Incomplete reversal of β‐adrenoceptor desensitization in human and guinea‐pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors

Wynne, D.; Poole‐Wilson, Philip A.; Harding, Siân E.

doi:10.1111/j.1476-5381.1993.tb13731.x

Cited by 14 publications

(11 citation statements)

References 37 publications

(44 reference statements)

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“…The present study is the first to suggest that these changes can be attributed directly to sympathetic overactivation and abnormalities in signal transduction, rather than to diffuse myocardial damage and contractile dysfunction. More importantly, some prior studies have demonstrated a reduced inotropic response to 3-isobutyl-1-methylxanthine (IBMX), a nonselective PDE inhibitor, after chronic β-AR activation [18,35]. However, the daily dose of β-AR agonist employed in these studies was approximately 200 times greater than that used in this study, and basal contractile function was not defined [18,35].…”

Section: Discussionmentioning

confidence: 50%

“…More importantly, some prior studies have demonstrated a reduced inotropic response to 3-isobutyl-1-methylxanthine (IBMX), a nonselective PDE inhibitor, after chronic β-AR activation [18,35]. However, the daily dose of β-AR agonist employed in these studies was approximately 200 times greater than that used in this study, and basal contractile function was not defined [18,35]. Hence, the reduced PDE inhibitor responsiveness could be ascribed to generalized cardiac changes secondary to necrotic or apoptotic damage, well known to occur at high doses of β-AR agonists [3,8].…”

Section: Discussionmentioning

confidence: 99%

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Contractile responses to selective phosphodiesterase inhibitors following chronic β-adrenoreceptor activation

Osadchii

Woodiwiss

Norton

2005

Pflugers Arch - Eur J Physiol

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Contractile responses to phosphodiesterase (PDE) inhibitors are attenuated in heart failure, an effect limiting the clinical value of these agents. In this study, we sought to determine whether abnormalities in the beta-adrenoreceptor (beta-AR)-cyclic adenosine monophosphate (cAMP) signal transduction are sufficient to account for downregulation of PDE inhibitor-induced inotropic responses following chronic sympathetic activation. Sustained beta-AR activation produced by administration of isoproterenol (ISO) (50 microg kg(-1) day(-1) i.p. for 1 month) to rats resulted in cardiac hypertrophy, but did not affect baseline cardiac systolic function, as assessed in vivo by echocardiography and ex vivo under controlled loading conditions and heart rate (left ventricular systolic pressure-volume and stress-strain relations). Moreover, chronic ISO administration did not alter the baseline myocardial norepinephrine release or inotropic responses to incremental concentrations of Ca(2+) in isolated, perfused heart preparations. However, left ventricular contractile responses to ISO, the PDE III inhibitor amrinone, and the PDE IV inhibitor rolipram were attenuated following chronic beta-AR activation. Myocardial cAMP concentrations after stimulation with amrinone and rolipram were similar in ISO-treated and control rats. However, in ISO-treated rats, a marked decrease in contractile responsiveness to the cell-permeable, PDE-resistant cAMP analogue, 8-bromoadenosine cAMP, was noted. In conclusion, these data suggest that in cardiac disease, sustained beta-AR activation, without producing ventricular systolic dysfunction or enhanced myocardial norepinephrine release, is sufficient to account for the downregulation of contractile responses to PDE inhibitors. This effect appears to be largely mediated through abnormalities in signal transduction between cAMP and Ca(2+)-induced Ca(2+) release.

