bluuebunny/crossref_metadata_2025 huggingface dataset:
DEMOCRATIC POLITICS IN LATIN AMERICA: New Debates and Research Frontiers
Authors: Munck Gerardo L.
Published: May 2004

▪ Abstract  This assessment of research on contemporary democratic politics in Latin America is organized around the distinction between institutional and alternative approaches. Initially it considers institutionalism on its own terms and, through an assessment of the debate about the institutional causes of gridlock, draws attention to key strengths of this literature. Thereafter, this article adopts a broader perspective that exposes some limitations but also other strengths of institutional analyses and considers the possibility of combining insights developed from institutional and alternative theoretical perspectives. The suggested terms of integration are as follows. With regard to causal theorizing, institutionalists need to borrow ideas from a broader literature on political regimes, especially regarding the causes of transitions to, and the breakdown of, democracy. With regard to descriptive theorizing, in contrast, students of the quality of democracy need to incorporate the contributions of institutionalists, especially regarding principal-agent relationships among citizens, policy makers, and policy administrators. Throughout this review, various pointed suggestions to advance research are offered.
DIRECT DEMOCRACY: New Approaches to Old Questions
Authors: Lupia Arthur , Matsusaka John G.
Published: May 2004

▪ Abstract  Until recently, direct democracy scholarship was primarily descriptive or normative. Much of it sought to highlight the processes' shortcomings. We describe new research that examines direct democracy from a more scientific perspective. We organize the discussion around four “old” questions that have long been at the heart of the direct democracy debate: Are voters competent? What role does money play? How does direct democracy affect policy? Does direct democracy benefit the many or the few? We find that recent breakthroughs in theory and empirical analysis paint a comparatively positive picture of the initiative and referendum. For example, voters are more competent, and the relationship between money and power in direct democracy is less nefarious, than many observers allege. More new studies show that the mere presence of direct democracy induces sitting legislatures to govern more effectively.
ADVOCACY AND SCHOLARSHIP IN THE STUDY OF INTERNATIONAL WAR CRIME TRIBUNALS AND TRANSITIONAL JUSTICE
Authors: Vinjamuri Leslie , Snyder Jack
Published: May 2004

▪ Abstract  In this essay, we survey the literature on international criminal tribunals and transitional justice. We argue that the literature has been dominated by two general orientations, a legalism that is premised on a logic of appropriateness and a pragmatism premised on a logic of consequences. We also consider a third orientation, guided by a logic of emotions, that recognizes the significance of transitional justice but emphasizes strategies that diverge from the model of legalism. Our primary concern is with scholarship in political science, although we also consider work from the disciplines of law, history, and sociology and from practitioners and advocates. The normative positions of scholars have heavily influenced the development of literature in this field, in which scholarship, practice, and advocacy are deeply intertwined. Advocates and individuals who have played key roles in the development of international criminal justice institutions, domestic tribunals, and truth commissions have been prominent in setting the agenda for scholars. Nonetheless, there is also a growing body of rigorous social science research that attempts to assess empirically—and sometimes critically—the claims of advocates and practitioners and to explain changing strategies of justice.
LATINO POLITICS
Authors: de la Garza Rodolfo O.
Published: May 2004

▪ Abstract  This review addresses key issues in the study of Latino politics. Foremost among these is the question of low voter turnout. Such factors as income, education, nativity, religion, political party, organizational involvement, neighborhood composition, ethnic attachments, and mobilization of Hispanic turnout have a limited impact on Hispanic votes. I suggest that this is due to differences in the political socialization of Latinos and Anglos. The review also shows that immigrants are focused on U.S. politics rather than home-country politics. Additionally, it describes significant differences regarding the factors that shape Hispanic versus Anglo partisanship. Among the other issues considered is the limited significance of ethnic factors, as compared to partisanship and state of residence, in determining electoral and policy preferences.
GLOBAL MEDIA AND POLITICS: Transnational Communication Regimes and Civic Cultures
Authors: Bennett W. Lance
Published: May 2004

