The force and frequency of myocardial contraction and active myocardial relaxation are physiologically regulated by neurotransmitters and hormones. Norepinepherine released by the sympathetic nerves in the heart and epinephrine released into the circulation by adrenal glands increase myocardial contractility and relaxation by acting primarily on beta-adrenergic receptors on heart muscles49 (Figure 18.1). Myocardial responsiveness to beta-adrenergic agonists decreases with age.100 The mechanism is not clear, but the presence of NO in aged myocardium may make some contribution.
Evidence shows that iNOS expression may result in decreased beta-adrenergic responses of cardiac myocytes. In the early 1990s, experiments with neonatal cardiac myocytes showed that cytokine treatment resulted in decreased contractile responsiveness to adrenergic agonists associated with attenuation of normal increases in intrac-ellular cAMP.101 Decreased beta-adrenergic responsiveness due to iNOS expression was also observed using cultures of rat ventricular myocytes in coculture with iNOS-expressing endothelial cells. Other groups used isolated contracting cardiomyocytes or papillary muscles exposed to LPS alone or in combination with other cytokines. The responsiveness was fully reversed upon cotreatment with NOS inhibitors.102-105
In heart failures with different etiologies including sepsis, transplant rejection, and ischemic or dilated cardiomyopathy, the decreased responsiveness to beta-adrenergic agonists was also found to be related to the expression of iNOS. Drexler et al. found muscle strips from failing hearts exhibited decreased responsiveness to beta-adrenergic stimulation. The alterations were significantly correlated with the abundance of iNOS activity and mRNA in the same hearts. Importantly, these alterations were corrected upon the treatment of the muscles with the NOS inhibitor, L-NMMA 27.
Hare et al. observed a potentiation of the inotropic response to peripheral infusion of dobutamine after intracoronary administration of L-NMMA in patients with dilated cardiomyopathies.29 In rats with congestive heart failure induced by artificial aorto-caval fistula, iNOS expression and activity increased about twofold in ventricular myocytes. Isoproterenol-positive inotropic and lusitropic effects were markedly attenuated in papillary muscles of the heart failure rats. Selective iNOS inhibitor improved the attenuated beta-adrenergic responsiveness in the heart failure rats.106 Funakoshi found disruption of the iNOS gene improved beta-adrenergic inotropic responsiveness.107 Finally, the ability of exogenous NO donors to produce quantitatively and qualitatively similar effects in isolated atrial and ventricular strips from human failing and nonfailing hearts adds further evidence for a significant role of NO as a modulator of beta-adrenergic responsiveness.108
The major mechanism for iNOS-related decreases in beta-adrenergic responsiveness is to activate cGMP-activated phosphodiesterase (PDE II) through the cGMP-dependent pathway (see Figure 18.1). Cardiac myocytes from a variety of species express PDE II. The muscarinic cholinergic "accentuated antagonism" on the L-type calcium channel was completely abolished by a PDE II-specific inhibitor, EHNA, indicating that PDE II is the major target for cGMP produced by soluble guanylate cyclase after muscarinic receptor is activated by acetylcholine.109
In circumstances where high levels of intracellular cGMP are produced, such as those generated upon NO production by iNOS, the resultant activation of PDE II leads to an attenuation of isoproterenol-stimulated increase in cAMP and shortening of adult rat myocytes in culture.47 102 The same mechanism is utilized by beta3 adrenergic receptors through activation of the eNOS pathway to decrease ventricular contractility110 (see Figure 18.1). This mechanism was further supported by Sula-khe's finding that attenuated contraction in response to isoprenaline in isolated muscles was paralleled by increased iNOS activity in myocytes, while the phospho-rylation of phospholamban was decreased compared to extracts from control rats because phospholamban is phosphorylated by PKA which is activated by cAMP.111 In addition to activating PDE II, NO produced by iNOS can attenuate myocardial responsiveness to adrenergic agonists via the PKG pathway (see Figure 18.1) and cGMP-independent pathway (see Figure 18.2).
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