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(Circulation. 1997;95:1989-1991.)
© 1997 American Heart Association, Inc.
Articles |
Through the Looking Glass
A Positive Inotropic Drug and Ischemic Preconditioning
the Program in Molecular and Cellular Cardiology, Departments of Pathology and Medicine, and Center for Molecular Medicine and Genetics, Harper Hospital and Wayne State University School of Medicine, Detroit, Mich.
Correspondence to James D. Marsh, MD, Wayne State University School of Medicine, 421 E Canfield Ave, Detroit, MI 48201. E-mail marsh{at}cardiology.harper.wayne.edu
Key Words: Editorials • infarction • inotropic agents • ischemia
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Introduction |
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 Top Introduction Problem of Infarct Size...Role of Ecto-5'-Nucleotidase in...Other Mechanisms of Vesnarinone...ConclusionsReferences |
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`When I use a word,' Humpty Dumpty said in a rather scornful tone, `it means just what I choose it to mean—neither more nor less.'1
—Lewis Carroll, Through the Looking Glass
But words may mean more or less than we suspect, and affixing a noun or adjective can constrain our thinking. That is a lesson that the Oxford mathematician and logician Charles Dodgson, otherwise known as Lewis Carroll, conveys in his satiric novel Through the Looking Glass, published 125 years ago. When we label a drug a "positive inotropic agent," does it make it so—neither more nor less? Apparently not. Escaping the constraints of a label, investigators have sought novel mechanisms of action of the drug vesnarinone, which has been under development as a positive inotropic agent for several years. There is no doubt that vesnarinone has positive inotropic effects, but in light of the creative thinking of Kitakaze and colleagues,2 it appears that "vesnarinone" means more than that. Vesnarinone underwent extensive development and testing as a positive inotropic drug for use in congestive heart failure. The initial clinical studies using vesnarinone to treat heart failure demonstrated that in a dose of 60 mg/d, 6 months of therapy with vesnarinone resulted in a clear-cut decrease in morbidity and mortality and improved the quality of life for patients with congestive heart failure.3 However, higher doses of vesnarinone increased mortality, as well as inducing the troublesome side effect of neutropenia. Therefore, as a cardiotonic drug, vesnarinone has shown promise as an orally active agent and perhaps a useful alternative to the only currently FDA-approved orally active positive inotropic drug, digoxin. However, like digoxin, it appears to have a narrow therapeutic index. Because of its distinctive and important properties, it has been approved by the Japanese Ministry of Health and Welfare for use in chronic heart failure refractory to conventional therapy, but vesnarinone has not yet received FDA approval in the United States. It is becoming clear that there is more to vesnarinone than its categorization as a cardiotonic agent would suggest. In the current issue of Circulation, Kitakaze and colleagues2 have looked beyond the label and explored vesnarinone as a potential cardioprotective agent. They now report that vesnarinone pretreatment can dramatically limit infarct size in a canine model and that it acts at least in part through an adenosine-dependent mechanism.
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Problem of Infarct Size Limitation by Use of Pharmacological Agents |
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TopIntroductionProblem of Infarct Size...Role of Ecto-5'-Nucleotidase in...Other Mechanisms of Vesnarinone...ConclusionsReferences |
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Pharmacologically limiting infarct size has been a goal of investigative and clinical cardiologists since at least the 1970s. Many agents have been tried, often with promising effects in animal models but with disappointing results in patients. In recent years, much work on limitation of infarct size has focused on pharmacologically mimicking the process of ischemic preconditioning. Ischemic preconditioning refers to a process in which a brief, reversible period of ischemia followed by reperfusion leads to limitation in the size of an infarct after a subsequent prolonged, potentially lethal episode of ischemia.4 Compared with the myriad pharmacological agents examined in an attempt to limit infarct size in the past 20 years, ischemic preconditioning has produced the most reproducible, dramatic limitation of infarct size. However, the cellular mechanisms underlying this endogenous cardioprotective effect have remained elusive. Instead, it has become increasingly clear that ischemic preconditioning is a complex process that may have multiple proximal triggers and pathways that may converge on a final common pathway that is not yet fully understood. To date, many pharmacological agents have been shown to mimic in part the cardioprotective effects of ischemic preconditioning. It has been hypothesized that pharmacological effectors bind to sarcolemmal receptors and initiate transmembrane signals that ultimately lead to a cardioprotective effect. More recently, activation of protein kinases, specifically PKC, has been implicated as a downstream pathway through which multiple triggers may act. Indeed, several sarcolemmal receptors activated by pharmacological interventions activate PKC, including
1-adrenergic receptors, muscarinic cholinergic receptors, and endothelin, angiotensin II, and adenosine A1 receptors.5 Activation of PKC results in phosphorylation of many proteins; the crucial proteins and details of the distal signaling processes leading to protection against further ischemia remain to be identified. Of note, Kitakaze and coworkers have previously shown that activation of PKC may lead to phosphorylation and activation of ecto-5'-nucleotidase.6 Other recent reports propose that oxygen-derived free radicals, long considered detrimental to myocytes, may participate in ischemic preconditioning.7 In the present study, Kitakaze and coworkers2 studied the effect of the synthetic inotropic agent vesnarinone on both adenosine release during coronary hypoperfusion and infarct size in a canine model of regional myocardial infarction. The study was conducted in a rigorous fashion, using a carefully controlled series of experiments that included 57 dogs. Myocardial infarcts were produced by occlusion of the left anterior descending coronary artery for 90 minutes followed by 6 hours of reperfusion. Vesnarinone was administered at 20 µg·kg-1·min-1 for 10 minutes before occlusion and for the first hour of reperfusion. It was not administered during the coronary occlusion. Given in this manner, vesnarinone decreased the infarct size from 45% of the area at risk in controls to 7% in treated animals.
