Effects of Isomazole on Force of Contraction and Phosphodiesterase Isoenzymes I-IV in Nonfailing and Failing Human Hearts

Bethke, Thomas D.; Klimkiewicz, Anna; Kohl, Claudia; Leyen, Heiko von der; Mehl, H. G.; Mende, Ulrike; Meyer, Wilfried; Neumann, Joachim; Schmitz, Wilhelm; Starbatty, Jutta; Stein, Birgitt; Wenzlaff, H.; Döring, Volker; Kalmár, P.; Haverich, Axel

doi:10.1097/00005344-199109000-00012

Cited by 21 publications

(19 citation statements)

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“…The cyclic AMP PDE activity was also assayed in the presence of 0.51iM cyclic GMP (additional characterization of PDE II-IV). To differentiate further between PDE III and IV, the selective PDE IV inhibitor, rolipram (Reeves et al, 1987) and the selective PDE III inhibitor, UD-CG 212 Cl (Bethke et al, 1991a) were used. Appropriate peak fractions were pooled (referred to as PDE I-IV), stored at 4'C, and used for the drug experiments within 2 weeks.…”

Section: Methodsmentioning

confidence: 99%

“…To elucidate whether PDE inhibitors are similarly effective in inhibiting PDE activity from isolated cardiomyocytes and multicellular cardiac preparations we investigated the effects of selective (UD-CG 212 Cl, PDE III inhibitor, Bethke et al, 1991a;rolipram, PDE IV inhibitors, Reeves et al, 1987) and nonselective PDE inhibitors (IBMX, Bethke et al, 1991b). In both preparations, similar results were obtained with the PDE inhibitors investigated.…”

Section: Effects Ofphosphodiesterase Inhibitors On Pde Activitymentioning

confidence: 99%

“…der Leyen, 1989). Inhibition of PDE III is probably mainly involved in positive inotropic effects of many positive inotropic agents regarded as selective PDE III inhibitors like amrinone and milrinone (Kariya et al, 1982;Wilmshurst et al, 1984;Weishaar et al, 1986) enoximone (Kariya et al, 1982;Bethke et al, 1989;1992), isomazole (Bethke et al, 1991a), pimobendan v. der Leyen et al, 1991), adibendan (Bethke et al, 1988) and saterinone .…”

Section: Effects Ofphosphodiesterase Inhibitors On Pde Activitymentioning

confidence: 99%

“…Five different families exist and more than 20 distinct isoenzymes are now recognized (Beavo & Reifsnyder, 1990). In the human heart four subtypes (PDE I-IV) have been defined by anion exchange chromatography (Reeves et al, 1987;Bethke et al, 1989;Silver et al, 1990). The PDE isoenzymes vary according to substrate specificity and kinetic characteristics (Weishaar et al, 1986;Reeves et al, 1987; der .…”

Section: Introductionmentioning

confidence: 99%

“…The PDE inhibiting effects of compounds such as milrinone and amrinone (Kariya et al, 1982;Wilmshurst et al, 1984;Weishaar et al, 1986), adibendan (Bethke et al, 1988), pimobendan der Leyen et al, 1991), saterinone , isomazole (Bethke et al, 1991a) and enoximone (Kariya et al, 1982;Bethke et al, 1992) have been mainly investigated in PDE isoenzymes from homogenates of entire multicellular ventricular tissue. Recently, the PDE inhibitory effects of milrinone, rolipram and some other compounds have been examined in cardiomyocytes from the rat heart (Bode et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

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Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea‐pig hearts

Bethke

Meyer

Schmitz

et al. 1992

British J Pharmacology

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The present study compared the cyclic nucleotide phosphodiesterase (PDE) activities in cardiomyocytes and ventricular cardiac tissue from guinea‐pigs. The aim of the study was to determine whether PDE activities in ventricular tissue accurately reflect the isoenzymes present in cardiomyocytes. In homogenates of cardiomyocytes and multicellular ventricular tissue, four distinct soluble PDE activities could be separated by DEAE‐sepharose chromatography. In multicellular cardiac tissue as well as in cardiomyocyte preparations, adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) PDE isoenzymes I‐IV were comparable in terms of substrate affinities, and inhibition or stimulation by guanosine 3′:5′‐cyclic monophosphate (cyclic GMP). However, in cardiomyocytes the Vmax values of PDE I‐IV were lower by a factor of about 2 to 7 and the basal activities were lower by a factor of about 3 to 5 as compared to multicellular cardiac tissue. To investigate whether the PDE I‐IV activities were similarly inhibited by PDE inhibitors in both preparations, we studied the effects of 3‐isobutyl‐1‐methylxanthine (IBMX), UD‐CG 212 Cl (2‐(4‐hydroxy‐phenyl)‐5‐(5‐methyl‐3‐oxo‐4,5‐dihydro‐2H‐6‐pyridazinyl)benzimidazole HCl) and rolipram. UD‐CG 212 Cl was a selective PDE III inhibitor in cardiomyocytes (IC50 0.3 μmol l−1) and in ventricular tissue (IC50 value 0.1 μmol l−1). Rolipram selectively inhibited PDE IV in cardiomyocytes (IC50 1.4 μmol ml−1) and in ventricular tissue (IC50 1.1 μmol l−1) whereas IBMX was a nonselective PDE inhibitor in both preparations. It is concluded that the PDE isoenzymes I‐IV from multicellular ventricular tissue can be used as a representative system for investigating PDE inhibiting properties of PDE inhibitors in the myocardium since comparable PDE isoenzymes I‐IV exist in guinea‐pig ventricular cardiomyocytes and multicellular ventricular tissue.

