Inducible nitric oxide synthase inhibits oxygen consumption in collateral-dependent myocardium
Yingjie Chen1, Ping Zhang, Jingxin Li
1Departments of Medicine and Integrative Biology/Physiology, University of Minnesota Medical School, Minneapolis, Minnesota; and.
Insights
Nitric oxide (NO) from inducible NO synthase (iNOS) restrains myocardial oxygen consumption, enhancing blood flow to collateral-dependent heart regions. This mechanism protects the heart during ischemia by optimizing oxygen supply and demand.
Area of Science:
- Cardiovascular Physiology
- Myocardial Ischemia Research
- Vascular Biology
Background:
- Coronary artery occlusion triggers collateral vessel growth to supply ischemic myocardium.
- Inflammation, cytokines, growth factors, and nitric oxide synthases (NOS) are involved in collateral development.
- Nitric oxide (NO) is a known vasodilator crucial for collateral function.
Purpose of the Study:
- To investigate whether NO from inducible NO synthase (iNOS) or constitutive NOS regulates myocardial blood flow (MBF) in collateral regions.
- To elucidate the role of iNOS-derived NO in myocardial oxygen consumption (MVo2) and vasodilation.
Main Methods:
- Utilized nonselective NOS inhibition with N(G)-nitro-l-arginine (LNA) and selective iNOS inhibition with 1400W.
- Measured myocardial blood flow (MBF) and myocardial oxygen consumption (MVo2) in collateral regions during exercise.
- Assessed the impact of NOS inhibition on hemodynamic parameters.
Main Results:
- Nonselective NOS inhibition (LNA) decreased MBF in collateral regions during exercise.
- Selective iNOS inhibition (1400W) increased MBF by 21 ± 5% in collateral regions.
- Increased MBF after iNOS blockade correlated with increased MVo2, suggesting metabolic vasodilation.
Conclusions:
- NO produced by iNOS inhibits MVo2 in collateralized regions, thereby restraining blood flow.
- Selective iNOS blockade leads to increased MVo2 and subsequent metabolic vasodilation, enhancing MBF.
- Coordinated iNOS (restraining MVo2) and eNOS (maintaining vasodilation) optimize oxygen supply-demand, protecting ischemic myocardium.
Abstract:
Following coronary artery occlusion growth of collateral vessels can provide an effective blood supply to the dependent myocardium. The ischemia, which results in growth of collateral vessels, recruits an inflammatory response with expression of cytokines and growth factors, upregulation of endothelial nitric oxide (NO) synthase (eNOS) in vascular endothelial cells, and expression of inducible nitric oxide synthase (iNOS) in both vessels and cardiac myocytes. Because NO is a potent collateral vessel dilator, this study examined whether NO derived from iNOS or constitutive NOS regulates myocardial blood flow (MBF) in the collateral region. Nonselective NOS inhibition with N(G)-nitro-l-arginine (LNA) caused vasoconstriction with a significant decrease in MBF to the collateral region during exercise. In contrast, the highly selective iNOS inhibitor 1400W caused a 21 ± 5% increase of MBF in the collateral region. This increase in MBF following selective iNOS blockade was proportionate to an increase in myocardial O2 consumption (MVo2). The results suggest that NO produced by iNOS inhibits MVo2 in the collateralized region, so that the increase in MBF following iNOS blockade was the result of metabolic vasodilation secondary to an increase in MVo2. Thus the coordinated expression of iNOS to restrain MVo2 and eNOS to maintain collateral vasodilation act to optimize the O2 supply-demand relationship and protect the collateralized myocardium from ischemia.
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