Vesnarinone, a quinolinone derivative, has pleomorphic effects. Potential processes by which vesnarinone may limit infarct size may be grouped into at least two broad categories: processes that modulate adenosine metabolism and processes that modulate inflammatory cytokines. There is little doubt that processes that increase the concentration of adenosine in the interstitial fluid surrounding ischemic myocytes can improve the ability of myocytes to tolerate a subsequent episode of ischemia, at least in some experimental models. Vesnarinone inhibits both nucleoside and nucleobase transport in mammalian cells, which will lead to enhanced adenosine concentration in the interstitial fluid.8 Vesnarinone also appears to activate myocardial ecto-5'-nucleotidase in experimental systems, the product of which is adenosine.2 Activation of this enzyme, located in the cell membrane, will also enhance the interstitial fluid concentration of adenosine. Vesnarinone is also a phosphodiesterase inhibitor and may modulate potassium channel properties as well. In the present study, the authors argue that the cardioprotective effect of vesnarinone is adenosine-mediated. First, they convincingly demonstrate that vesnarinone increases adenosine release during coronary hypoperfusion to four times that in control hearts. Second, the cardioprotective effect of vesnarinone was completely abolished by the nonselective adenosine receptor antagonist 8-SPT and partially inhibited by dipyridamole, an inhibitor of adenosine uptake. Taken together, these results suggest that vesnarinone may mediate its cardioprotective effects at least in part through an adenosine-mediated pathway.
The ability of vesnarinone, a positive inotropic agent, to markedly limit infarct size is quite exciting. However, several issues related to the role of adenosine in mediating cardioprotection merit consideration in light of these new findings. First, as in all experimental studies, the data should be reproducible in other laboratories under similar conditions. Second, it is not clear at what point in the infarct protocol vesnarinone is acting to limit infarct size. The drug is given 10 minutes before onset of ischemia and again for the first hour of reperfusion. The drug is not present during the 90-minute coronary occlusion, which may mimic clinical scenarios in which an infarct-limiting drug might be used. Third, the presence of an adenosine-dependent mechanism of action does not exclude other coincident processes. Some studies have shown that infusion of adenosine limits infarct size in rabbit and canine models of infarction.9 10 However, it is not universally accepted that adenosine receptor stimulation during reperfusion is capable of limiting infarct size in canine models11 ; it may depend on the pretreatment. Furthermore, it is notoriously difficult to interpret studies that used nonselective receptor antagonists (eg, 8-SPT), because the drug may have many other effects besides blocking adenosine receptors. Finally, complete inhibition of the ecto-5'-nucleotidase with the inhibitor ,ß-methyleneadenosine 5'-diphosphate did not completely block the protective effect of vesnarinone, again suggesting that the mechanism of action of vesnarinone may be more complex than solely that of a modulator of adenosine metabolism. Therefore, although the data from the Kitakaze study implicate adenosine and adenosine receptor stimulation in the cardioprotective effects of vesnarinone, caution should be used in attributing all the cardioprotective effects to adenosine.
