CGMPDependent Pathway

Activation of soluble guanylate cyclase by NO (Figure 18.1) results in conversion of guanosine trisphosphate (GTP) to second messenger cyclic guanosine monophosphate (cGMP).38 Once biosynthesized, cGMP binds to different effecter proteins. In mammalian cardiomyocytes, the most important effecter proteins are cGMP-depen-dent protein kinase (PKG) and cGMP-activated/inhibited cAMP-phosphodiesterase (PDEII/PDE III).3940 Stimulation of PKG results in inhibition of voltage-dependent L-type calcium channels through phosphorylation of the a2 subunit,41 leading to decreased calcium transient augmentation and decreased contractility. This effect was evident at high concentrations of cGMP and/or cGMP analogs.42,43 PKG can also phosphorylate troponin I, resulting in desensitization of cardiac myofilaments to calcium and then a decrease in contractility.44,45

Inhibition of PDE III has been observed at low concentrations of cGMP (<1 mM) and NO (50 nM) that resulted in increased cAMP content in cardiomyocytes.46 Higher concentrations of cGMP resulting from larger amounts of NO (>100 mM) produced by iNOS activated PDE II which hydrolyzed cAMP and then decreased the cAMP content in cardiomyocytes.40,47,48 The cAMP activated PKA, which phos-phorylated L-type calcium channels and phospholamban (PLB), resulting in an increase of calcium influx from L-type calcium channels and contractility, an increase in function of SERCA 2a, and active relaxation of the LV.49 When the cAMP content decreased, the activity of PKA decreased, resulting in impairment of contractility (systolic dysfunction) and active relaxation (diastolic dysfunction).

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