Effects of Enoximone and Isobutylmethylxanthine on Contractile Tension and Cyclic Nucleotide Levels in Isolated Blood-Perfused Dog Papillary Muscle

Cc, Hsieh; Kariya, Takashi; Rc, Dage; Sj, Ruberg

doi:10.1097/00005344-198702000-00017

Cited by 11 publications

(3 citation statements)

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“…These results are in marked contrast to those of other investigators (Ahn et al, 1986;Endoh & Blinks, 1987;Hsieh et al, 1987) who indicated a significant elevation in levels of cyclic AMP, in accordance with evidence showing that this compound is a highly selective inhibitor of the PDE III isoform. The effect of enoximone on rat isolated cardiomyocytes in this study was an unusual contrast to the positive action of all the other PDE inhibitors examined.…”

Section: Effects Of Pde Inhibitors On Contractile Activitycontrasting

confidence: 48%

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Kelso

McDermott

Silke

1993

British J Pharmacology

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1 The contractile effects of the novel cardiotonic agent HN-10200 (2-[3-methoxy-5-methylsulphinyl-2-thienyl]-lH-imidazo-[4,5-c]-pyridine hydrochloride), were examined and comparisons made with the responses obtained to a structurally similar compound, sulmazole, and to a number of other compounds which are known to inhibit phosphodiesterase (PDE) isoenzymes with differing selectivities; namely, enoximone (PDE III inhibitor), Ro 20-1724 (PDE IV inhibitor) and 3-isobutyl-1-methylxanthine (nonselective PDE inhibitor). 2 Contractile function, as measured by mechanical shortening, and biochemical systems involving cyclic AMP were investigated in ventricular cardiomyocytes isolated from adult Sprague-Dawley rats (200-250 g). 3 HN-10200 exerted a concentration-dependent (10-8 M-10-4 M) positive contractile effect, which was independent of a-or 0-adrenoceptor, or histamine receptor stimulation. 4 The efficacies of the contractile responses to the PDE inhibitors were of the order: HN-10200> IBMX> sulmazole> enoximone and maximum stimulations, which were obtained at concentrations of 10-4M, were 54 ± 4%, 41 ± 7%, 38 ± 7% and 26 ± 5% (mean ± s.e.) greater than basal levels, respectively (n = 6); the basal value of contractile amplitude (dL), in the absence of PDE inhibitors was 7.39 ± 0.18% (mean ± s.e.). Ro 20-1724 did not have any effect on contractile activity. 5 Due to low basal levels of cyclic nucleotides in isolated cells, accumulation of cyclic AMP due to the presence of the PDE inhibitors was detected only when the levels of cyclic nucleotide were enhanced with forskolin (10 fM). 6 The PDE inhibitors increased levels of cyclic AMP only at concentrations> 10-' M. HN-10200 and sulmazole had similar concentration-dependent profiles for the accumulation of cyclic AMP; their potencies were lower than that of IBMX (concentrations of forskolin required to increase cyclic AMP by 4 pmol mg-' protein, in the presence of maximum concentrations of the PDE inhibitors, were 13 ± 3 11M, 14 ± 3 JAM and 3 ± 0.6 JAM [mean ± s.e.], respectively). 7 These results indicate that a similar mechanism, probably through a weak inhibition of the cyclic AMP-specific PDE isoenzymes, is responsible for the increase in levels of cyclic AMP by HN-10200 and sulmazole. However, cyclic AMP is only partially responsible for the positive contractile effect of HN-10200 and, similarly, sulmazole and IBMX. The lack of apparent increase in levels of cyclic AMP by enoximone, highlights its degree of selectivity for the PDE III isoenzyme, such that the PDE IV isoform is still present in sufficient quantity to degrade cyclic AMP within the cell. On the other hand, the potent action of Ro 20-1724 on accumulation of cyclic AMP, in addition to the lack of effect on contractile function, is in agreement with the selectivity of this compound for the PDE IV isoenzyme and compartmentalization of cyclic AMP in rat isolated ventricular cardiomyocytes.

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Section: Effects Of Pde Inhibitors On Contractile Activitycontrasting

confidence: 48%

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Kelso

McDermott

Silke

1993

British J Pharmacology

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“…The vasodi lation in the hind limb was not attenuated by surgical sympathectomy, indicating that it was directly mediated. Enoximone was a more effective positive inotropic agent than vasodilator in the isolated, blood-perfused dog papillary muscle preparation [6].…”

Section: Introductionmentioning

confidence: 87%

“…7) [13], Specific inhibition of type IV phospho diesterase seems to have a role in the posi tive inotropic action of enoximone; this agent was reported to produce an increase in cyclic AMP in the dog ventricular muscle during the peak of its inotropic effect ( fig. 8) [6,7], A cyclic-AMP-dependent mechanism of inotropism for enoximone is supported by a report showing inhibition of the positive inotropic effect of enoximone in isolated dog trabeculae by carbachol, an agent known to attenuate adenylate cyclase activity and cy clic AMP formation [7], Studies in vivo and in vitro with appro priate antagonists have indicated that the cardiac and vasodilator effects of enoximone are not mediated by stimulation of either aor p-adrenergic receptors or H| -or H?-histaminergic receptors. Furthermore, the vasodi lator effect does not involve stimulation of muscarinic receptors or altered prostanoid formation [2,4], Enoximone, 1 mmol/1, does not alter the calcium sensitivity of chemi cally skinned (glycerinated) myocardial fi bers from pig hearts [14], and it did not stim ulate the Mg2+-ATPase of dog cardiac myofi brils [Kariya and Dage, unpubl.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Pharmacology and Pharmacokinetics of Enoximone

Dage¹,

Okerholm²

1990

Cardiology

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Enoximone is an inotropic vasodilating agent. Its principal effects are positive inotropism and vasodilation, which are not accompanied by changes in myocardial oxygen consumption. An inotropic dose of enoximone increases the level of cyclic AMP in the isolated, blood-perfused dog papillary muscle owing to its selective inhibition of the one isoform of cyclic AMP phosphodiesterase from the dog heart that is inhibited by cyclic GMP. Studies on the metabolism and pharmacokinetic profile of enoximone have been carried out in the rat, dog and monkey. Enoximone is metabolized mainly by oxidation to enoximone sulphoxide in all species studied, and this is reversible. In congestive heart failure patients, approximately 74% of a rapidly administered intravenous dose of enoximone is excreted in a 24-hour urine collection as the sulphoxide metabolite; only about 0.49% is recoverable as intact drug. Enoximone sulphoxide has the same inotropic and vasodilator activities as enoximone but is 0.13-0.14 times as potent and has a 13 times longer duration of inotropic action in the dog. It is suggested that the metabolite may contribute to some of the effects that follow enoximone administration.

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Synthesis of 2‐imino‐4‐thiazolines, 2‐imino‐4‐alkoxythiazolidines, thiazoles and 4‐imidazolin‐2‐ones from α‐halomethyl ketimines

Kimpe

Cock

Keppens

et al. 1996

Journal of Heterocyclic Chem

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Effects of Enoximone and Isobutylmethylxanthine on Contractile Tension and Cyclic Nucleotide Levels in Isolated Blood-Perfused Dog Papillary Muscle

Cited by 11 publications

References 0 publications

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Pharmacology and Pharmacokinetics of Enoximone

Synthesis of 2‐imino‐4‐thiazolines, 2‐imino‐4‐alkoxythiazolidines, thiazoles and 4‐imidazolin‐2‐ones from α‐halomethyl ketimines

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