Two Isoforms of cGMP-Inhibited Cyclic Nucleotide Phosphodiesterases in Human Tissues Distinguished by Their Responses to Vesnarinone, a New Cardiotonic Agent

Mikami, Hiroshi; M, Ito; Sugioka, Masaki; Kozeki, H.; Konishi, Tokuji; Tanaka, Toshio; Nakano, Takeshi

doi:10.1006/bbrc.1993.1063

Cited by 23 publications

(5 citation statements)

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“…Although cardiovascular complications of a PDE3 inhibitor may preclude the development of this hybrid inhibitor for asthma, the knowledge that the effect of PDE3 in cardiac muscle (PDE3A) differs from that of the isoform (PDE3B) expressed by proinflammatory cells, such as T lymphocytes, provides an opportunity to synthesize compounds with reduced activity against PDE3A [4]. Theoretically, an inhibitor with more-selective action against PDE3B can be synthesized, because a new cardiotonic agent, vesnarinone, which is tenfold more potent against PDE3A than PDE3B, has been synthesized [24]. In addition to its antiasthmatic property, it has been reported that the inhibition of PDE3B enhances PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia [25].…”

Section: Discussionmentioning

confidence: 98%

Inhibitory effects of quercetin derivatives on phosphodiesterase isozymes and high-affinity [3 H]-rolipram binding in guinea pig tissues

et al. 2008

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Rolipram has high (PDE4(H)) and low (PDE4(L)) affinities for phosphodiesterase (PDE)-4, respectively. In general, it is believed that inhibitions by PDE4(H) and PDE4(L) are respectively associated with an adverse response and with anti-inflammatory and bronchodilating effects. This has provided a rational basis for designing new compounds with high PDE4(H)/PDE4(L) ratios. In the present study, we attempted to determine the PDE4(H)/PDE4(L) ratios of quercetin (1), qercetin-3-O-methylether (3-MQ, 2), quercetin-3,7,4'-O-trimethylether (ayanin, 3), quercetin-3,7,3',4'-O- tetramethylether (QTME, 4), quercetin-3,5,7,3',4'-O-petamethylether (QPME, 5), quercetin-3,5,7,3',4'-O-pentaacetate (QPA, 6), and quercetin-3-O-methyl-5,7,3',4'-O-tetraacetate (QMTA, 7). The activities of PDE1 approximately 5, which were partially separated from homogenates of guinea pig lungs and hearts, were measured by a two-step procedure using adenosine 3',5'-cyclic monophosphate (cAMP) with [(3) H]-cAMP or guanosine 3',5'-cyclic monophosphate (cGMP) with [(3) H]-cGMP as substrates. The IC(50) values of all of these compounds except quercetin (1), 3-MQ (2), and QMTA (7) on PDE1 approximately 5 inhibition were determined. The anti-inflammatory effects of PDE4 inhibitors were reported to be associated with inhibition of PDE4 catalytic activity. Therefore, these IC(50) values for PDE4 inhibition were taken as the PDE4(L) values. The effective concentration (EC(50)), at which one half of the [(3) H]-rolipram bound to high-affinity rolipram binding sites (HARBSs) of brain cell membranes was replaced, was defined as the PDE4(H) value. In the present results, the PDE4(H)/PDE4(L) ratios of quercetin (1), ayanin (3), and QPME (5) were >30, >19, and 11, respectively (Table 1), which are higher than or equal to that of AWD12-281, the selective PDE4 inhibitor with the greatest potential currently undergoing clinical trials for treating asthma and chronic obstructive pulmonary disease.

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Section: Discussionmentioning

confidence: 98%

Inhibitory effects of quercetin derivatives on phosphodiesterase isozymes and high-affinity [3 H]-rolipram binding in guinea pig tissues

et al. 2008

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“…For example, vesnarinone may display some degree of selectivity for the cardiac phosphodiesterase III isoform, inhibiting neutrophil and monocyte phosphodiesterase IV at significantly higher concentrations. 28 Thus pharmacokinetic or pharmacodynamic explanations for any observed differences between the 2 drugs cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Vesnarinone and amrinone reduce the systemic inflammatory response syndrome

Takeuchi

Nido

Ibrahim

et al. 1999

The Journal of Thoracic and Cardiovascular Surgery

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“…It is, therefore, interesting that vesnarinone, in contrast to other compounds tested, has been reported to inhibit the soluble cardiac PDE3 (presumably PDE3A) ten-fold more effectively than platelet PDE3A. 51 The basis for this difference is not clear.…”

