CGMPIndependent Pathway

In addition to activating the cGMP-PKG pathway, high concentrations of NO decrease cardiac function through other means (Figure 18.2). Elevated NO concentrations inhibit functioning of calcium cycling proteins such as ryanodine receptor

T Tubule

T Tubule

FIGURE 18.1 NO regulates cardiac function via the cGMP-dependent pathway. P1 and P2 adrenergic receptor agonists (PjAR and P2AR) such as dobutamine improve systolic function (contractility) and diastolic function (active relaxation) by coupling with stimulatory G protein (Gs) and activating cAMP-dependent protein kinase (PKA). PKA phosphrylates L-type calcium channels to increase Ca2+ influx (ICa) and ryanodine receptor (RyR) to increase Ca2+ release from sarcoplasmic reticulum (SR), resulting in increasing Ca2+ transience and contractility. PKA also phosphorylates phospholamban (PLB), releasing the inhibition of PLB to sarco(endo)reticulum 2a (SERCA 2a), and increases the rate of Ca2+ uptake from the cytosol, resulting in an increasing rate of relaxation. Since Ca2+ transience is controlled by SR Ca2+ content and increased SERCA 2a function increases SR Ca2+ content, increased SERCA 2a function increases Ca2+ transience and then the contractility of the myocytes. The M2 receptor and P3AR agonists decrease cardiac function (opposite to PjAR and P2AR agonists) by coupling Gj protein and activating calmodulin (CaM)/eNOS through an unknown mechanism. This confirms that NO inhibits cardiac function, especially at high levels. High levels of NO produced by iNOS from L-arginine (L-Arg) increase levels of cGMP, the second messenger, by activating soluble guanylyl cyclase (sGC). High levels of cGMP inhibit contractility and relaxation by (1) activating phosphodiesterase II (PDE II) which decreases cAMP level and PKA activity, attenuating inotropic and lusitropic effects of PKA; and (2) activating cGMP-dependent kinase (PKG) which phosphorylates (i) troponin I, leading to calcium desensitization, sarcomere relaxation, and a consequent negative inotropic effect; (ii) L-type calcium channel, decreasing the Ca2+ influx and promoting a negative inotropic effect; and (iii) possible protein phosphotase type 1 and type 2A (PP1 and PP 2A), decreasing phosphorylation of PLB, increasing PLB inhibition to SERCA 2a, decreasing Ca2+ uptake and consequent prolonged relaxation (negative lusitropic effect). * CaM KII = Calmodulin-dependent kinase II.

FIGURE 18.2 NO regulates cardiac function via a cGMP-independent pathway. NO and its derivative (ONOO-) cause negative inotropic and lusitropic effects by directly affecting calcium cycling proteins, mitochondria, and cell death. NO can nitrosylate the L-type calcium channel (ICa) and ryanodine receptor (RyR), leading to decreased calcium transience and contractility. NO and ONOO- can also inhibit sarco(endo)plasmic reticulum calcium ATPase 2a (SERCA 2a) by nitrosylation and nitration, leading to negative lusitropic effects. Nitrosy-lation by NO can be rapidly reversed by reducing agents such as dithiothreitol (DTT) and mercaptoethanol. Reversal of nitration caused by ONOO- is not documented. NO and ONOO-decrease mitochondrial ATP product by inhibiting complexes of respiratory chain and mito-chondrial creatine kinase. Both can cause mitochondrial permeability transition and cyto-chrome C release, resulting in apoptosis. ONOO- can also cause DNA fragmentation, initiating apoptosis through the p53 pathway and activating poly(ADP-ribose) polymerase (PARP) which results in depletion of ATP. Large amounts of ONOO- cause necrosis immediately by rapidly damaging mitochondria, increasing Ca2+ efflux from mitochondria, and depleting ATP.

FIGURE 18.2 NO regulates cardiac function via a cGMP-independent pathway. NO and its derivative (ONOO-) cause negative inotropic and lusitropic effects by directly affecting calcium cycling proteins, mitochondria, and cell death. NO can nitrosylate the L-type calcium channel (ICa) and ryanodine receptor (RyR), leading to decreased calcium transience and contractility. NO and ONOO- can also inhibit sarco(endo)plasmic reticulum calcium ATPase 2a (SERCA 2a) by nitrosylation and nitration, leading to negative lusitropic effects. Nitrosy-lation by NO can be rapidly reversed by reducing agents such as dithiothreitol (DTT) and mercaptoethanol. Reversal of nitration caused by ONOO- is not documented. NO and ONOO-decrease mitochondrial ATP product by inhibiting complexes of respiratory chain and mito-chondrial creatine kinase. Both can cause mitochondrial permeability transition and cyto-chrome C release, resulting in apoptosis. ONOO- can also cause DNA fragmentation, initiating apoptosis through the p53 pathway and activating poly(ADP-ribose) polymerase (PARP) which results in depletion of ATP. Large amounts of ONOO- cause necrosis immediately by rapidly damaging mitochondria, increasing Ca2+ efflux from mitochondria, and depleting ATP.

(RyR) and SERCA 2a, inhibit mitochondrial function, and induce apoptosis and necrosis by formation of peroxynitrite.50

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