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Published on: June 18, 2012
Vasodilator mechanisms in the coronary circulation of endothelial nitric oxide synthase-deficient mice
K G Lamping1, D W Nuno, E G Shesely
1Departments of Internal Medicine and Pharmacology, The Cardiovascular Center, University of Iowa, and Veterans Affairs Medical Center, Iowa City, Iowa 52246, USA. klamping@blue.weeg.uiowa.edu
Abstract:
Previous studies have demonstrated that responses to endothelium-dependent vasodilators are absent in the aortas from mice deficient in expression of endothelial nitric oxide synthase (eNOS -/- mice), whereas responses in the cerebral microcirculation are preserved. We tested the hypothesis that in the absence of eNOS, other vasodilator pathways compensate to preserve endothelium-dependent relaxation in the coronary circulation. Diameters of isolated, pressurized coronary arteries from eNOS -/-, eNOS heterozygous (+/-), and wild-type mice (eNOS +/+ and C57BL/6J) were measured by video microscopy. ACh (an endothelium-dependent agonist) produced vasodilation in wild-type mice. This response was normal in eNOS +/- mice and was largely preserved in eNOS -/- mice. Responses to nitroprusside were also similar in arteries from eNOS +/+, eNOS +/-, and eNOS -/- mice. Dilation to ACh was inhibited by N(G)-nitro-L-arginine, an inhibitor of NOS in control and eNOS -/- mice. In contrast, trifluoromethylphenylimidazole, an inhibitor of neuronal NOS (nNOS), decreased ACh-induced dilation in arteries from eNOS-deficient mice but had no effect on responses in wild-type mice. Indomethacin, an inhibitor of cyclooxygenase, decreased vasodilation to ACh in eNOS-deficient, but not wild-type, mice. Thus, in the absence of eNOS, dilation of coronary arteries to ACh is preserved by other vasodilator mechanisms.
Insights
In mice lacking endothelial nitric oxide synthase (eNOS), coronary arteries still dilate to acetylcholine. This preserved vasodilation in eNOS-deficient mice is mediated by neuronal NOS and cyclooxygenase pathways.
Area of Science:
- Cardiovascular Physiology
- Vascular Biology
- Nitric Oxide Signaling
Background:
- Endothelium-dependent vasodilation is crucial for regulating blood flow.
- Endothelial nitric oxide synthase (eNOS) is a primary mediator of vasodilation.
- Previous studies showed impaired vasodilation in eNOS-deficient aortas but preserved responses in cerebral microcirculation.
Purpose of the Study:
- To investigate compensatory vasodilator mechanisms in coronary arteries lacking eNOS.
- To test the hypothesis that alternative pathways preserve endothelium-dependent relaxation in eNOS knockout mice.
Main Methods:
- Isolated, pressurized mouse coronary arteries (eNOS -/-, +/-, and wild-type) were studied.
- Vessel diameters were measured using video microscopy following stimulation with acetylcholine (ACh).
- Pharmacological inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX) were used to probe vasodilator pathways.
Main Results:
- Acetylcholine induced significant vasodilation in coronary arteries from eNOS -/- mice, similar to wild-type.
- This vasodilation in eNOS -/- mice was partially inhibited by a neuronal NOS (nNOS) inhibitor and an indomethacin (COX inhibitor).
- Nitroprusside responses were unaffected by eNOS deficiency, indicating preserved smooth muscle function.
Conclusions:
- Coronary artery vasodilation to acetylcholine is largely preserved in the absence of eNOS.
- Neuronal NOS and cyclooxygenase pathways compensate for the lack of eNOS in mediating endothelium-dependent relaxation in coronary arteries.
- These findings highlight the functional redundancy of vasodilator mechanisms in the coronary circulation.