Section: Phosphodiesterase 3 (Pde3)mentioning

confidence: 99%

Cyclic Nucleotides and Phosphodiesterases in Platelets

Haslam¹,

Dickinson²,

Jang³

1999

Thromb Haemost

136

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IntroductionIt is now almost 30 years since the discovery that prostaglandin E1 (PGE1) inhibits platelet responses to aggregating agents, together with finding that the effects of this compound are mediated by adenosine 3′, 5′-cyclic monophosphate (cAMP) initiated interest in the physiological and pharmacological regulation of platelet function by other agents that increase platelet cAMP, as reviewed elsewhere.1 The most important agonists that stimulate cAMP formation in platelets have now been identified as prostacyclin (PGI2), prostaglandin D2 (PGD2), and adenosine, which exert their effects through receptors of the serpentine or seven transmembrane segment class (IP, DP and A2 receptors, respectively).2 The latter then stimulate cAMP formation by adenylyl cyclase via the GTP-dependent activation of the G-protein, Gs (Fig. 1). In the classical view, cAMP exerts its effects solely by binding to the RI and RII regulatory subunits of type I and type II cAMP-dependent protein kinases (PKA). The catalytic subunits of the kinases then dissociate and phosphorylate selected serine and threonine residues on target proteins that prevent or reverse platelet activation.2 A crucial role is played by cAMP phosphodiesterases, which degrade cAMP to 5′-AMP, thereby diminishing and terminating the effects of agonists that stimulate cAMP formation (Fig. 1). In early studies, this was demonstrated by the ability of first-generation inhibitors of cAMP phosphodiesterases, particularly the methylxanthines, to inhibit platelet aggregation and potentiate the inhibitory effects of activators of platelet adenylyl cyclase.1 Such studies provided the rationale for the subsequent development of more potent and selective phosphodiesterase inhibitors as potential antithrombotic agents.Interest in the role of guanosine 3′,5′-cyclic monophosphate (cGMP) in platelets closely followed the discovery of the inhibitory action of cAMP. An early hypothesis that cGMP might potentiate platelet aggregation was abandoned by 1978, after it was shown that some inhibitors of platelet aggregation, such as nitroprusside (NP), also increased platelet cGMP.1 It soon emerged that all nitrovasodilators release nitric oxide and activate soluble guanylyl cyclase (GC) and that the cGMP formed stimulates cGMP-dependent protein kinases (PKG) in many cells and tissues (Fig. 1), including vascular smooth muscle and platelets.3 The crucial physiological importance of this pathway was established with the identification of endothelium-derived relaxing factor (EDRF) as nitric oxide.4 cGMP phosphodiesterases play an essential role by limiting increases in cellular cGMP, and inhibition of these enzymes was found to potentiate the effects of nitric oxide and nitric oxide donors on platelets and other cells.5 The ability of cAMP and cGMP to activate distinct protein kinases led to a persistent view that these two cyclic nucleotides operate in parallel and independent ways to inhibit platelet function, cAMP mediating the effects of agonists such as PGI2, and cGMP mediating the effects of nitric oxide.2,3 However, over the last 10 years, considerable evidence has accumulated to indicate that this is not the case in platelets (or in many other cells) and that cross-talk between the cAMP and cGMP systems may occur on at least two levels, affecting both cyclic nucleotide phosphodiesterase (PDE) and protein kinase activities (Fig. 1). One of the most significant of these interactions is through the effects of cGMP on the hydrolysis of cAMP by PDEs. It is the purpose of this chapter to describe platelet PDEs and to discuss how their individual characteristics and regulation may impact platelet function and the design of useful antithrombotic agents. In addition, evidence that both cGMP and cAMP may activate PKG and that these cyclic nucleotides may exert effects in platelets that do not involve either PKA or PKG will be discussed briefly.

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Two Isoforms of cGMP-Inhibited Cyclic Nucleotide Phosphodiesterases in Human Tissues Distinguished by Their Responses to Vesnarinone, a New Cardiotonic Agent

Cited by 23 publications

References 0 publications

Inhibitory effects of quercetin derivatives on phosphodiesterase isozymes and high-affinity [3 H]-rolipram binding in guinea pig tissues

Inhibitory effects of quercetin derivatives on phosphodiesterase isozymes and high-affinity [3 H]-rolipram binding in guinea pig tissues

Vesnarinone and amrinone reduce the systemic inflammatory response syndrome

Cyclic Nucleotides and Phosphodiesterases in Platelets

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