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Section: Methodsmentioning

confidence: 99%

Section: Effects Ofphosphodiesterase Inhibitors On Pde Activitymentioning

confidence: 99%

Section: Effects Ofphosphodiesterase Inhibitors On Pde Activitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea‐pig hearts

Bethke

Meyer

Schmitz

et al. 1992

British J Pharmacology

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4‐(4‐Guanidinobenzoyl)‐2‐imidazolones and Related Compounds: Phosphodiesterase Inhibitors and Novel Cardiotonics with Combined Histamine H₂ Receptor Agonist and PDE III Inhibitor Activity

Glass

Buschauer

Tenor

et al. 1995

Archiv der Pharmazie

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A series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazolone-type phosphodiesterase (PDE) inhibitor enoximone and guanidine-type histamine H2 receptor agonists such as arpromidine. All compounds are para-substituted 4-benzoyl-5-alkyl-2-imidazolones. H2 agonism was incorporated by p-(hetero)arylalkyl substituents, in particular by an imidazolylpropyl guanidine group. In addition analogous ureas, cyanoguanidines, alkyl guanidine carboxylates, and amides were prepared. These functional groups were either directly attached to the phenyl ring or linked by an appropriate spacer. The compounds were screened for positive inotropic activity in the isolated electrically stimulated guinea pig papillary muscle and for inhibition of PDE III (cGMP-inhibited cAMP PDE, isolated from guinea pig heart). The cardiotonics obtained proved to be either PDE III inhibitors, some of them surmounting up to 3-fold the potency of enoximone, or pharmacological hybrids combining both PDE III inhibitor and histamine H2 receptor agonist activities. These hybrids were the most potent positive inotropic substances at the papillary muscle, probably due to their synergistic mechanism of action. The participation of histamine H2 receptors could be demonstrated in the papillary muscle preparation by pretreatment with the H2 antagonist famotidine (10 microM) as well as by further pharmacological experiments using isolated perfused hearts of guinea pigs and rats, isolated guinea pig right atria, adenylyl cyclase and H2 receptor binding assays. At equieffective concentrations the moderate PDE III inhibitor and histamine H2 agonist N1-(4-[(1,3-dihydro-5-methyl-2-oxo-3H-imidazol-4-yl)-carbonyl]phenyl)-N2 - [3-(1H-imidazol-4-yl)propyl]guanidine 65 and the 5-ethyl homologue 66 were about 2 and 10 times more potent than enoximone at the papillary muscle. Moreover, both compounds produced a 2.5-fold higher maximal response than the reference compound.

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Myocardial Effects of Cyclic AMP Phosphodiesterase Inhibition Are Dampened in Thyroxine-Induced Cardiac Hypertrophy

Straznicka¹,

Leone²,

Scholz³

et al. 1998

Journal of Surgical Research

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Effects of Isomazole on Force of Contraction and Phosphodiesterase Isoenzymes I-IV in Nonfailing and Failing Human Hearts

Cited by 21 publications

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Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea‐pig hearts

Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea‐pig hearts

4‐(4‐Guanidinobenzoyl)‐2‐imidazolones and Related Compounds: Phosphodiesterase Inhibitors and Novel Cardiotonics with Combined Histamine H₂ Receptor Agonist and PDE III Inhibitor Activity

Myocardial Effects of Cyclic AMP Phosphodiesterase Inhibition Are Dampened in Thyroxine-Induced Cardiac Hypertrophy

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Effects of Isomazole on Force of Contraction and Phosphodiesterase Isoenzymes I-IV in Nonfailing and Failing Human Hearts

Cited by 21 publications

References 0 publications

Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea‐pig hearts

Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea‐pig hearts

4‐(4‐Guanidinobenzoyl)‐2‐imidazolones and Related Compounds: Phosphodiesterase Inhibitors and Novel Cardiotonics with Combined Histamine H2 Receptor Agonist and PDE III Inhibitor Activity

Myocardial Effects of Cyclic AMP Phosphodiesterase Inhibition Are Dampened in Thyroxine-Induced Cardiac Hypertrophy

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4‐(4‐Guanidinobenzoyl)‐2‐imidazolones and Related Compounds: Phosphodiesterase Inhibitors and Novel Cardiotonics with Combined Histamine H₂ Receptor Agonist and PDE III Inhibitor Activity