Effect of L-canavanine, an Inhibitor of inducible nitric oxide synthase, on myocardial dysfunction during septic shock

Area of Science:

• Cardiovascular Physiology
• Pharmacology
• Sepsis Pathophysiology

Background:

• Septic shock involves nitric oxide (NO) overproduction by inducible NO synthase (iNOS).
• Proinflammatory cytokines like IL-1beta and TNF-alpha contribute to cardiac contractility depression in sepsis.
• Understanding iNOS's role in sepsis-induced cardiac dysfunction is crucial for therapeutic development.

Purpose of the Study:

• To compare the effects of two nitric oxide synthase (NOS) inhibitors with differing isoform selectivity on cardiac function in a septic shock model.
• To investigate the role of iNOS in cytokine-mediated cardiac contractility depression.
• To differentiate the effects of nonselective NOS inhibition versus selective iNOS inhibition on cardiac and coronary function.

Main Methods:

• Isolated working rat heart model subjected to perfusion.
• Administration of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) to induce cardiac dysfunction.
• Treatment with N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, and L-canavanine, a selective iNOS inhibitor.
• Measurement of cardiac contractility and coronary flow.

Main Results:

• Both L-NAME and L-canavanine prevented the depression of cardiac contractility induced by IL-1beta and TNF-alpha.
• L-NAME administration alone, without cytokines, significantly reduced coronary flow and depressed cardiac contractility.
• L-canavanine did not prevent the decline in coronary conductance observed in cytokine-treated hearts, unlike L-NAME.

Conclusions:

• Cardiac dysfunction in IL-1beta and TNF-alpha-treated hearts is mediated, at least partly, by increased intracardiac iNOS activity.
• L-canavanine selectively inhibits iNOS, offering a potential therapeutic strategy for sepsis-induced cardiac dysfunction without adverse effects on coronary flow.
• L-NAME's vasopressor action in cytokine-treated hearts differs from L-canavanine's selective iNOS inhibition.