Opposing functional effects of cyclic GMP and cyclic AMP may act through protein phosphorylation in rabbit cardiac myocytes

Yan, Lin; Lee, H.; Huang, Mou Tuan; Scholz, Peter; Weiss, Harvey R.

doi:10.1046/j.1365-2680.2000.00177.x

Cited by 8 publications

(15 citation statements)

References 35 publications

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“…There is also evidence that the cyclic GMP-affected cyclic AMP phosphodiesterases can play an important role in the functional effects of cyclic GMP through changes in the level of cyclic AMP in the heart and myocytes [13,14,27] . At rest, the cyclic AMP levels in control myocytes was about 15 times that of cyclic GMP, as has been reported previously [9,11,13,20,23] . In the current study, zaprinast signifi cantly increased the level of cyclic GMP without affecting the level of cyclic AMP.…”

Section: Discussionsupporting

confidence: 87%

“…Many of these effects are related to activation of the cyclic AMP-dependent protein kinase, which may phosphorylate membrane channels or parts of the contractile machinery [6,9] , as well as nonprotein kinase effects [10] . There is some evidence that nitric oxide can activate the cyclic AMP protein kinase, but this may be through effects on the cyclic GMP-affected cyclic AMP phosphodiesterases [13,25] .…”

Section: Discussionmentioning

confidence: 99%

“…One effect of cyclic GMP is that it inhibits L-type calcium channels [15,26] . Many of the actions of cyclic GMP are through changes in protein phosphorylation caused by activation of the cyclic GMP protein kinase [8,9,15] . There is also evidence that the cyclic GMP-affected cyclic AMP phosphodiesterases can play an important role in the functional effects of cyclic GMP through changes in the level of cyclic AMP in the heart and myocytes [13,14,27] .…”

Section: Discussionmentioning

confidence: 99%

“…Freshly isolated ventricular myocytes were prepared by a standard method as described previously [9,13] . The control and 1K1C rabbits were anesthetized and the heart was rapidly removed after an overdose of pentobarbital (90 mg/kg).…”

Section: Cell Dissociationmentioning

confidence: 99%

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Functional Interaction of a β-Adrenergic Agonist and Cyclic GMP Phosphodiesterase Inhibitor in Control and Hypertrophic Cardiomyocytes

Zhang

Rodríguez²,

Scholz³

et al. 2006

Pharmacology

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This study tested the hypothesis that the positive inotropic effect of β-adrenoceptor stimulation would be inhibited by increases in cyclic GMP in control cardiomyocytes and that this response would be modified in hypertrophic cardiomyocytes. Cell functional data as well as GMP and cyclic AMP data were collected from 7 control and 7 1K1C (one-kidney-one-clip) renal hypertensive hypertrophic rabbits. Using isolated control and IKIC ventricular myocytes, data were obtained at baseline and after treatment with the β-adrenoceptor agonist isoproterenol (10^{–8, –6} mol/l) or the cyclic GMP-phosphodiesterase inhibitor zaprinast (10^–5 mol/l) followed by isoproterenol (10^{–8, –6} mol/l). We found that in control rabbits, isoproterenol (10^–6 mol/l) increased percent shortening (4.8 ± 0.2 to 6.4 ± 0.3%) and cyclic AMP (2.3 ± 0.3 to 5.0 ± 0.7 pmol/10⁵ cells). Zaprinast 10^–5 mol/l increased cyclic GMP (150 ± 20 to 209 ± 14 fmol/10⁵ cells) and decreased percent shortening (6.2 ± 0.4 to 5.2 ± 0.3). Zaprinast 10^–5 mol/l prevented the functional response to isoproterenol in control (5.2 ± 0.3 to 4.7 ± 0.3), without changing cyclic AMP levels. In 1K1C rabbits, isoproterenol (10^–6 mol/l) increased cyclic AMP (4.9 ± 0.8 to 7.6 ± 1.4 pmol/10⁵ cells) without changing function. Zaprinast 10^–5 mol/l increased cyclic GMP (182 ± 23 to 233 ± 24 fmol/10⁵ cells) and decreased percent shortening (6.6 ± 0.9 to 4.7 ± 0.5), but did not alter the lack of effect of isoproterenol in 1K1C. In control cardiomyocytes, cyclic GMP blunted the isoproterenol contraction response without changing cyclic AMP levels, but isoproterenol’s functional effect was not seen in 1K1C cardiomyocytes.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cell Dissociationmentioning

confidence: 99%

See 2 more Smart Citations

Functional Interaction of a β-Adrenergic Agonist and Cyclic GMP Phosphodiesterase Inhibitor in Control and Hypertrophic Cardiomyocytes

