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Inhibition of inducible nitric oxide synthase after myocardial ischemia increases coronary flow
P E Parrino1, V E Laubach, J R Gaughen
1Department of Surgery, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Background:
The role of nitric oxide synthase in myocardial ischemia-reperfusion injury is complex. Our hypothesis was that inducible nitric oxide synthase has a role in the regulation of coronary flow after ischemia.
Methods:
Four groups of isolated blood-perfused rabbit hearts underwent sequential periods of perfusion, ischemia, and reperfusion (20, 30, and 20 minutes). Two groups underwent 40 minutes of perfusion. Ischemic groups received saline vehicle, N omega-nitro-L-arginine methyl ester (L-NAME) or the highly specific inducible nitric oxide synthase inhibitor 1400W in low or high doses during reperfusion. Two nonischemic groups were treated with saline vehicle or 1400W during the last 20 minutes of perfusion. Left ventricular developed pressure and coronary flow were measured after each perfusion period. Ventricular levels of myeloperoxidase and cyclic guanosine monophosphate were measured at the end of the second perfusion period.
Results:
Coronary flow was significantly increased in both 1400W groups versus L-NAME (p < 0.001) and in high-dose 1400W versus control (p < 0.001). Coronary flow was not significantly different between the nonischemic groups. Left ventricular developed pressure was not significantly different among the ischemic groups or between the two nonischemic groups. There were no differences in cyclic guanosine monophosphate levels in any of the ischemic hearts. Myeloperoxidase levels were significantly elevated in L-NAME versus high-dose 1400W, nonischemic 1400W, and nonischemic saline groups (p < 0.02).
Conclusions:
Highly selective inhibition of inducible nitric oxide synthase results in increased coronary flow after ischemia but not after continuous perfusion. This occurs with decreased neutrophil accumulation and a trend toward increased contractility without elevation of cyclic guanosine monophosphate levels.
Insights
Selective inhibition of inducible nitric oxide synthase significantly increased coronary flow after ischemia. This effect was observed with reduced neutrophil accumulation and improved contractility, highlighting its role in myocardial ischemia-reperfusion injury.
Area of Science:
- Cardiovascular Physiology
- Biomedical Research
- Pharmacology
Background:
- Nitric oxide synthase (NOS) plays a complex role in myocardial ischemia-reperfusion (I/R) injury.
- Inducible nitric oxide synthase (iNOS) is hypothesized to regulate coronary blood flow post-ischemia.
Purpose of the Study:
- To investigate the role of iNOS in regulating coronary blood flow following myocardial ischemia.
- To assess the impact of iNOS inhibition on cardiac function and inflammatory markers during I/R.
Main Methods:
- Isolated blood-perfused rabbit hearts subjected to ischemia-reperfusion protocols.
- Treatment with N omega-nitro-L-arginine methyl ester (L-NAME) or the selective iNOS inhibitor 1400W during reperfusion.
- Measurement of left ventricular developed pressure, coronary flow, myeloperoxidase, and cyclic guanosine monophosphate.
Main Results:
- Selective iNOS inhibition with 1400W significantly increased coronary flow post-ischemia compared to L-NAME and control.
- No significant differences in left ventricular developed pressure or cyclic guanosine monophosphate levels were observed among ischemic groups.
- Myeloperoxidase levels were elevated in L-NAME treated hearts, indicating reduced neutrophil accumulation with 1400W.
Conclusions:
- Highly selective iNOS inhibition enhances coronary flow post-ischemia, independent of cyclic guanosine monophosphate levels.
- This inhibition is associated with decreased neutrophil infiltration and a trend toward improved contractility.
- iNOS plays a critical role in modulating coronary blood flow dynamics during myocardial I/R injury.