▪ Abstract  There is much debate about the effects of media market deregulation and the resulting growth of vast global media corporations. Some observers argue that deregulatory pressures have undermined public service broadcasting and media social-responsibility norms, resulting in deterioration of information quality and political disengagement of citizens in many nations. Others herald deregulatory trends as expanding information choices and enabling citizens to find their preferred levels of political engagement. This analysis proposes that we understand global trends in media deregulation as part of a transnational political regime in which many players and institutional arenas shape norms for media ownership, social responsibility, and citizen information. The players include multinational corporations, parties and public officials, interest associations, and citizen advocacy organizations. The institutional settings include national legislatures and regulatory commissions as well as international trade organizations, European Union commissions, and United Nations agencies. The outcomes of contests among these players at different institutional levels influence the degrees of normative consensus on ownership and content policies in the regime and explain how different nations engage with media deregulation and the market forces that increasingly shape the content of democratic public life.
MODELS OF VETOES AND VETO BARGAINING
Authors: Cameron Charles , McCarty Nolan
Published: May 2004

▪ Abstract  Models of veto bargaining have become an important tool for formal institutional analysis. This chapter reviews the core model of veto bargaining and some of its more interesting and useful extensions, focusing on one of the best developed applications, the presidential veto over legislation. One of the primary attractions of these models is that they often produce crisp, testable empirical predictions. Our review focuses on 18 such predictions. We conclude with a brief review of the empirical evidence related to these hypotheses.
POLITICAL REPRESENTATION IN COMPARATIVE POLITICS
Authors: Powell G. Bingham
Published: May 2004

▪ Abstract  Two large research programs have analyzed election-based connections between citizens and policy makers in different democracies. Studies of vote-seat representation in the tradition of Rae (1967) begin with citizens' party votes and have made substantial progress in elucidating the impact of election laws, geographic vote distributions, and the number of parties and their interactions on the proportionality of party representation. Studies of substantive representation in the tradition of Miller & Stokes (1963) begin with citizen issue preferences and link these to the positions of their representatives. Most studies outside the United States, confronting multimember districts and the cohesion of party representatives, have focused on voter-party dyads rather than geographic constituencies, and confirmed the importance of issues linked to a common electoral discourse and the greater structure of legislator issue positions. Recently, a number of explicitly comparative analyses have begun to analyze collective correspondence and confront other limitations of the literature.
MEASURING THE EFFECTS OF TELEVISED POLITICAL ADVERTISING IN THE UNITED STATES
Authors: Goldstein Kenneth , Ridout Travis N.
Published: May 2004

▪ Abstract  In the United States, televised political advertising is the main way that modern campaigns communicate with voters. Although political scientists have made great progress in the study of its effects in recent decades, much of that progress has come in the area of advertising's indirect effects: its impact on learning and the effect of its tone on voter turnout. This essay reviews what scholars know about how political advertising affects voter decisions, voter knowledge, and election outcomes. We argue that scholars still have a long road to travel before being able to speak definitively about whether and to what extent political advertisements are successful in achieving the goal of their sponsors: winning elections. This state of affairs may be due to the vast number of methods used to measure the key independent variable in these studies: advertising exposure. Accordingly, in the last section of the essay, we review and critique seven approaches to the study of political advertising.
NOT YOUR PARENTS' POLITICAL SOCIALIZATION: Introduction for a New Generation
Authors: Sapiro Virginia
Published: May 2004

▪ Abstract  The field of political socialization is often stereotyped in terms of some of the earliest work in the field and is neglected outside certain areas of American political behavior. However, the continuing and vibrant stream of work in political socialization holds potential for addressing many critical issues across American, comparative, and international politics. This article discusses three themes: the construction of a more genuinely comparative field of political socialization, a reconsideration of the relevance of childhood to politics following its virtual abandonment by the field for many years, and the importance of understanding the origins of preferences. Cidadania não tem tamanho/Tamanho não é documento. You don't have to be big to be a citizen/Size is not important.           Augusto Sérgio Suares Dutra, a 10-year-old Brazilian,                quoted in Guerra 2002 , p. 77
WHAT DOES POLITICAL ECONOMY TELL US ABOUT ECONOMIC DEVELOPMENT—AND VICE VERSA?
Authors: Keefer Philip
Published: May 2004

▪ Abstract  This essay reviews how three pillars of political economy—collective action, institutions, and political market imperfections—help us answer the following question: Why do some countries develop and not others? Each advances our understanding of who wins and who loses in government decision making, generally, but only a subset of this literature helps us answer the question. The study of political market imperfections strongly suggests that the lack of credibility of pre-electoral political promises and incomplete voter information are especially robust in explaining development outcomes. From the institutional literature, the most powerful explanation of contrasting development outcomes links political checks and balances to the credibility of government commitments.
THE CENTRALITY OF RACE IN AMERICAN POLITICS
Authors: Hutchings Vincent L. , Valentino Nicholas A.
Published: May 2004

