Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia

Abstract

We investigated whether increased nitric oxide (NO) synthase activity within cardiac myocytes contributes to the depressed cardiac contractility observed in endotoxic shock. Isolated ventricular myocytes were studied to examine the effects of substrates and inhibitors of NO synthase on myocyte contractility. When stimulated electrically, the resting length of myocytes from control animals shortened by 5.3 +/- 0.3% (means +/- SE, n = 32). Baseline contraction of myocytes from endotoxin-treated animals was reduced to 3.0 +/- 0.3% (n = 17, P < 0.001). The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) had no effect on myocytes from control animals, but it increased the contraction of myocytes from endotoxin-treated animals by 40% (fractional shortening increased to 4.3 +/- 0.4%, P < 0.01). Similar results were obtained with NG-methyl-L-arginine. The effect of L-NAME could be reversed by excess L-arginine, but not D-arginine. The effect of endotoxin was abolished by dexamethasone pretreatment. Methylene blue also reversed the effects of endotoxin but had toxic effects on myocytes. Agents that either prevent synthesis or the effects of NO reverse the depression of myocyte contraction seen following endotoxin treatment.

Comparison of the ability of nicardipine, theophylline and zaprinast to restore cardiovascular haemodynamics following inhibition of nitric oxide synthesis

“…Thus we would expect that inhibition of endocardial or myocardial NO synthesis by L-NAME would increase myocardial contractility if it is to have any direct effect. In fact, previous work has shown that administration of NO synthase inhibitors to isolated cardiac myocytes from healthy animals neither augments nor reduces their contractility (Amrani et al, 1992;Brady et al, 1992). In our experiments cardiac output decreased following inhibition of NO synthesis and was completely restored by nicardipine which is a vasodilator with little or no direct inotropic action (Rousseau et al, 1985).…”

“…This mechanism may contribute to myocardial dysfunction in endotoxic shock (Brady et al, 1992) and in dilated cardiomyopathy (de Belder et al, 1993). Thus we would expect that inhibition of endocardial or myocardial NO synthesis by L-NAME would increase myocardial contractility if it is to have any direct effect.…”

Inhibition of the skeletal muscle ryanodine receptor calcium release channel by nitric oxide

“…The effect of NO on SR Ca z+ release could account for the previously observed NO-induced force reduction in both skeletal [5] and cardiac muscle [3,4]. Whether or not NO has a role in regulating muscle contraction on a twitch-by-twitch (or beatby-beat) basis is too early to speculate.…”

“…More recently, NO has been implicated in cytokine-and endotoxin-evoked decreases in cardiac contractility [3,4] and found to depress contractile function in fast skeletal muscle where the brain type constitutive NO-synthase (NOS) has been shown to be expressed [5]. The reduction of skeletal muscle contractile force by NO was only partially ascribable to its stimulatory effect on guanylate cyclase [5], the often reported signaling pathway in NO action [1,2,6].…”

Role of nitric oxide following cardiac transplantation

“…11 Nitric oxide can exert a negative inotropic effect in cultured guinea pig myocytes, an effect augmented by enhanced nitric oxide production induced by endotoxin. 12 In addition, nitric oxide can also affect diastolic function by quickening ventricular relaxation and enhancing chamber passive relaxation. [13][14][15] The actions of nitric oxide on the coronary circulation have been well studied.…”