Nitric oxide modulation of TNF-alpha-induced cardiac contractile dysfunction is concentration dependent

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Inflammation Research

Background:

• Tumor necrosis factor-alpha (TNF-alpha) is linked to cardiac dysfunction, but the underlying mechanisms, particularly the role of cardiac nitric oxide (NO), are not fully understood.
• Conflicting reports exist regarding the effects of NO on cardiac function during inflammation, suggesting a complex, possibly dose-dependent, role.

Purpose of the Study:

• To investigate the dual effects of nitric oxide (NO) donors on TNF-alpha-induced cardiac dysfunction and injury.
• To elucidate the concentration-dependent protective or detrimental mechanisms of NO in the context of TNF-alpha-mediated cardiac inflammation.

Main Methods:

• Utilized Langendorff perfused heart preparations and isolated cardiomyocyte models.
• Administered TNF-alpha with varying concentrations of NO donors (S-nitroso-N-acetyl-penicillamine [SNAP] and (Z)-1-[N-(3-ammonio-propyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate [PAPA/NO]).
• Assessed cardiac contractility, relaxation, cellular injury (creatine kinase release, Trypan blue exclusion), and intracellular calcium handling ([Ca(2+)](i)).

Main Results:

• TNF-alpha alone impaired cardiac contraction, relaxation, and induced cardiomyocyte injury.
• Low concentrations of NO donors (SNAP, PAPA/NO) attenuated TNF-alpha-induced cardiac injury and improved contractile function.
• High concentrations of NO donors exacerbated TNF-alpha-mediated cardiac dysfunction and cellular damage.

Conclusions:

• Nitric oxide (NO) exhibits a concentration-dependent effect on TNF-alpha-induced cardiac pathology.
• Low-dose NO is cardioprotective against TNF-alpha-induced inflammation, whereas high-dose NO is detrimental.
• These findings offer a potential explanation for disparate outcomes in previous studies on NO and inflammation in the heart.