▪ Abstract  The study of race and U.S. politics has always been controversial in the discipline. Theory and evidence are often ignored or misconstrued. Furthermore, literatures that examine the impact of race have developed in relative isolation from one another. We try to address this shortcoming here. We examine research on the influence of race on the political attitudes, behavior, and institutions of both blacks and whites. Our focus is on partisanship, voting, policy opinions, and representation. We identify linkages across these domains and then discuss the implications of this work for assessing the nation's progress toward achieving racial justice.
CITIZENSHIP AND EDUCATION
Authors: Callan Eamonn
Published: May 2004

▪ Abstract  This paper surveys three sources of conflict about citizenship and education in contemporary normative political theory: the extent to which rival conceptions of citizenship differ in the ends they prescribe for civic education; disagreement about the educational processes needed to yield accepted civic educational ends and how some of those processes might best be institutionalized via schooling; and disagreement about how liberal legitimacy constrains state action undertaken for the sake of democratic education.
MARTIN SHAPIRO AND THE MOVEMENT FROM “OLD” TO “NEW” INSTITUTIONALIST STUDIES IN PUBLIC LAW SCHOLARSHIP
Authors: Gillman Howard
Published: May 2004

▪ Abstract  This article uses Martin Shapiro's body of work as a point of departure for tracing the development over the past few decades of “institutionalist” approaches to the study of law and courts. It begins by reviewing some of the distinctive characteristics of Shapiro's brand of institutional analysis, including the pluralist and process models that informed his vision of politics and his preference for using historical-interpretive case study methods rather than more quantitative or formal approaches. This lays the groundwork for the claim that he was a progenitor of what emerged in the late 1980s as the so-called “new institutionalism” in public law scholarship. After then reviewing some of Shapiro's provocative (and not entirely positive) reactions to the emergent literature, the article explores the useful ways in which more recent institutionalist scholarship has moved beyond Shapiro's agenda.
ACTORS, NORMS, AND IMPACT: Recent International Cooperation Theory and the Influence of the Agent-Structure Debate
Authors: O'Neill Kate , Balsiger Jörg , VanDeveer Stacy D.
Published: May 2004

▪ Abstract  This article reviews three recent developments in international cooperation theory: the introduction of nonstate actors, the study of norms and ideas, and increased examination of the effectiveness, or impact, of international cooperation. Through the lens of the agent-structure debate, we critique the literature that addresses these themes. We argue, first, for a view of structure that goes beyond material properties; second, that more attention could be paid to what distinguishes agency in actors; and third, that this would provide insights into how reflexivity and learning, as well as preference and identity formation, contribute to structural transformation in the international system through iterated processes of cooperation. We also develop ways of applying the agent-structure debate to empirical as well as metatheoretical questions. The article concludes by discussing directions for further research.
"BUSINESS" IS NOT AN INTEREST GROUP: On the Study of Companies in American National Politics
Authors: Hart David M.
Published: May 2004

▪ Abstract  Individual companies are neglected in American politics scholarship, despite their empirical and normative significance. Interest group theory does not provide an adequate framework for understanding them. Neoclassical microeconomic theory has begun to be developed for political analysis, but its assumptions restrict the scope of its utility. Cyert & March's (1992) “behavioral theory of the firm” provides a more promising foundation, one that dovetails with the historical and institutional tradition in political science. Research in this tradition has begun to analyze how the personal preferences of senior managers, institutional structures, cultural norms, and learning over time affect the political positions and strategies of firms.
PUBLIC DELIBERATION, DISCURSIVE PARTICIPATION, AND CITIZEN ENGAGEMENT: A Review of the Empirical Literature
Authors: Carpini Michael X. Delli , Cook Fay Lomax , Jacobs Lawrence R.
Published: May 2004

