The phosphodiesterase 3 inhibitor cilostamide enhances inotropic responses to glucagon but not to dobutamine in rat ventricular myocardium

Juan-Fita, María Jesús; Vargas, Marı́a Luisa; Hernández, Jesús

doi:10.1016/j.ejphar.2005.01.056

Cited by 17 publications

(13 citation statements)

References 15 publications

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“…In contrast to CGP12177, the inotropic and cyclic AMP‐elevating responses to (−)‐noradrenaline were unaffected by PDE3 inhibition with cilostamide. These results are consistent with a failure of cilostamide to enhance the inotropic and cyclic AMP‐elevating responses of dobutamide, mediated through rat ventricular β 1 ‐adrenoceptors ( Juan‐Fita et al ., 2005 ). Furthermore, in agreement with our results of cilostamide vs (−)‐noradrenaline, the PDE3‐selective inhibitor milrinone also failed to enhance the inotropic and cyclic AMP responses to isoprenaline in rat ventricle ( Katano & Endoh, 1992 ).…”

Section: Discussionsupporting

confidence: 92%

Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

Vargas

Hernández

Kaumann

2006

British J Pharmacology

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1 The cardiostimulant effects of CGP12177, mediated through a b 1 -adrenoceptor site with low affinity for (À)-propranolol, are potentiated by the nonselective PDE inhibitor IBMX but the role of PDE isoenzymes is unknown. We studied the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4-selective inhibitor rolipram (1 mM) on the positive inotropic and cyclic AMPenhancing effects of CGP12177 and noradrenaline in right ventricular strips of rat. 2 CGP12177 (under (À)-propranolol 200 nM) only increased contractile force in the presence of either cilostamide or rolipram with ÀlogEC 50 M 6.7 (E max ¼ 23% over basal) and 7.1 (E max ¼ 50%) respectively. The combination of cilostamide and rolipram caused CGP12177 to enhance contractile force with ÀlogEC 50 M ¼ 7.7 and E max ¼ 178%. 3 The positive inotropic effects of noradrenaline (ÀlogEC 50 M ¼ 6.9) were potentiated by rolipram (ÀlogEC 50 M ¼ 7.4) but not by cilostamide (ÀlogEC 50 M ¼ 7.0). 4 In the presence of rolipram and (À)-propranolol, noradrenaline (2 mM) and CGP12177 (10 mM) produced matching inotropic effects but failed to increase cyclic AMP levels. 20 mM (À)-noradrenaline increased cyclic AMP levels, a response further enhanced by rolipram. 5 Both PDE3 and PDE4 of rat ventricle appear to hydrolyse cyclic AMP generated through the low-affinity b 1 -adrenoceptor site, thereby preventing inotropic responses of CGP12177. When (À)-noradrenaline interacts with the b 1 -adrenoceptor, the generated cyclic AMP is hydrolysed only by PDE4, thereby reducing cardiostimulation.

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Section: Discussionsupporting

confidence: 92%

Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

Vargas

Hernández

Kaumann

2006

British J Pharmacology

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“…On the one hand, the collective evidence presented in Fig. (2B) [63][64][65][66][67][68][69][70][71][72] verifies that the concentration-effect curves for increases in AC/cAMP and contractile force overlap, supporting the long-held and wellestablished view that the signal mediating mechanical actions of the hormone on the heart is indeed cAMP/PKAdependent. As in adipose tissue, the roles of cAMP and downstream intracellular events responsible for the contractile response in heart have been thoroughly described [73].…”

Section: Heartsupporting

confidence: 55%

“…All curves are composites compiled from multiple reports: A) [13,[23][24][25][26][27]; B) [63][64][65][66][67][68][69][70][71][72]; and C) [24,69,[88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103]. The shaded area is the average glucagon blood range in the rat, from references [30][31][32][33][34][35][36][37][38][39].…”

Section: Fig (2)mentioning

confidence: 99%

Glucagon and Cyclic AMP: Time to Turn the Page?

Rodgers

2012

CDR

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It is well established that glucagon can stimulate adipose lipolysis, myocardial contractility, and hepatic glucose output by activating a GPCR and adenylate cyclase (AC) and increasing cAMP production. It is also widely reported that activation of AC in all three tissues requires pharmacological levels of the hormone, exceeding 0.1 nM. Extensive evidence is presented here supporting the view that cAMP does not mediate metabolic actions of glucagon on adipose, heart, or liver in vivo. Only pharmacological levels stimulate AC, adipose lipolysis, or cardiac contractility. Physiological concentrations of glucagon (below 0.1 nM) duplicate metabolic effects of insulin on the heart by activating a PI3K-dependent signal without stimulating AC. In the liver, glucagon can enhance gluconeogenesis and glucose output -by increasing the expression of PEPCK or inhibiting the activity of PK -at pharmacological concentrations by activating AC coupled to a low-affinity GPCR, but also at physiological concentrations by activating a high affinity receptor without generating cAMP. Plausible AC/cAMP-independent signals mediating the increase in gluconeogenesis include p38 MAPK (PEPCK expression) and IP3/DAG/Ca 2+ (PK activity). None of glucagon's physiological effects can be explained by activation of spare receptors or amplification of the AC/cAMP signal. In a new model proposed here, glucagon antagonizes insulin on the liver but mimics insulin on the heart without activating AC. Confirmation of the model would have broad implications, applicable not only to the general field of metabolic endocrinology but also to the specific role of glucagon in the pathogenesis and treatment of diabetes.

