Differential effects of Ro 20-1724 and isobutylmethylxanthine on the basal force of contraction and β-adrenoceptor-mediated response in the rat ventricular myocardium

doi:10.1016/0006-291X(90)91739-F

Biochemical and Biophysical Research Communications

Volume 167, Issue 1, 28 February 1990, Pages 123-129

https://doi.org/10.1016/0006-291X(90)91739-F Get rights and content

Abstract

Effects of Ro 20-1724, a selective inhibitor of soluble cGMP-insensitive type IV phosphodiesterase, on the force and cAMP levels were compared with those of 3-isobutyl-1-methylxanthine, a non-selective inhibitor, in the rat ventricular myocardium. Ro 20-1724 scarcely affected the basal force of contraction and cAMP levels, whereas it enhanced the positive inotropic effect and cAMP accumulation induced by isoproterenol more effectively than 3-isobutyl-1-methylxanthine. These results imply that inhibition of the soluble cGMP-insensitive type IV PDE by Ro 20-1724 may be crucially involved in the regulation of myocardial contractility through the interaction with cAMP generation in the rat ventricular myocardium.

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In adult ventricular myocytes from rat and mice, PDE4 has no effect on basal cAMP levels but becomes crucial to hydrolyze cAMP generated during β-AR stimulation [25,37,60,61,65,98] and for the control of PKA phosphorylation of key proteins involved in ECC such as LTTC [61,99], RyR2 [100] and PLB [92]. As a consequence, PDE4 inhibition strongly potentiates the inotropic effects of β-AR stimulation in these species [101–104]. However, although less studied, the role of PDE4 appears more modest in larger mammals and in humans.
In the light of the knowledge accumulated over the years, it becomes clear that intracellular cAMP is not uniformly distributed within cardiomyocytes and that cAMP compartmentation is required for adequate processing and targeting of the information generated at the membrane. Localized cAMP signals may be generated by interplay between discrete production sites and restricted diffusion within the cytoplasm. In addition to specialized membrane structures that may limit cAMP spreading, degradation of the second messenger by cyclic nucleotide phosphodiesterases (PDEs) appears critical for the formation of dynamic microdomains that confer specificity of the response to various hormones. This review will cover the role of the different cAMP-PDE isoforms in this process. This article is part of a Special Issue entitled “Local Signaling in Myocytes.”
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The experimental procedures to simultaneously detect contractile activity and Ca²⁺ transients by means of the Ca²⁺ sensitive bioluminescent protein aequorin in multicellular preparations, and the fluorescent dye indo-1 in single myocytes, provide powerful tools to differentiate the regulatory mechanisms of intrinsic and external inotropic interventions in intact cardiac muscle. The regulatory process of cardiac excitation-contraction coupling is classified into three categories; upstream (Ca²⁺ mobilization), central (Ca²⁺ binding to troponin C), and/or downstream (thin filament regulation of troponin C property or crossbridge cycling and crossbridge cycling activity itself) mechanisms. While a marked increase in contractile activity by the Frank-Starling mechanism is associated with only a small alteration in Ca²⁺ transients (downstream mechanism), the force-frequency relationship is primarily due to a frequency-dependent increase of Ca²⁺ transients (upstream mechanism) in mammalian ventricular myocardium. The characteristics of regulation induced by β- and α-adrenoceptor stimulation are very different between the two mechanisms: the former is associated with a pronounced facilitation of an upstream mechanism, whereas the latter is primarily due to modulation of central and/or downstream mechanisms. α-Adrenoceptor-mediated contractile regulation is mimicked by endothelin ET_A- and angiotensin II AT₁-receptor stimulation. Acidosis markedly suppresses the regulation induced by Ca²⁺ mobilizers, but certain Ca²⁺ sensitizers are able to induce the positive inotropic effect with central and/or downstream mechanisms even under pathophysiological conditions.
