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Analytical Techniques for Assaying Nitric Oxide Bioactivity
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Uncoupled cardiac nitric oxide synthase mediates diastolic dysfunction.

Gad A Silberman1, Tai-Hwang M Fan, Hong Liu

  • 1Department of Medicine (Division of Cardiology), Emory University School of Medicine, Atlanta, GA, USA.

Circulation
|January 20, 2010
PubMed
Summary
This summary is machine-generated.

Tetrahydrobiopterin (BH(4)) deficiency contributes to cardiac oxidation and diastolic dysfunction in hypertension. Supplementing BH(4) improves cardiac function, suggesting it as a potential treatment for heart failure with preserved ejection fraction.

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Area of Science:

  • Cardiovascular Physiology
  • Oxidative Stress Biology
  • Pharmacology

Background:

  • Hypertension is a leading cause of heart failure with preserved ejection fraction, characterized by impaired cardiac diastolic relaxation.
  • Reduced nitric oxide (NO) bioavailability due to uncoupled NO synthase (NOS), often caused by tetrahydrobiopterin (BH(4)) depletion, is implicated in diastolic dysfunction.
  • Oxidative stress and BH(4) deficiency may impair cardiac diastolic function independently of vascular effects.

Purpose of the Study:

  • To investigate the role of cardiac oxidation and BH(4) deficiency in hypertension-induced diastolic dysfunction.
  • To explore the therapeutic potential of BH(4) supplementation for diastolic dysfunction.

Main Methods:

  • Utilized a hypertensive mouse model (unilateral nephrectomy, deoxycorticosterone acetate pellet, saline drinking) to assess cardiac function, oxidation, and NOS coupling.
  • Measured cardiac BH(4) levels, oxidized biopterins, NO and superoxide production, and phospholamban phosphorylation.
  • Administered BH(4) to hypertensive mice and assessed its effects on cardiac function and molecular markers.
  • Conducted isolated cardiomyocyte experiments to evaluate relaxation properties.

Main Results:

  • Hypertensive mice exhibited diastolic dysfunction, cardiac oxidation, reduced cardiac BH(4), and uncoupled NOS with decreased NO production.
  • BH(4) supplementation, but not hydralazine or tetrahydroneopterin, improved cardiac BH(4) levels, phospholamban phosphorylation, and diastolic function.
  • Isolated cardiomyocytes showed impaired relaxation normalized by BH(4) treatment.
  • Cardiac-specific angiotensin-converting enzyme overexpression induced similar oxidative and diastolic dysfunction phenotypes.

Conclusions:

  • Cardiac oxidation, independent of vascular factors, can lead to uncoupled NOS and diastolic dysfunction.
  • Tetrahydrobiopterin (BH(4)) replenishment is a promising therapeutic strategy for diastolic dysfunction associated with hypertension.