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Inhibition of nitric oxide synthesis causes myocardial ischemia in endotoxemic rats
J A Avontuur1, H A Bruining, C Ince
1Department of Surgery, University Hospital Rotterdam, Netherlands.
Abstract:
Inhibitors of nitric oxide (NO) synthesis have been used in the treatment of septic and endotoxic shock. However, several studies question the beneficial effect of inhibiting NO production in sepsis and endotoxemia. We have investigated the effect of inhibition of NO synthesis after endotoxemia in the isolated perfused rat heart. In hearts from endotoxin-treated animals, coronary flow was elevated 64% and oxygen consumption was elevated 20% compared with control hearts. NADH fluorescence imaging was used as an indicator of regional hypoperfusion. A homogeneous low-surface NADH fluorescence, indicative of adequate tissue perfusion, was observed in both control and endotoxin-treated hearts. The increase in coronary flow and oxygen consumption could only partially be prevented by pretreatment of the animals with dexamethasone. Addition of N omega-nitro-L-arginine (NNLA), an inhibitor of NO synthesis, to the perfusion medium eliminated differences in coronary flow and oxygen consumption between normal and endotoxin-treated hearts. However, NADH surface fluorescence images of endotoxin-treated hearts after NNLA revealed areas of high fluorescence, indicating local ischemia, whereas the control hearts remained without signs of ischemia. The ischemic areas were present at various perfusion pressures and disappeared after the infusion of L-arginine, the natural precursor of NO, or the exogenous NO donor sodium nitroprusside. Methylene blue (MB), an inhibitor of soluble guanylate cyclase, the effector enzyme of NO, also eliminated differences in coronary flow and produced similar areas of local myocardial ischemia in endotoxin-treated hearts but not in control hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Inhibiting nitric oxide (NO) synthesis in endotoxemia paradoxically caused heart ischemia. Restoring NO production or its downstream signaling reversed these harmful effects, highlighting NO
Area of Science:
- Cardiovascular Physiology
- Sepsis Pathophysiology
- Nitric Oxide Signaling
Background:
- Nitric oxide (NO) synthesis inhibitors are used for septic shock, but their efficacy is debated.
- Endotoxemia increases coronary flow and oxygen consumption in isolated rat hearts.
- NADH fluorescence imaging assesses tissue perfusion and regional hypoperfusion.
Purpose of the Study:
- Investigate the effects of inhibiting NO synthesis on endotoxemia-induced changes in the isolated perfused rat heart.
- Determine if NO inhibition exacerbates or ameliorates myocardial ischemia in endotoxemia.
Main Methods:
- Isolated perfused rat heart model subjected to endotoxemia.
- Measurement of coronary flow and oxygen consumption.
- NADH fluorescence imaging to assess regional myocardial perfusion.
Main Results:
- Endotoxemia elevated coronary flow and oxygen consumption.
- Inhibition of NO synthesis (NNLA) normalized flow and consumption but induced localized ischemia.
- Ischemia was reversed by L-arginine or sodium nitroprusside, and by methylene blue, an inhibitor of soluble guanylate cyclase.
Conclusions:
- Inhibition of NO synthesis in endotoxemia leads to detrimental local myocardial ischemia.
- NO plays a critical protective role in maintaining myocardial perfusion during endotoxemia.
- Targeting NO signaling pathways requires careful consideration of potential adverse effects on cardiac perfusion.