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Antishock and endothelial protective actions of a NO donor in mesenteric ischemia and reperfusion
C Carey1, M R Siegfried, X L Ma
1Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107.
Insights
A nitric oxide (NO) donor, C873754, significantly improved short-term survival in cats experiencing splanchnic artery occlusion (SAO) shock. It reduced harmful mediators, attenuated endothelial dysfunction, and decreased inflammatory cell adherence.
Area of Science:
- Cardiovascular Physiology
- Shock Pathophysiology
- Pharmacology
Background:
- Splanchnic artery occlusion (SAO) in cats induces circulatory shock with endothelial dysfunction and hypotension.
- This shock is linked to the release of proteases, free radicals, and humoral mediators.
Purpose of the Study:
- To investigate the therapeutic potential of a nitric oxide (NO) donor, C873754, in mitigating SAO-induced shock.
- To assess the effects of C873754 on humoral mediators, endothelial function, and survival rates.
Main Methods:
- SAO was induced in cats for 2 hours, followed by 2 hours of reperfusion.
- Cats received either C873754 (a NO donor) or a vehicle control prior to reperfusion.
- Plasma levels of cathepsin D and myocardial depressant factor (MDF) were measured.
- Endothelium-derived relaxing factor (EDRF) release and neutrophil adherence were assessed in vitro.
Main Results:
- C873754 significantly reduced plasma cathepsin D and MDF levels compared to the vehicle group.
- Administration of C873754 improved short-term survival rates in SAO-challenged cats.
- C873754 attenuated the decline in EDRF release and decreased neutrophil adherence to the endothelium.
Conclusions:
- The NO donor C873754 effectively reduced the accumulation of harmful humoral mediators in SAO shock.
- C873754 demonstrated significant protective effects by attenuating endothelial dysfunction and improving short-term survival.
Abstract:
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.