Nitric Oxide In The Failing Heart

NO has been implicated as contributing to myocardial dysfunction in the failing heart.58'59 A leading theory is that inflammation60'61 or cytokine activation62-64 causes induction of NOS2, a high-output isoform.65 NOS2, not normally present in myocardium, has been detected by immunohistochemistry, western blot, polymerase chain reaction,66 and arginine-to-citrulline conversion assays67,68 in myocardium from patients with heart failure due to idiopathic dilated cardiomyopathy, ischemic cardiomyopathy, valvular heart disease, and myocarditis.69,70 Functionally, patients with heart failure58,59 and dogs with pacing-induced heart failure18 are more responsive to L-NG-monomethyl arginine (L-NMMA) augmentation of P-adrenergic contractility than are subjects with normal left ventricular function (Fig. 6-2). Augmentation of P-adrenergic inotropic responses has been used as a functional marker of NOS activity within the heart. In myocarditis and sepsis,71 increased NO production due to induction of NOS2 clearly contributes to this process.

Fig. 6-2. Impact of the nitric oxide synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA) on the positive inotropic response to dobutamine in conscious dogs. Dobutamine was infused intravenously in dogs before (A) and after (B) heart failure was induced by rapid pacing for 4 weeks. Dobutamine was infused at baseline (d)and after a 60-min infusion of L-NMMA at either 10 (A) or 20 (O) mg/kg. Before heart failure, 20 but not 10 mg/kg L-NMMA augmented the inotropic response to dobutamine. After heart failure, the lower infusion of L-NMMA (10 mg/kg) was equally effective at enhancing inotropic responses as the higher infusion. These data demonstrate an increased sensitivity to NOS-related influences over myocardial contractile regulation and are consistent with an increased biologic activity of NOS in heart failure. (Data from Hare et al.18)

Dobutamine, ^g/min

Fig. 6-2. Impact of the nitric oxide synthase (NOS) inhibitor L-NG-monomethyl arginine (L-NMMA) on the positive inotropic response to dobutamine in conscious dogs. Dobutamine was infused intravenously in dogs before (A) and after (B) heart failure was induced by rapid pacing for 4 weeks. Dobutamine was infused at baseline (d)and after a 60-min infusion of L-NMMA at either 10 (A) or 20 (O) mg/kg. Before heart failure, 20 but not 10 mg/kg L-NMMA augmented the inotropic response to dobutamine. After heart failure, the lower infusion of L-NMMA (10 mg/kg) was equally effective at enhancing inotropic responses as the higher infusion. These data demonstrate an increased sensitivity to NOS-related influences over myocardial contractile regulation and are consistent with an increased biologic activity of NOS in heart failure. (Data from Hare et al.18)

There are, however, mechanisms in addition to increased NO production that contribute to this phenomenon. Because P-adrenergic inotropic responses likely result from the balance between cGMP and cAMP, down-regulation in cAMP pathways, as occurs in heart failure,72 could also lead to enhanced effects of NO. There is also the potential for abnormal signaling of NO with regard to S-NO reactions. To the extent that these reactions are the mode of NO signaling in the SR and mitochondria, they may contribute to the energetic abnormalities that are characteristic of the failing heart. Given that NO signaling appears to be locally regulated, it is plausible that one pathway may appear to have an increased or unchanged activity (sarcolemmal NOS3 influencing guanylyl cyclase activity or L-type function or both) while another is decreased or abnormal (SR NOS1 influencing the CRC or Ca2+-ATPase or both).

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