Antishock and endothelial protective actions of a NO donor in mesenteric ischemia and reperfusion.
Splanchnic artery occlusion (SAO) of the celiac, superior mesenteric, and inferior mesenteric arteries for 2 hr, followed by a 2-hr reperfusion period in cats produces a severe form of circulatory shock characterized by endothelial dysfunction, increased lysosomal leakage, and severe hypotension resulting from release of proteases, oxygen-derived free radicals, and other humoral mediators into the circulation. Administration of 0.75 mg/kg/hr of C873754, a nitric oxide (NO) donor, 10 min prior to reperfusion, significantly attenuated the accumulation of plasma cathepsin D from 12 +/- 3 U/ml in the SAO + vehicle group to 5 +/- 1 U/ml (P < 0.05) in the C87-3754 treated SAO group. A similar attenuation of plasma myocardial depressant factor (MDF) activity was observed in the C87-3754 treated cats (P < 0.02). Administration of C87-3754 significantly increased short term (i.e., 2-hr) survival rate (P < 0.05, compared to the vehicle group). Moreover, C87-3754 attenuated the SAO shock induced decline in release of endothelium-derived relaxing factor (EDRF) from isolated superior mesenteric artery (SMA) rings stimulated by acetylcholine and A23187. Additionally, C87-3754 significantly decreased PMN adherence to the superior mesenteric venous endothelium in vitro. Thus, treatment with the NO donor, C87-3754 reduced the accumulation of humoral mediators into the plasma while significantly attenuating endothelial dysfunction and improving short term survival.
Carey
C
C
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Siegfried
M R
MR
Ma
X L
XL
Weyrich
A S
AS
Lefer
A M
AM
D000818:Animals; D002402:Cathepsin D / Q000097:blood; D002415:Cats; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000187:drug effects*; D008297:Male; D008641:Mesenteric Vascular Occlusion / Q000150:complications / Q000503:physiopathology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D015427:Reperfusion Injury / Q000517:prevention & control*; D012769:Shock / Q000517:prevention & control*; D013558:Sydnones / Q000494:pharmacology*
D013558:Sydnones; C072857:3-(cis-2,6-dimethylpiperidino)sydnonimine; D009569:Nitric Oxide; D002402:Cathepsin D