▪ Abstract  Many theorists have long extolled the virtues of public deliberation as a crucial component of a responsive and responsible democracy. Building on these theories, in recent years practitioners—from government officials to citizen groups, nonprofits, and foundations—have increasingly devoted time and resources to strengthening citizen engagement through deliberative forums. Although empirical research has lagged behind theory and practice, a body of literature has emerged that tests the presumed individual and collective benefits of public discourse on citizen engagement. We begin our review of this research by defining “public deliberation”; we place it in the context of other forms of what we call “discursive participation” while distinguishing it from other ways in which citizens can voice their individual and collective views on public issues. We then discuss the expectations, drawn from deliberative democratic theory, regarding the benefits (and, for some, pitfalls) assumed to derive from public deliberation. The next section reviews empirical research as it relates to these theoretical expectations. We conclude with recommendations on future directions for research in this area.
Evaluation of the teaching strategy of cardiovascular system in a problem-based curriculum: student perception
Authors: Abu-Hijleh Marwan F. , Kassab Salah , Al-Shboul Qasim , Ganguly Pallab K.
Published: May 2004

It is generally acknowledged that an integrated approach to teaching cardiovascular system (CVS) is clinically relevant. However, very little attention has been paid with respect to student perception of teaching CVS in an integrated problem-based curriculum. A questionnaire on the feedback and perception of medical students ( n = 60) to their learning experience of CVS exposed early in the problem-based integrated curriculum at the Arabian Gulf University (AGU) was used. The average percentage scores of positive student responses to items related to knowledge was 62.7%, to integration was 87.3%, and to skills was 77.1%. A significant positive correlation was observed among skills and knowledge ( r = 0.408, P = 0.002), skills and integration ( r = 0.506, P < 0.000), and integration and knowledge ( r = 0.294, P = 0.028). The lowest individual percentage score related to knowledge items was given to the role of resource sessions in understanding difficult concepts (32.7%). Interestingly, 90.7% of the students were aware of the presence of gaps in their knowledge. On the other hand, 92.7% of students expressed their satisfaction with the study experience of CVS in the integrated problem-based approach. These results indicate that students overall achieved satisfactory learning outcome during the study of CVS in the problem-based integrated curriculum at AGU. The study also points out issues where improvement and fine tuning of the educational system can take place.
Overexpression of human KCNA5 increases IK(V) and enhances apoptosis
Authors: Brevnova Elena E. , Platoshyn Oleksandr , Zhang Shen , Yuan Jason X.-J.
Published: May 2004

Apoptotic cell shrinkage, an early hallmark of apoptosis, is regulated by K+ efflux and K+ channel activity. Inhibited apoptosis and downregulated K+ channels in pulmonary artery smooth muscle cells (PASMC) have been implicated in development of pulmonary vascular medial hypertrophy and pulmonary hypertension. The objective of this study was to test the hypothesis that overexpression of KCNA5, which encodes a delayed-rectifier voltage-gated K+ (Kv) channel, increases K+ currents and enhances apoptosis. Transient transfection of KCNA5 caused 25- to 34-fold increase in KCNA5 channel protein level and 24- to 29-fold increase in Kv channel current ( IK(V)) at +60 mV in COS-7 and rat PASMC, respectively. In KCNA5-transfected COS-7 cells, staurosporine (ST)-mediated increases in caspase-3 activity and the percentage of cells undergoing apoptosis were both enhanced, whereas basal apoptosis (without ST stimulation) was unchanged compared with cells transfected with an empty vector. In rat PASMC, however, transfection of KCNA5 alone caused marked increase in basal apoptosis, in addition to enhancing ST-mediated apoptosis. Furthermore, ST-induced apoptotic cell shrinkage was significantly accelerated in COS-7 cells and rat PASMC transfected with KCNA5, and blockade of KCNA5 channels with 4-aminopyridine (4-AP) reduced K+ currents through KCNA5 channels and inhibited ST-induced apoptosis in KCNA5-transfected COS-7 cells. Overexpression of the human KCNA5 gene increases K+ currents (i.e., K+ efflux or loss), accelerates apoptotic volume decrease (AVD), increases caspase-3 activity, and induces apoptosis. Induction of apoptosis in PASMC by KCNA5 gene transfer may serve as an important strategy for preventing the progression of pulmonary vascular wall thickening and for treating patients with idiopathic pulmonary arterial hypertension (IPAH).
Growth factors induce monocyte binding to vascular smooth muscle cells: implications for monocyte retention in atherosclerosis
Authors: Cai Qiangjun , Lanting Linda , Natarajan Rama
Published: May 2004

