Proinflammatory cytokines depress cardiac efficiency by a nitric oxide-dependent mechanism

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Inflammation and Immunity

Background:

• Proinflammatory cytokines (Cytomix) can depress myocardial contractile function.
• Nitric oxide (NO) and peroxynitrite are known to inhibit myocardial oxygen consumption (MVO2).
• The precise mechanism by which cytokines impair cardiac work, particularly concerning NO/peroxynitrite and mitochondrial function, requires further elucidation.

Purpose of the Study:

• To investigate whether NO and peroxynitrite contribute to cytokine-induced depression of cardiac work.
• To examine the role of inducible nitric oxide synthase (iNOS) in mediating these effects.
• To determine if NO/peroxynitrite impair cardiac function by inhibiting mitochondrial respiration or by affecting ATP utilization for contractile work.

Main Methods:

• Isolated working rat heart model subjected to Cytomix treatment.
• Measurement of cardiac work, myocardial oxygen consumption (MVO2), and cardiac efficiency.
• Assessment of iNOS expression and inhibition using mercaptoethylguanidine (MEG) and dexamethasone (Dex).

Main Results:

• Cytomix significantly depressed cardiac work and efficiency, with reduced MVO2 observed later.
• MEG and Dex abolished the cardiac depression induced by Cytomix.
• Cytomix increased iNOS expression 10-fold, an effect abolished by Dex but not MEG.
• Cardiac work depression by Cytomix preceded the reduction in MVO2.

Conclusions:

• Cytokine-induced cardiac dysfunction involves the stimulation of iNOS.
• The findings suggest that NO and/or peroxynitrite impair cardiac function by reducing the heart's ability to utilize ATP for contractile work, rather than by inhibiting mitochondrial respiration.
• This highlights a novel mechanism of inflammatory cardiomyopathy.