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“…12 Moreover, in right ventricular strips from adult rat, PDE3 inhibition had no effect on the contractile response to the ␤ 1 -AR agonist dobutamine but potentiated that of Glu. 27 In parallel cAMP assays, these authors found that PDE3 inhibition also had no effect on the response to dobutamine but revealed a substantial cAMP increase caused by Glu. Although obvious differences in developmental stage, cardiac territory, or rat strains might account for some of the discrepancies, one should emphasize that CNG channels provide a readout of subsarcolemmal cAMP, whereas other methods measure cytosolic or total cAMP.…”

Section: Rochais Et Al Pdes and Hormone-specific Camp Signals 1085mentioning

confidence: 99%

A Specific Pattern of Phosphodiesterases Controls the cAMP Signals Generated by Different G _s -Coupled Receptors in Adult Rat Ventricular Myocytes

Rochais

Abi-Gerges

Horner

et al. 2006

Circulation Research

160

157

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Abstract-Compartmentation of cAMP is thought to generate the specificity of G s -coupled receptor action in cardiac myocytes, with phosphodiesterases (PDEs) playing a major role in this process by preventing cAMP diffusion. We tested this hypothesis in adult rat ventricular myocytes by characterizing PDEs involved in the regulation of cAMP signals and L-type Ca 2ϩ current (I Ca,L ) on stimulation with ␤ 1 -adrenergic receptors (␤ 1 -ARs), ␤ 2 -ARs, glucagon receptors (Glu-Rs) and prostaglandin E 1 receptors (PGE 1 -Rs). All receptors but PGE 1 -R increased total cAMP, and inhibition of PDEs with 3-isobutyl-1-methylxanthine strongly potentiated these responses. When monitored in single cells by high-affinity cyclic nucleotide-gated (CNG) channels, stimulation of ␤ 1 -AR and Glu-R increased cAMP, whereas ␤ 2 -AR and PGE 1 -R had no detectable effect. Selective inhibition of PDE3 by cilostamide and PDE4 by Ro 20-1724 potentiated ␤ 1 -AR cAMP signals, whereas Glu-R cAMP was augmented only by PD4 inhibition. PGE 1 -R and ␤ 2 -AR generated substantial cAMP increases only when PDE3 and PDE4 were blocked. For all receptors except PGE 1 -R, the measurements of I Ca,L closely matched the ones obtained with CNG channels. Indeed, PDE3 and PDE4 controlled ␤ 1 -AR and ␤ 2 -AR regulation of I Ca,L , whereas only PDE4 controlled Glu-R regulation of I Ca,L thus demonstrating that receptor-PDE coupling has functional implications downstream of cAMP. PGE 1 had no effect on I Ca,L even after blockade of PDE3 or PDE4, suggesting that other mechanisms prevent cAMP produced by PGE 1 to diffuse to L-type Ca 2ϩ channels. These results identify specific functional coupling of individual PDE families to G s -coupled receptors as a major mechanism enabling cardiac cells to generate heterogeneous cAMP signals in response to different hormones. Key Words: cAMP Ⅲ heart Ⅲ G-protein-coupled receptor Ⅲ phosphodiesterase C ardiac myocytes express a number of G s -coupled receptors (G s PCRs) that raise intracellular cAMP levels and activate cAMP-dependent protein kinase (PKA) but exert different downstream effects. For instance, ␤ 1 -adrenergic receptor (␤ 1 -AR) stimulation produces a major and sustained increase in force of contraction, accelerates relaxation, and stimulates glycogen phosphorylase. 1 ␤ 2 -AR stimulation also increases contractile force but does not activate glycogen phosphorylase 2 and does not accelerate relaxation 1,3 (see also ref. 2); glucagon receptor (Glu-R) stimulation activates phosphorylase and exerts positive inotropic and lusitropic effects, but the contractile effects fade with time. 4 Finally, prostaglandin E 1 (PGE 1 ) has no effect on contractile activity or glycogen metabolism. 5,6 Such observations led to the proposal that activation of different G s PCRs results in the accumulation of cAMP and phosphorylation of hormone target proteins in distinct compartments. 7 The discovery of A-kinase anchoring proteins, responsible for the subcellular distribution of particulate PKA, 8 and the development of new method...

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The phosphodiesterase 3 inhibitor cilostamide enhances inotropic responses to glucagon but not to dobutamine in rat ventricular myocardium

Cited by 17 publications

References 15 publications

Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

Glucagon and Cyclic AMP: Time to Turn the Page?

A Specific Pattern of Phosphodiesterases Controls the cAMP Signals Generated by Different G _s -Coupled Receptors in Adult Rat Ventricular Myocytes

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The phosphodiesterase 3 inhibitor cilostamide enhances inotropic responses to glucagon but not to dobutamine in rat ventricular myocardium

Cited by 17 publications

References 15 publications

Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

Glucagon and Cyclic AMP: Time to Turn the Page?

A Specific Pattern of Phosphodiesterases Controls the cAMP Signals Generated by Different G s -Coupled Receptors in Adult Rat Ventricular Myocytes

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A Specific Pattern of Phosphodiesterases Controls the cAMP Signals Generated by Different G _s -Coupled Receptors in Adult Rat Ventricular Myocytes