Identification and characterization of isoenzymes of cyclic nucleotide phosphodiesterase in human kidney and heart, and the effects of new cardiotonic agents on these isoenzymes

Sugioka, Masaki; M, Ito; Mikami, Hiroshi; Ichikawa, Kazuhito; Konishi, Tokuji; Tanaka, Toshio; Nakano, Takeshi

doi:10.1007/bf00175034

Cited by 31 publications

(22 citation statements)

References 32 publications

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“…However, most of the PDE cAMP-hydrolyzing activity is present in cytosol. Indeed, in human heart, 69% of the total PDE cAMP-hydrolyzing activity is present in cytosol [35], whereas in dog [36,37], rat [38,39] and guinea-pig [40,41] cytosolic cAMP PDEs accounts for 80-90% of the total PDE activity. Microsomal fraction is represented by membrane-bound PDEs attached to sarcolemma, T tubule, mitochondria and sarcoplasmic reticulum [29,[42][43][44].…”

Section: General Considerationsmentioning

confidence: 99%

“…In human [35,45], bovine [46], dog [33,37,42], and rabbit [44,47] myocardium, the main membrane-bound isoenzyme is PDE3, whereas in rat [44,47] and frog [48] ventricular tissue microsomal PDE activity is largely represented by PDE4. In dog myocardial tissue, the percentage ratio of microsomal PDE3 and PDE4 was found to be 78%-to−21% [42].…”

Section: General Considerationsmentioning

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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Section: General Considerationsmentioning

confidence: 99%

Section: General Considerationsmentioning

confidence: 99%

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

Osadchii

2007

Cardiovasc Drugs Ther

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“…No reports, however, have addressed the direct cardioprotection by short-time exposure to PDEIII-Is and the underlying mechanisms. Therefore, we tested whether transient exposure to the potent PDEIII-Is olprinone 16 or milrinone 17 limits infarct size and whether PKA, PKC, or MAPK activation is involved in the underlying mechanisms.…”

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confidence: 99%

Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors

et al. 2001

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Background-Phosphodiesterase III inhibitors (PDEIII-Is) improve the hemodynamic status of heart failure via inotropic/vasodilatory effects attributable to the increase in intracellular cAMP level. Direct cardioprotection by PDEIII-Is and its underlying mechanisms, however, have not been identified. We tested the infarct size-limiting effect of PDEIII-Is and the roles of cAMP, protein kinase (PK) A, PKC, and mitogen-activated protein kinase (MAPK) families in open-chest dogs. Methods and Results-Milrinone, olprinone (PDEIII-Is), or dibutyryl-cAMP (db-cAMP) was injected intravenously 30 minutes before 90-minute ischemia, followed by 6 hours of reperfusion. Olprinone was also examined with an intracoronary cotreatment with a PKA inhibitor (H89), a PKC inhibitor (GF109203X), an extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059), or a p38 MAPK inhibitor (SB203580) throughout the preischemic period. Either PDEIII-Is or db-cAMP caused substantial hemodynamic changes, which returned to control levels in 30 minutes. Collateral flow and percent risk area were identical for all groups. Both PDEIII-Is and db-cAMP increased myocardial p38 MAPK activity during the preischemic period, which was blocked by H89, but not by GF109203X.

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“…1,19 The accumulation of cAMP that results from PDE III inhibition enhances calcium extrusion across the sarcolemma by two possible mechanisms: (1) cAMP-dependent protein kinase present in vascular smooth muscle is known to stimulate the sarcolemmal calcium pump, and (2) cAMP stimulation of sarcolemmal Na ϩ ,K ϩ -ATPase causes hyperpolarization and removal of intracellular sodium. Extracellular sodium then exchanges with intracellular calcium (Na ϩ /Ca 2ϩ exchanger), resulting in relaxation of both arterial and venous smooth muscle.…”

Section: Discussionmentioning

confidence: 99%

Acute Effects of Toborinone on Vascular Capacitance and Conductance in Experimental Heart Failure

1998

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Background-Toborinone (OPC-18790), a phosphodiesterase III inhibitor, enhances cardiac contractility and is an arterial dilator. However, its effects on the venous system have not yet been clearly defined. Because toborinone administration reduces left ventricular (LV) end-diastolic pressure, it is probably also a venodilator. Because of the known arterial effects and the hypothesized venous effects, we compared changes in systemic vascular conductance (the inverse of resistance) with changes in venous capacitance. Methods and Results-In 15 anesthetized, splenectomized dogs (10 treatment, 5 control), pressures were measured in the right atrium, aorta, portal vein, and LV. A cuff constrictor was placed around the portal vein. Cardiac output was measured by thermodilution, and splanchnic vascular capacitance was measured by blood-pool scintigraphic methods. Data were collected at baseline, after induction of heart failure (microsphere embolization into the left coronary artery), and then after toborinone boluses of 0.1, 0.2, 0.4, and 0.8 mg/kg. Heart failure was associated with decreased capacitance and conductance (to 87Ϯ3% and 64Ϯ4% of baseline values, respectively, PϽ0.05). After administration of the lower doses of toborinone, capacitance increased more than conductance; however, the effects were more balanced at the higher doses. Compared with nitroglycerin, hydralazine, and enalaprilat (results of an earlier study) in the same model, toborinone increased capacitance to a degree similar to that with nitroglycerin, at higher doses increased conductance similarly to hydralazine, and increased both capacitance and conductance considerably more than did enalaprilat. Conclusions-Toborinone is a potent balanced venous and arterial dilator in experimental acute heart failure. These marked effects suggest that it may prove to be a clinically important alternative to other vasodilators. (Circulation. 1998;98:58-63.)

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Identification and characterization of isoenzymes of cyclic nucleotide phosphodiesterase in human kidney and heart, and the effects of new cardiotonic agents on these isoenzymes

Cited by 31 publications

References 32 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

Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors

Acute Effects of Toborinone on Vascular Capacitance and Conductance in Experimental Heart Failure

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