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Role of Ecto-5'-Nucleotidase in Limitation of Infarct Size |
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TopIntroductionProblem of Infarct Size...Role of Ecto-5'-Nucleotidase in...Other Mechanisms of Vesnarinone...ConclusionsReferences |
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Kitakaze's group has previously published several convincing studies regarding the role of the ecto-5'-nucleotidase in cardioprotection from lethal ischemic injury.12 13 14 However, it may not be only this form of the nucleotidase that is important in limitation of infarct size. A recent study by Darvish et al15 in canine myocardium showed that the AMP-specific cytosolic 5'-nucleotidase activity predominates over ecto-5'-nucleotidase activity in the canine heart, especially under conditions in which ADP and magnesium levels increase, ie, myocardial ischemia. In that study, Darvish et al showed that the "ecto" form of 5'-nucleotidase contributes
25% of the adenosine production measured under their assay conditions but that the majority was produced by the cytosolic form. Therefore, although the data from the present investigation and previous studies by Kitakaze and colleagues argue convincingly for a role of the ecto-5'-nucleotidase in the production of adenosine during ischemia and reperfusion, the role of the cytoplasmic form may also be important. |
Other Mechanisms of Vesnarinone Action |
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TopIntroductionProblem of Infarct Size...Role of Ecto-5'-Nucleotidase in...Other Mechanisms of Vesnarinone...ConclusionsReferences |
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The ability of inflammatory cytokines to modulate necrosis and apoptosis after an ischemic insult is not fully defined but may prove to be important. Vesnarinone has a number of immunomodulating effects, including inhibition of apoptosis in some cells.16 Interferon-
induces nitric oxide synthase in cardiac myocytes, and this is significantly reduced by vesnarinone.17 In human blood, vesnarinone inhibits the production of tumor necrosis factor- and interferon- and suppresses expression of the inflammatory cytokines IL-1 and IL-1ß.18 Vesnarinone has also been reported to decrease production of IL-2 by human blood mononuclear cells.19 Clearly, augmentation in expression of inflammatory cytokines can be prompt after myocardial ischemia; interdiction of their production and effects by vesnarinone may limit the effects of cytokines in the ischemic zone as well as on the coronary vascular bed. Thus, in the standard canine model for studying ischemic preconditioning, 90 minutes of coronary occlusion followed by 6 hours of reperfusion, the temporal course may permit the immunomodulating effects of vesnarinone to play a role in modifying infarct size. |
Conclusions |
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TopIntroductionProblem of Infarct Size...Role of Ecto-5'-Nucleotidase in...Other Mechanisms of Vesnarinone...ConclusionsReferences |
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The effect of vesnarinone on infarct size reported in the present study is exciting and potentially important. Much of the action of vesnarinone appears to be adenosine mediated, and this certainly strengthens the concept that adenosine-modulating drugs may have a role to play in limiting infarct size. Moreover, the immunomodulating properties of vesnarinone may play a contributing role, and this approach to limiting infarct size deserves further exploration. However, enthusiasm for the use of vesnarinone in congestive heart failure has recently been dampened after release of initial data from the VEST trial, in which vesnarinone given in doses of both 30 and 60 mg/d to patients with congestive heart failure appeared to have no favorable effect on mortality, and perhaps an adverse effect. Thus, whether vesnarinone ultimately proves to be a clinically useful drug for heart failure or for limitation of infarct size remains to be determined, but the mechanistic insights gained by looking beyond its appellation as a positive inotropic drug are important.
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Selected Abbreviations and Acronyms |
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionProblem of Infarct Size...Role of Ecto-5'-Nucleotidase in...Other Mechanisms of Vesnarinone...ConclusionsReferences |
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2.
Kitakaze M, Minamino T, Funaya H, Node K, Shinozaki Y, Mori H, Hori M. Vesnarinone limits infarct size via adenosine-dependent mechanisms in the canine heart. Circulation. 1997;95:2108-2114.
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Feldman AM, Bristow MR, Parmley WW, Carson PE, Pepine CJ, Gilbert EM, Strobeck JE, Hendrix GH, Powers ER, Bain RP, White BG. Effects of vesnarinone on morbidity and mortality in patients with heart failure. N Engl J Med. 1993;329:149-155.
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9.
Yao Z, Gross GJ. Acetylcholine mimics ischemic preconditioning in dogs: role of nitric oxide, muscarinic receptors and the K-ATP channel. Circ Res. 1993;73:1193-1201.
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12.
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Kitakaze M, Hori M, Minamino T, Morioka T, Takashima S, Sato H, Shinozaki Y, Chujo M, Mori H, Inoue M, Kamada T. Infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of 5'-nucleotidase activity and attenuation of adenosine release. Circulation. 1994;89:1237-1244.
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16.
Oyaizu N, McCloskey TW, Than S, Pahwa S. Inhibition of CD4 cross-linking-induced lymphocyte apoptosis by vesnarinone as a novel immunomodulating agent: vesnarinone inhibits Fas expression and apoptosis by blocking cytokine secretion. Blood. 1996;87:2361-2368.
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