cerebral arteries were harvested for quantitative real-time polymerase chain reaction, immunohistochemistry and analysis of contractile responses to endothelin-1 (ET-1; ET(A) and ET(B) receptor agonist) and 5-carboxamidotryptamine (5-CT; 5-HT1 receptor agonist) in a sensitive myograph. To investigate if ERK1/2 inhibition had an influence on the local and global CBF after SAH, an autoradiographic technique was used. At 48 h after induced SAH, global and regional CBF were reduced by 50%. This reduction was prevented by treatment with SB386023-b. The ERK1/2 inhibition also decreased the maximum contraction elicited by application of ET-1 and 5-CT in cerebral arteries compared with SAH. In parallel, ERK1/2 inhibition downregulated ET(B) and 5-HT(1B) receptor messenger ribonucleic acid and protein levels compared with the SAH. Cerebral ischemia after SAH involves vasoconstriction and subsequent reduction in the CBF. The results suggest that ERK1/2 inhibition might be a potential treatment for the prevention of cerebral vasospasm and ischemia associated with SAH.

• Authors: Saema A S Beg, Jacob A Hansen-Schwartz, Petter J Vikman, Cang-Bao Xu, Lars I H Edvinsson
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 26 Issue 6 Pg. 846-56 (Jun 2006) ISSN: 0271-678X [Print] United States
• PMID: 16251886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Enzyme Inhibitors
• RNA, Messenger
• Receptor, Endothelin B
• Receptor, Serotonin, 5-HT1B
• Serotonin Receptor Agonists
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Autoradiography
• Brain (blood supply, physiopathology)
• Cerebral Arteries (drug effects, physiology)
• Cerebrovascular Circulation (drug effects, physiology)
• Disease Models, Animal
• Endothelin-1 (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, drug effects, metabolism)
• Immunohistochemistry
• Male
• Muscle Contraction (drug effects, physiology)
• Muscle, Smooth, Vascular (drug effects, metabolism)
• RNA, Messenger (analysis)
• Rats
• Rats, Sprague-Dawley
• Receptor, Endothelin B (metabolism)
• Receptor, Serotonin, 5-HT1B (metabolism)
• Regional Blood Flow
• Reverse Transcriptase Polymerase Chain Reaction
• Serotonin Receptor Agonists (pharmacology)
• Subarachnoid Hemorrhage (metabolism, physiopathology)
• Up-Regulation
• Vasoconstriction (drug effects, physiology)