Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling.

Abstract

RATIONALE:

Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury.

OBJECTIVE:

No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy.

METHODS AND RESULTS:

Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.

CONCLUSIONS:

These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.

• Authors: Shashi Bhushan, Kazuhisa Kondo, David J Polhemus, Hiroyuki Otsuka, Chad K Nicholson, Ya-Xiong Tao, Hui Huang, Vasiliki V Georgiopoulou, Toyoaki Murohara, John W Calvert, Javed Butler, David J Lefer
• Journal: Circulation research (Circ Res) Vol. 114 Issue 8 Pg. 1281-91 (Apr 11 2014) ISSN: 1524-4571 [Electronic] United States
• PMID: 24599803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Nitric Oxide
• Cyclic GMP
• Sodium Nitrite

Topics

• Aged
• Animals
• Biological Availability
• Cyclic GMP (metabolism)
• Cytoprotection (physiology)
• Disease Models, Animal
• Female
• Heart Failure (drug therapy, metabolism, physiopathology)
• Hemodynamics (drug effects)
• Humans
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Nitric Oxide (physiology)
• Signal Transduction (drug effects, physiology)
• Sodium Nitrite (pharmacology, therapeutic use)
• Stroke Volume (drug effects)
• Ventricular Dysfunction, Left (drug therapy, physiopathology)