Adhesive interactions between monocytes and vascular smooth muscle cells (VSMC) may contribute to subendothelial monocyte-macrophage retention in atherosclerosis. We investigated the effects of angiotensin II (ANG II) and platelet-derived growth factor (PDGF)-BB on VSMC-monocyte interactions. Treatment of human aortic VSMC (HVSMC) with ANG II or PDGF-BB significantly increased binding to human monocytic THP-1 cells and to peripheral blood monocytes. This was inhibited by antibodies to monocyte β1- and β2-integrins. The binding was also attenuated by blocking VSMC arachidonic acid (AA) metabolism by inhibitors of 12/15-lipoxygenase (12/15-LO) or cyclooxygenase-2 (COX-2). Conversely, binding was enhanced by overexpression of 12/15-LO or COX-2. Direct treatment of HVSMC with AA or its metabolites also increased binding. Furthermore, VSMC derived from 12/15-LO knockout mice displayed reduced binding to mouse monocytic cells relative to genetic control mice. Using specific signal transduction inhibitors, we demonstrated the involvement of Src, phosphoinositide 3-kinase, and MAPKs in ANG II- or PDGF-BB-induced binding. Interestingly, after coculture with HVSMC, THP-1 cell surface expression of the scavenger receptor CD36 was increased. These results show for the first time that growth factors may play additional roles in atherosclerosis by increasing monocyte binding to VSMC via AA metabolism and key signaling pathways. This can lead to monocyte subendothelial retention, CD36 expression, and foam cell formation.
Modeling action potential generation and propagation in NRK fibroblasts
Authors: Torres J. J. , Cornelisse L. N. , Harks E. G. A. , van Meerwijk W. P. M. , Theuvenet A. P. R. , Ypey D. L.
Published: May 2004

Normal rat kidney (NRK) fibroblasts change their excitability properties through the various stages of cell proliferation. The present mathematical model has been developed to explain excitability of quiescent (serum deprived) NRK cells. It includes as cell membrane components, on the basis of patch-clamp experiments, an inwardly rectifying potassium conductance ( GKir), an L-type calcium conductance ( GCaL), a leak conductance ( Gleak), an intracellular calcium-activated chloride conductance [ GCl(Ca)], and a gap junctional conductance ( Ggj), coupling neighboring cells in a hexagonal pattern. This membrane model has been extended with simple intracellular calcium dynamics resulting from calcium entry via GCaL channels, intracellular buffering, and calcium extrusion. It reproduces excitability of single NRK cells and cell clusters and intercellular action potential (AP) propagation in NRK cell monolayers. Excitation can be evoked by electrical stimulation, external potassium-induced depolarization, or hormone-induced intracellular calcium release. Analysis shows the roles of the various ion channels in the ultralong (∼30 s) NRK cell AP and reveals the particular role of intracellular calcium dynamics in this AP. We support our earlier conclusion (De Roos A, Willems PH, van Zoelen EJ, and Theuvenet AP. Am J Physiol Cell Physiol 273: C1900–C1907, 1997) that AP generation and propagation may act as a rapid mechanism for the propagation of intracellular calcium waves, thus contributing to fast intercellular calcium signaling. The present model serves as a starting point to further analyze excitability changes during contact inhibition and cell transformation.
Dibasic phosphorylation sites in the R domain of CFTR have stimulatory and inhibitory effects on channel activation
Authors: Vais Horia , Zhang Rugang , Reenstra William W.
Published: May 2004

To better understand the mechanisms by which PKA-dependent phosphorylation regulates CFTR channel activity, we have assayed open probabilities ( Po), mean open time, and mean closed time for a series of CFTR constructs with mutations at PKA phosphorylation sites in the regulatory (R) domain. Forskolin-stimulated channel activity was recorded in cell-attached and inside-out excised patches from transiently transfected Chinese hamster ovary cells. Wild-type CFTR and constructs with a single Ser-to-Ala mutation as well as octa (Ser-to-Ala mutations at 8 sites) and constructs with one or two Ala-to-Ser mutations were studied. In cell-attached patches, Ser-to-Ala mutations at amino acids 700, 795, and 813 decreased Po, whereas Ser-to-Ala mutations at 737 and 768 increased Po. In general, differences in Po were due to differences in mean closed time. For selected constructs with either high or low values of Po, channel activity was measured in excised patches. With 1 mM ATP, Po was similar to that observed in cell-attached patches, but with 10 mM ATP, all constructs tested showed elevated Po values. ATP-dependent increases in Po were due to reductions in mean closed time. These results indicate that R-domain phosphorylation affects ATP binding and not the subsequent steps of hydrolysis and channel opening. A model was developed whereby R-domain phosphorylation, in a site-dependent manner, alters equilibrium between forms of CFTR with low and high affinities for ATP.
Defect in glucokinase translocation in Zucker diabetic fatty rats
Authors: Fujimoto Yuka , Donahue E. Patrick , Shiota Masakazu
Published: May 2004