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The effects of selective inhibitors of phosphodiesterase type IV (PDE4) on ischemia-reperfusion-induced gastric injuries were investigated in rats. Gastric ischemia was induced by applying a small clamp to the celiac artery, and reoxygenation was performed by removal of the clamp. Ischemia-reperfusion produced gastric hemorrhagic injuries and increased the content of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) activity in gastric mucosa. Rolipram (0.03 – 0.3 mg/kg, s.c.) and Ro-20-1724 (0.3–3mg/kg, s.c.) prevented the development of gastric injury in a dose-dependent manner, and it also inhibited the increase in mucosal TNF-α content and MPO activity induced by ischemia-reperfusion. The anti-ulcer drug irsogladine (1 – 10 mg/kg, p.o.), which is known to possess a PDE4 inhibitory action, also inhibited the gastric injury produced by ischemia-reperfusion, as well as the increase in TNF-α levels and MPO activity. It is concluded that the ability of PDE4 inhibitors to inhibit cytokine TNF-α synthesis and the infiltration of polymorphonuclear leukocytes underlies their gastroprotective effects in ischemia-reperfusion-induced gastric injury. Our experiments suggest that drugs that inhibit PDE4 isoenzyme, such as the anti-ulcer drug irsogladine, may be a useful adjunct therapy for the treatment of the gastric damage that follows ischemia-reperfusion.
Cyclic AMP-specific phosphodiesterase inhibitor rolipram and RO-20-1724 promoted apoptosis in HL60 promyeloctic leukemic cells via cyclic AMP-independent mechanism
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Phosphodiesterases (PDEs) are responsible for the hydrolysis of cAMP and cGMP which act as intracellular second messengers in a variety of cellular functions. In this paper we report that PDE3 and PDE4 were two dominant classes of PDEs expressed in HL60 cells. The influence of specific PDE inhibitors on apoptosis in HL60 cells was studied. The non-specific inhibitor IBMX and PDE3 specific inhibitors (milrinone and trequinsin) did not promote apoptosis. They inhibited apoptosis induced by paclitaxel or thapsigargin. However, PDE4 specific inhibitors (rolipram and RO-20-1724) promoted apoptosis within 5 h. In HL60 cells, other cAMP-eliciting reagents (8-bromo-cAMP, Sp-cAMP and forskolin) also inhibited apoptosis, while cell-permeable cGMP analogs did not affect apoptosis. Therefore, IBMX and PDE3 specific inhibitors may prevent HL60 cells from apoptosis by increasing intracellular cAMP. However, apoptosis induced by PDE4 specific inhibitors is not likely due to increased cAMP level. These results suggest that rolipram and RO-20-1724 promoted apoptosis in HL60 cells through cAMP-independent mechanism.
Cytosolic and membrane-bound cyclic nucleotide phosphodiesterases from guinea pig cardiac ventricles
1992, European Journal of Pharmacology: Molecular Pharmacology
Cyclic nucleotide phosphodiesterase (PDE) activities were characterized in the cytosolic and post-nuclear membrane preparations of guinea pig cardiac ventricles. The cytosolic PDE activities were stimulated 5-fold by calmodulin (CaM) on both substrates (1 μM) and 1.2-fold by cGMP (5 μM) on cAMP hydrolysis. Conversely, in the membrane preparation, CaM only stimulated PDE activities 1.2- to 1.4-fold, but cGMP induced a 3-fold increase of the hydrolysis of cAMP. In both the cytosolic and the membrane preparations, the hydrolysis of cAMP was inhibited by 100 μM of either the PDE III inhibitor SK & F 94120 (27% and 31% respectively) or the PDE IV inhibitor rolipram (14% and 23% respectively). Four peaks were resolved from the cytosolic preparation by chromatography. Peak A and peak B hydrolyzed both cAMP and cGMP and were stimulated respectively by CaM and cGMP. Peak C and peak D selectively hydrolyzed cAMP. Peak C had an apparent K_m value for cAMP of 3.3 μM and was inhibited by PDE IV inhibitors. Peak D showed an apparent K_m value for cAMP of 0.43 μM and was inhibited by cGMP and by cardiotonic inhibitors of PDE III. Similar potencies of these inhibitors were observed in the membrane preparation. These results suggest that in guinea pig cardiac ventricles: (1) PDE I (CaM-activated) is almost exclusively cytosolic; (2) PDE II (cGMP-stimulated), PDE III (cGMP-inhibited and cardiotonic-sensitive) and PDE IV (rolipram-sensitive) are present in cytosolic and membrane preparations; (3) PDE III and PDE IV differ in their apparent K_m values for cAMP. The latter observation could explain the differential effects of PDE III and PDE IV inhibitors in the regulation of cardiac contraction.
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Differential effects of Ro 20-1724 and isobutylmethylxanthine on the basal force of contraction and β-adrenoceptor-mediated response in the rat ventricular myocardium

Abstract

Biochem. Biophys. Res. Commun

J. Biol. Chem

J. Mol. Cell. Cardiol

Japan. J. Pharmacol

J. Cardiovasc. Pharmacol

J. Pharmacol. Exp. Ther

J. Med. Chem