Zhang

Rodríguez²,

Scholz³

et al. 2006

Pharmacology

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“…Maximal activation of PKG was observed at a dose of 10 mol/L cGMP in rabbit cardiomyocytes. 31 PKG-induced swelling was also inhibited by glibenclamide, a nonselective K ATP antagonist, and 5HD and TPP ϩ , selective mitoK ATP blockers, confirming PKG caused swelling by opening mitoK ATP . In contrast, HMR1098, a surface K ATP channel blocker, was ineffective, indicating the effect of PKG on mitochondrial swelling is specifically the result of its action on mitoK ATP .…”

Section: Discussionmentioning

confidence: 70%

Protein Kinase G Transmits the Cardioprotective Signal From Cytosol to Mitochondria

Costa

Garlid

West

et al. 2005

Circulation Research

271

239

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Abstract-Ischemic and pharmacological preconditioning can be triggered by an intracellular signaling pathway in which G i -coupled surface receptors activate a cascade including phosphatidylinositol 3-kinase, endothelial nitric oxide synthase, guanylyl cyclase, and protein kinase G (PKG). Activated PKG opens mitochondrial K ATP channels (mitoK ATP ) which increase production of reactive oxygen species. Steps between PKG and mitoK ATP opening are unknown. We describe effects of adding purified PKG and cGMP on K ϩ transport in isolated mitochondria. Light scattering and respiration measurements indicate PKG induces opening of mitoK ATP similar to K ATP channel openers like diazoxide and cromakalim in heart, liver, and brain mitochondria. This effect was blocked by mitoK ATP inhibitors 5-hydroxydecanoate, tetraphenylphosphonium, and glibenclamide, PKG-selective inhibitor KT5823, and protein kinase C (PKC) inhibitors chelerythrine, Ro318220, and PKC-⑀ peptide antagonist ⑀V 1-2 . MitoK ATP are opened by the PKC activator 12-phorbol 13-myristate acetate. We conclude PKG is the terminal cytosolic component of the trigger pathway; it transmits the cardioprotective signal from cytosol to inner mitochondrial membrane by a pathway that includes PKC-⑀. (Circ Res. 2005;97:329-336.)Key Words: ATP-sensitive K ϩ channel Ⅲ cGMP Ⅲ preconditioning Ⅲ protein kinase C Ⅲ protein kinase G I schemic (IPC) and pharmacological preconditioning by ligands such as acetylcholine and bradykinin initiates a signaling cascade that opens mitochondrial ATP-sensitive K ϩ channels (mitoK ATP ). Many components of this signaling pathway have been identified. 1 Surface receptors activate phosphatidylinositol 3-(PI3-) kinase by transactivation of epidermal growth factor receptors (EGFRs). A signaling complex composed of transactivated EGFR, Src kinase, and PI3-kinase causes phosphorylation of phosphatidylinositol bisphosphate, which in turn activates the phosphatidylinositol-dependent kinases (PDKs). 2 The PDKs then phosphorylate Akt 3 which activates the remainder of the cytosolic signaling pathway (Figure 1) including phosphorylation of endothelial nitric oxide synthase (eNOS), production of NO, stimulation of guanylyl cyclase, generation of cGMP, and activation of protein kinase G (PKG).cGMP and presumably PKG activation are important during preconditioning. Delayed preconditioning by diazoxide involves NO, 4 and cGMP accumulation after inhibition of cGMP-specific phosphodiesterase by sildenafil induces acute and delayed preconditioning. 5 Direct activation of PKG increases generation of reactive oxygen species (ROS) in cardiomyocytes, and this effect depends on mitoK ATP opening. 3 Whereas PKG antagonists abort ROS generation by PKG activators, they have no effect on ROS triggered by diazoxide, a direct opener of mitoK ATP , indicating PKG is upstream of mitoK ATP . A direct activator of PKG mimics IPC in intact hearts. 6 We hypothesized that PKG opens mitoK ATP by causing its phosphorylation, 7 and that the open channel increases generation of mi...

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Negative functional effects of cyclic GMP are altered by cyclic AMP phosphodiesterases in rabbit cardiac myocytes

Weiss¹,

Lazar²,

Punjabi³

et al. 2003

European Journal of Pharmacology

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Opposing functional effects of cyclic GMP and cyclic AMP may act through protein phosphorylation in rabbit cardiac myocytes

Cited by 8 publications

References 35 publications

Functional Interaction of a β-Adrenergic Agonist and Cyclic GMP Phosphodiesterase Inhibitor in Control and Hypertrophic Cardiomyocytes

Functional Interaction of a β-Adrenergic Agonist and Cyclic GMP Phosphodiesterase Inhibitor in Control and Hypertrophic Cardiomyocytes

Protein Kinase G Transmits the Cardioprotective Signal From Cytosol to Mitochondria

Negative functional effects of cyclic GMP are altered by cyclic AMP phosphodiesterases in rabbit cardiac myocytes

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