Hepatic glucose fluxes and intracellular movement of glucokinase (GK) in response to increased plasma glucose and insulin were examined in 10-wk-old, 6-h-fasted, conscious Zucker diabetic fatty (ZDF) rats and lean littermates. Under basal conditions, plasma glucose (mmol/l) and glucose turnover rate (GTR; μmol·kg−1·min−1) were slightly higher in ZDF (8.4 ± 0.3 and 53 ± 7, respectively) than in lean rats (6.2 ± 0.2 and 45 ± 4, respectively), whereas plasma insulin (pmol/l) was higher in ZDF (1,800 ± 350) than in lean rats (150 ± 14). The ratio of hepatic uridine 5′-diphosphate-glucose3H specific activity to plasma glucose3H specific activity ([3H]UDP-G/[3H]G; %), total hepatic glucose output (μmol·kg−1·min−1), and hepatic glucose cycling (μmol·kg−1·min−1) were higher in ZDF (35 ± 5, 87 ± 16, and 33 ± 10, respectively) compared with lean rats (18 ± 3, 56 ± 6, and 11 ± 2, respectively). [3H]glucose incorporation into glycogen (μmol glucose/g liver) was similar in lean (1.0 ± 0.7) and ZDF (1.6 ± 0.8) rats. GK was predominantly located in the nucleus in both rats. With elevated plasma glucose and insulin, GTR (μmol·kg−1·min−1), [3H]UDP-G/[3H]G (%), and [3H]glucose incorporation into glycogen (μmol glucose/g liver) were markedly higher in lean (191 ± 22, 62 ± 3, and 5.0 ± 1.4, respectively) but similar in ZDF rats (100 ± 6, 37 ± 3, and 1.4 ± 0.4, respectively) compared with basal conditions. GK translocation from the nucleus to the cytoplasm occurred in lean but not in ZDF rats. The unresponsiveness of hepatic glucose flux to the rise in plasma glucose and insulin seen in prediabetic ZDF rats was associated with impaired GK translocation.
Atrioventricular nonuniformity of pericardial constraint
Authors: Hamilton Douglas R. , Sas Rozsa , Tyberg John V.
Published: May 2004

Physiologists and clinicians commonly refer to “pressure” as a measure of the constraining effects of the pericardium; however, “pericardial pressure” is really a local measurement of epicardial radial stress. During diastole, from the bottom of the y descent to the beginning of the a wave, pericardial pressure over the right atrium (PpRA) is approximately equal to that over the right ventricle (PpRV). However, in systole, during the interval between the bottom of the x descent and the peak of the v wave, these two pericardial pressures appear to be completely decoupled in that PpRVdecreases, whereas PpRAremains constant or increases. This decoupling indicates considerable mechanical independence between the RA and RV during systole. That is, RV systolic emptying lowers PpRV, but PpRAcontinues to increase, suggesting that the relation of the pericardium to the RA must allow effective constraint, even though the pericardium over the RV is simultaneously slack. In conclusion, we measured the pericardial pressure responsible for the previously reported nonuniformity of pericardial strain. PpRAand PpRVare closely coupled during diastole, but during systole they become decoupled. Systolic nonuniformity of pericardial constraint may augment the atrioventricular valve-opening pressure gradient in early diastole and, so, affect ventricular filling.
Differential activation of potassium channels in cerebral and hindquarter arteries of rats during simulated microgravity
Authors: Fu Zhao-Jun , Xie Man-Jiang , Zhang Li-Fan , Cheng Hong-Wei , Ma Jin
Published: May 2004

