Protein kinase C delta modulates endothelial nitric oxide synthase after cardiac arrest.

Abstract

We previously showed that inhibition of protein kinase C delta (PKCδ) improves brain perfusion 24 hours after asphyxial cardiac arrest (ACA) and confers neuroprotection in the cortex and CA1 region of the hippocampus 7 days after arrest. Therefore, in this study, we investigate the mechanism of action of PKCδ-mediated hypoperfusion after ACA in the rat by using the two-photon laser scanning microscopy (TPLSM) to observe cortical cerebral blood flow (CBF) and laser Doppler flowmetry (LDF) detecting regional CBF in the presence/absence of δV1-1 (specific PKCδ inhibitor), nitric oxide synthase (NOS) substrate (L-arginine, L-arg) and inhibitor (N(ω)-Nitro-L-arginine, NLA), and nitric oxide (NO) donor (sodium nitroprusside, SNP). There was an increase in regional LDF and local (TPLSM) CBF in the presence of δV1-1+L-arg, but only an increase in regional CBF under δV1-1+SNP treatments. Systemic blood nitrite levels were measured 15 minutes and 24 hours after ACA. Nitrite levels were enhanced by pretreatment with δV1-1 30 minutes before ACA possibly attributable to enhanced endothelial NOS protein levels. Our results suggest that PKCδ can modulate NO machinery in cerebral vasculature. Protein kinase C delta can depress endothelial NOS blunting CBF resulting in hypoperfusion, but can be reversed with δV1-1 improving brain perfusion, thus providing subsequent neuroprotection after ACA.

• Authors: Hung Wen Lin, Victoria L Gresia, Holly M Stradecki, Aleksey Alekseyenko, Cameron Dezfulian, Jake T Neumann, Kunjan R Dave, Miguel A Perez-Pinzon
• 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. 34 Issue 4 Pg. 613-20 (Apr 2014) ISSN: 1559-7016 [Electronic] United States
• PMID: 24447953 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Nitric Oxide Donors
• Nitrites
• Oligopeptides
• Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Glu-Ser-Leu
• Arginine
• Nitric Oxide Synthase Type III
• Nos3 protein, rat
• Protein Kinase C-delta

Topics

• Animals
• Arginine (pharmacology)
• Blood Flow Velocity (drug effects, physiology)
• Cerebral Cortex (blood supply, drug effects, enzymology)
• Cerebrovascular Circulation (drug effects, physiology)
• Enzyme Inhibitors (pharmacology)
• Heart Arrest (enzymology, physiopathology)
• Laser-Doppler Flowmetry
• Male
• Microscopy, Confocal
• Nitric Oxide Donors (pharmacology)
• Nitric Oxide Synthase Type III (antagonists & inhibitors, metabolism)
• Nitrites (blood)
• Oligopeptides (pharmacology)
• Protein Kinase C-delta (antagonists & inhibitors)
• Rats
• Rats, Sprague-Dawley
• Substrate Specificity