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Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Contractile responses to selective phosphodiesterase inhibitors following chronic β-adrenoreceptor activation

Osadchii

Woodiwiss

Norton

2005

Pflugers Arch - Eur J Physiol

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“…A high selectivity for PDE3 inhibition seems not to be a prerequisite for PDE inhibitor to exhibit contractile effect since potent inotropic responses could be elicited by agents like theophylline and IBMX which non-selectively inhibit PDE1, PDE2, PDE3 and PDE4 isoenzymes [65,112,163,164,167,176,177]. Likewise, both PDE3 selective and non-selective PDE inhibitors are able to potentiate "-ARmediated inotropic responses [55,163,164,169,178,179].…”

Section: Blockade Of Adenosine Receptorsmentioning

confidence: 93%

“…Likewise, both PDE3 selective and non-selective PDE inhibitors are able to potentiate "-ARmediated inotropic responses [55,163,164,169,178,179]. In failing myocardium, a reduction of inotropic responses to "-AR agonists is reversed by co-administration of PDE inhibitor [55,57,164,169].…”

Section: Blockade Of Adenosine Receptorsmentioning

confidence: 97%

“…Indeed, potent inotropic responses to selective PDE3 inhibitors have been demonstrated in atrial and ventricular myocardium [63,98,108,[155][156][157][158][159][160][161][162][163] as well as isolated ventricular myocytes [112,119,164] of various mammalian species including human [55,57,[165][166][167][168][169][170]. Moreover, contractile effects to PDE3 inhibitors were welldocumented in experiments on dogs in vivo [33,105,155,156,[171][172][173][174][175].…”

Section: Blockade Of Adenosine Receptorsmentioning

confidence: 99%

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Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Osadchii

2007

Cardiovasc Drugs Ther

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Phosphodiesterase (PDE) inhibitors are potent cardiotonic agents used for parenteral inotropic support in heart failure. Contractile effects of these agents are mediated through cAMP-protein kinase A-induced stimulation of I (Ca2+) which ultimately results in increased Ca(2+)-induced sarcoplasmic reticulum Ca(2+) release. A number of additional effects such as increases in sarcoplasmic reticulum Ca(2+) stores, stimulation of reverse mode Na(+)-Ca(2+) exchange, direct or cAMP-mediated effects on sarcoplasmic reticulum ryanodine receptor, stimulation of the voltage-sensitive sarcoplasmic reticulum Ca(2+) release mechanism, as well as A(1) adenosine receptor blockade could contribute to positive inotropic responses to PDE inhibitors. Moreover, some PDE inhibitors exhibit Ca(2+) sensitizer properties as they could increase the affinity of troponin C Ca(2+)-binding sites as well as reduce Ca(2+) threshold for thin myofilament sliding and facilitate cross-bridge cycling. Inotropic responses to PDE inhibitors are significantly reduced in cardiac disease, an effect largely attributed to downregulation of cAMP-mediated signalling due to sustained sympathetic activation. Four PDE isoenzymes (PDE1, PDE2, PDE3 and PDE4) are present in myocardial tissue of various mammalian species, of which PDE3 and PDE4 are particularly involved in regulation of cardiac myocyte contraction. PDE cAMP-hydrolysing activity is preserved in compensated cardiac hypertrophy but significantly reduced in animal models of heart failure. However, clinical studies have not revealed any changes in distribution profile as well as kinetic and regulatory properties of myocardial PDEs in failing human hearts. A reduction of PDE inhibitors-induced contractile responses in heart failure has therefore been ascribed to reduced cAMP synthesis due to uncoupling of adenylyl cyclase from beta-adrenoreceptor. In cardiac myocytes, PDEs are targeted to distinct subcellular compartments by scaffolding proteins such as myomegalin, mAKAP and beta-arrestins. Over subcellular microdomains, cAMP hydrolysis by PDE3 and PDE4 allows to control the activity of local pools of protein kinase A and therefore the extent of protein kinase A-mediated phosphorylation of cellular proteins.

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Myocardial Cell Abnormalities in Heart Failure: Experience from Studies on Single Myocytes

Davies¹,

Brown²,

Monte³

et al. 1995

Developments in Cardiovascular Medicine

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Incomplete reversal of β‐adrenoceptor desensitization in human and guinea‐pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors

Cited by 14 publications

References 37 publications

Contractile responses to selective phosphodiesterase inhibitors following chronic β-adrenoreceptor activation

Contractile responses to selective phosphodiesterase inhibitors following chronic β-adrenoreceptor activation

Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Myocardial Cell Abnormalities in Heart Failure: Experience from Studies on Single Myocytes

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