Role of nitric oxide and cGMP in human septic serum-induced depression of cardiac myocyte contractility

Abstract

Previous studies have demonstrated the existence of a circulating myocardial depressant substance during human septic shock. We have recently identified this substance as a synergistic combination of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This study utilized an in vitro cardiac myocyte assay to evaluate the potential mechanistic role of nitric oxide (NO) and cGMP in depression of myocyte contractility induced by TNF-α, IL-1β, TNF-α + IL-1β (at low concentrations), and human septic shock serum (HSS). TNF-α, IL-1β, TNF-α + IL-1β, and each of 5 sera from patients with acute septic shock caused depression of both maximum extent and peak velocity of cardiac myocyte shortening and an increase in intracellular cGMP concentration during 30 min of exposure (minimum P < 0.01). NO synthetase (NOS) and guanylate cyclase inhibitors such as N-methyl-l-arginine (l-NMA) and methylene blue prevented these effects; an excess ofl-arginine withl-NMA restored them (minimum P < 0.01). In contrast,d-arginine failed to reestablish cytokine-induced myocyte depression and cGMP accumulation prevented byl-NMA. Exposure of myocytes to TNF-α, IL-1β, or TNF-α + IL-1β produced a concentration-dependent increase in intracellular cGMP that paralleled the depression of cardiac myocyte contractility (minimum P < 0.001). In addition, TNF-α, IL-1β, TNF-α + IL-1β, or HSS application to cardiac myocytes resulted in increased NO gas generation, which was inhibited byl-NMA (minimum P < 0.01). Furthermore, unstimulated cardiac myocytes were shown to harbor constitutive but not inducible NOS activity. These data suggest that the sequential generation of NO by a constitutive NOS and cGMP by guanylate cyclase represents an important mechanism of cardiac myocyte depression by TNF-α, IL-1β, TNF-α + IL-1β, and the myocardial depressant substance(s) of septic shock.

Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

“…Studies examining the basis of depressed myocardial contractility in sepsis showed that TNF-a and IL-1b impair cardiac and cardiomyocyte contractility (46)(47)(48). These cytokines also induce mitochondrial injury (44).…”

Methylene Blue for Distributive Shock: A Potential New Use of an Old Antidote

“…cGMP has a central role in many other vital processes such as retinal phototransduction, electrolyte regulation, and mediation of vascular smooth muscle tone [45,46]. Excessive cGMP production, generally through abundant NO availability, is implicated in the pathophysiology of distributive shock such as sepsis and anaphylaxis [47]. Dysfunction within the NOcGMP pathway has been implicated in certain disease states of distributive shock such as sepsis and anaphylaxis.…”

“…The overproduction of NO by iNOS in sepsis results in increased production of cGMP contributing to the refractory hypotension observed with septic shock. Numerous animal studies demonstrate large increases of NO after exposure to lipopolysaccharide (i.e., endotoxin) with resultant hypotension [62][63][64][65][66][67].…”

Molecular Events in the Cardiomyopathy of Sepsis

“…However, its role and impact on septic cardiomyopathy is still a matter of debate. Whereas disproportionate levels of NO sustain the ability of the left ventricle to fill during diastole, and thereby crucially support adequate myocardial perfusion (107,108), cardiodepressant activity of proinflammatory cytokines also seems to involve NO synthase (NOS): exposure of rat cardiomyocytes to septic sera depressed contractility (see below), but NOS inhibition restored contractility to control levels (109). Moreover, intracoronary infusion of the NO donor sodium nitroprusside impaired systolic pressure development despite improved diastolic relaxation and distensibility (110).…”