The mechanical and biochemical effects of pentoxifylline on the perfused rat heart

Vittone, Leticia; Chiappe, Liliana E.; Argel, María Isabel; Cingolani, Horacio E.; Chiappe, Gladys E.

doi:10.1007/bf01965986

Cited by 7 publications

(3 citation statements)

References 22 publications

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“…Indeed, an accumulation of cAMP as well as PKA activation induced by non-selective PDE inhibitors, pentoxifylline, papaverine and theophylline, were not associated with positive inotropic responses in isolated rat hearts [224,225]. A similar finding was reported with regards to papaverine-induced effects in isolated guinea-pig heart [226].…”

Section: Compartmentalized Subcellular Camp Elimination By Pdessupporting

confidence: 78%

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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Section: Compartmentalized Subcellular Camp Elimination By Pdessupporting

confidence: 78%

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

Osadchii

2007

Cardiovasc Drugs Ther

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“…Am isoliert perfundierten Rattenherzen zeigt PTX einen moderaten inotropen und einen deutlichen lusitropen Effekt [2,53]. Nach I/R reduziert PTX die kardiale Dysfunktion [62].…”

Section: Rheologie Blutfluss Und Organfunktionunclassified

Anti-inflammatory effects of pentoxifylline

2009

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Initially introduced as a rheologic agent for use in intermittent claudication due to peripheral artery disease and in ischemic cerebrovascular disease, the methylxanthine derivative pentoxifylline (PTX) has been shown to possess several anti-inflammatory properties which make this drug an interesting immunomodulating adjunct for the management of patients undergoing cardiac surgery. As an unspecific phosphodiesterase inhibitor PTX ameliorates the inflammatory response following a septic stimulus and blunts organ dysfunction after ischemia-reperfusion injury. Apart from this several small clinical studies have shown that the use of PTX may blunt the inflammatory response induced by cardiac surgery using a cardiopulmonary bypass. Additionally it has been shown that the perioperative application of this drug may improve postoperative function of organs at risk, such as the kidneys and liver.

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“…The aim of our study was therefore to determine if cAMP contributes to the progression from compensated LVH to LV dilatation. Hence, we assessed whether the phosphodiesterase inhibitor (PDEI), pentoxifylline, previously shown to increase myocardial cAMP concentrations in rats [25], induces LV dilatation when administered for prolonged periods to spontaneously hypertensive rats (SHR) with compensated LVH.…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterase inhibition promotes the transition from compensated hypertrophy to cardiac dilatation in rats

Anamourlis

Badenhorst

Gibbs

et al. 2005

Pflugers Arch - Eur J Physiol

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The cellular signaling pathways responsible for the transition from compensated left ventricular hypertrophy (LVH) to LV dilatation (remodeling) and heart failure are unclear. As chronic administration of a beta-adrenoreceptor (beta-AR) agonist mediates the premature onset of cardiac remodeling without myocyte necrosis or myocardial dysfunction in LVH, we suggest that beta-AR activation is critical in promoting the transition from compensated LVH to cardiac dilatation. However, beta-AR mediated effects in the heart can occur via either the cyclic adenosine monophosphate (cAMP) system or via cAMP independent signaling pathways. To determine the role of cAMP in promoting adverse cardiac chamber remodeling, we evaluated whether phosphodiesterase inhibition (PDEI) promotes LV dilatation in rats with compensated LVH. The impact of chronic administration of the PDEI, pentoxifylline, on LV remodeling and function was assessed in spontaneously hypertensive rats (SHR) with compensated LVH. The PDEI mediated inotropic effects and increased cAMP concentrations in SHR. This dose of the PDEI administered for 4 months to SHR did not modify LV weight or influence intrinsic myocardial systolic function (as assessed in the absence of the PDEI) in SHR. However, the PDEI mediated the development of a right shift in LV end diastolic (LVED) pressure-internal dimension and LVED pressure-volume relations, LV wall thinning, and increments in myocardial soluble (non-cross-linked) collagen concentrations. In conclusion, chronic PDEI administration induces adverse geometric and interstitial cardiac remodeling in SHR, a finding that supports the notion that the beta-AR-cAMP system is important in mediating the progression to heart failure by promoting interstitial remodeling and LV dilatation in LVH.

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The mechanical and biochemical effects of pentoxifylline on the perfused rat heart

Cited by 7 publications

References 22 publications

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

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

Anti-inflammatory effects of pentoxifylline

Phosphodiesterase inhibition promotes the transition from compensated hypertrophy to cardiac dilatation in rats

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