Phosphodiesterase Isozyme Inhibition, Activation of the cAMP System, and Positive Inotropy Mediated by Milrinone in Isolated Guinea Pig Cardiac Muscle

Silver, Paul J.; Harris, Andrea; Canniff, Paul C.; Lepore, Rhonda E.; Bentley, Ross; Hamel, L T; Evans, Dale B.

doi:10.1097/00005344-198913040-00004

Cited by 55 publications

(17 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This recognition has pertinent therapeutic implications. Milrinone, a selective phosphodiesterase three inhibitor, causes relaxation of vascular smooth muscle, enhances myocardial contractility (inotropy effect) and improves myocardial relaxation (lusitropic effect) (10–12). There are recent pharmacokinetic and clinical neonatal data demonstrating its usefulness in improving oxygenation in term neonates with PPHN when used in conjunction with iNO or in PPHN refractory to iNO therapy (13,14).…”

Section: Discussionmentioning

confidence: 99%

Global myocardial function is compromised in infants with pulmonary hypertension

2012

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Global myocardial function is compromised in infants with pulmonary hypertension

2012

View full text Add to dashboard Cite

show abstract

“…Whilst the mechanisms of action of these agents have not been fully elucidated, these compounds have been shown to derive their inotropic and vasodilator actions, at least in part, from the selective inhibition of phosphodiesterase (PDE) isoenzymes, PDE III and PDE IV, which are specific for adenosine 3':5'-cyclic monophosphate (cyclic AMP) (Colucci et al, 1986;Prigent et al, 1988;Schmitz et al, 1989;Silver et al, 1989;Beavo & Reifsnyder, 1990;Nicholson et al, 1991). The effectiveness of these drugs at increasing intracellular levels of cyclic AMP varies considerably and evidence indicates that a potentially more useful drug would have a lesser effect mediated through cyclic AMP (Hohl & Li, 1991).…”

Section: Introductionmentioning

confidence: 99%

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Kelso

McDermott

Silke

1993

British J Pharmacology

View full text Add to dashboard Cite

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.

show abstract

“…In the PDE isoenzymes isolated from guinea-pig ventricular myocardium SCH00013 inhibited selec-tively the activity of PDE III, although the concentration range for the PDE III inhibition (IC 5o = 64.9 pmol/l) was much higher than that for the induction of PIE (EC 50 = 9.2 pmol/l). Therefore, the cAMP-dependent mechanism of SCH00013 due to the PDE III inhibition may contribute to the PIE of SCH00013, as a common mechanism to milrinone [29] and Vesnarinone [30]. SCH00013 was much less potent than Vesnarinone in inhibition of PDE III, whereas it was more potent than vesnarinone in inducing the PIE.…”

Section: Discussionmentioning

confidence: 97%

Investigation on SCH00013, a Novel Cardiotonic Agent with Ca++ Sensitizing Action

Hino

Sugawara

Yoshimura

et al. 2011

Arzneimittelforschung

View full text Add to dashboard Cite

In order to clarify the mechanism of action of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6- tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013), a novel cardiotonic agent with Ca++ sensitizing action, its effects on contractile force, atrial rate and action potential, and on the activity of Na+, K(+)-ATPase and phosphodiesterase (PDE) I-IV were studied in the guinea-pig heart. SCH00013 exerted a positive inotropic effect (PIE) on isolated right ventricular papillary muscles in a concentration-dependent manner (EC50 = 9.2 mumol/l): the relative potency was milrinone > SCH00013 > vesnarinone. The PIE of SCH00013 was not influenced by propranolol, a beta-blocker, and SCH00013 did not affect the activity of cardiac Na+, K(+)-ATPase. The PIE of SCH00013 was partially inhibited by carbachol, a muscarinic receptor agonist, which implies a partial contribution of the cAMP-dependent mechanism to the PIE. SCH00013 inhibited the activity of PDE III selectively, but the potency was weak: the IC50 value was 64.9 mumol/l, which was 46 and 3.9 times less potent than those of milrinone and vesnarinone, respectively. SCH00013 and vesnarinone elicited a moderate decrease in the rate of beating of isolated right atria, while milrinone increased it. SCH00013 markedly prolonged the action potential duration and the effective refractory period with no change in the resting membrane potential and dV/dtmax, an indication that SCH00013 may suppress the activity of delayed rectifying K+ channels. These results indicate that SCH00013, that primarily acts as a Ca++ sensitizer, possesses a weak selective PDE III inhibitory effect. The potential positive chronotropic effect of SCH00013 due to PDE III inhibition may be offset by its effect on K+ channels.

show abstract

Phosphodiesterase Isozyme Inhibition, Activation of the cAMP System, and Positive Inotropy Mediated by Milrinone in Isolated Guinea Pig Cardiac Muscle

Cited by 55 publications

References 0 publications

Global myocardial function is compromised in infants with pulmonary hypertension

Global myocardial function is compromised in infants with pulmonary hypertension

Cardiotonic actions of selective phosphodiesterase inhibitors in rat isolated ventricular cardiomyocytes

Investigation on SCH00013, a Novel Cardiotonic Agent with Ca++ Sensitizing Action

Contact Info

Product

Resources

About