The purpose of this study was to test the hypothesis that differential autoregulation of cerebral and hindquarter arteries during simulated microgravity is mediated or modulated by differential activation of K+ channels in vascular smooth muscle cells (VSMCs) of arteries in different anatomic regions. Sprague-Dawley rats were subjected to 1- and 4-wk tail suspension to simulate the cardiovascular deconditioning effect due to short- and medium-term microgravity. K+ channel function of VSMCs was studied by pharmacological methods and patch-clamp techniques. Large-conductance Ca2+-activated K+ (BKCa) and voltage-gated K+ (Kv) currents were determined by subtracting the current recorded after applications of 1 mM tetraethylammonium (TEA) and 1 mM TEA + 3 mM 4-aminopyridine (4-AP), respectively, from that of before. For cerebral vessels, the normalized contractility of basilar arterial rings to TEA, a BKCa blocker, and 4-AP, a Kv blocker, was significantly decreased after 1- and 4-wk simulated microgravity, respectively. VSMCs isolated from the middle cerebral artery branches of suspended rats had a more depolarized membrane potential ( Em) and a smaller K+ current density compared with those of control rats. Furthermore, the reduced total current density was due to smaller BKCa and smaller Kv current density in cerebral VSMCs after 1- and 4-wk tail suspension, respectively. For hindquarter vessels, VSMCs isolated from second- to sixth-order small mesenteric arteries of both 1- and 4-wk suspended rats had a more negative Em and larger K+ current densities for total, BKCa, and Kv currents. These results indicate that differential activation of K+ channels occur in cerebral and hindquarter VSMCs during short- and medium-term simulated microgravity. It is further suggested that different profiles of channel remodeling might occur in VSMCs as one of the important underlying cellular mechanisms to mediate and modulate differential vascular adaptation during microgravity.
Ghrelin induces vasoconstriction in the rat coronary vasculature without altering cardiac peptide secretion
Authors: Pemberton Chris J. , Tokola Heikki , Bagi Zsolt , Koller Akos , Pöntinen Juhani , Ola Antti , Vuolteenaho Olli , Szokodi István , Ruskoaho Heikki
Published: May 2004

We administered ghrelin, a novel growth hormone-releasing hormone, to isolated perfused rat hearts, coronary arterioles, and cultured neonatal cardiomyocytes to determine its effects on coronary vascular tone, contractility, and natriuretic peptide secretion and gene expression. We also determined cardiac levels of ghrelin and whether the heart is a source of the circulating peptide. Ghrelin dose dependently increased coronary perfusion pressure (44 ± 9%, P < 0.01), constricted isolated coronary arterioles (12 ± 2%, P < 0.05), and significantly enhanced the pressure-induced myogenic tone of arterioles. These effects were blocked by diltiazem, an L-type Ca2+ channel blocker, and bisindolylmaleimide (Bis), a protein kinase C (PKC) inhibitor. Interestingly, coinfusion of ghrelin with diltiazem completely restored myocardial contractile function that was decreased 30 ± 3% ( P < 0.01) by diltiazem alone. In contrast, combination of ghrelin with diltiazem or Bis did not significantly alter atrial natriuretic peptide (ANP) secretion, which was decreased 40% ( P < 0.01) and 50% ( P < 0.05) by these agents alone, respectively. Administration of ghrelin to cultured cardiomyocytes had no effect on ANP or B-type natriuretic peptide secretion or gene expression. Detectable amounts of low-molecular-weight ghrelin were present in cardiac tissue extracts but not in isolated heart perfusate. Thus we provide the first evidence that ghrelin has a coronary vasoconstrictor action that is dependent on Ca2+ and PKC. Furthermore, the data obtained from diltiazem infusion suggest that ghrelin has a role in regulation of contractility when L-type Ca2+ channels are blocked. Finally, the observation that immunoreactive ghrelin is found in cardiac tissue suggests the presence of a local cardiac ghrelin system.
Progressive apoptotic cell death triggered by transient oxidative insult in H9c2 rat ventricular cells: a novel pattern of apoptosis and the mechanisms
Authors: Han Hong , Long Hong , Wang Huizhen , Wang Jingxiong , Zhang Yiqiang , Wang Zhiguo
Published: May 2004

Many pathophysiological processes are associated with oxidative stress and progressive cell death. Oxidative stress is an apoptotic inducer that is known to cause rapid cell death. Here we show that a brief oxidative insult (5-min exposure to 400 μM H2O2), although it did not kill H9c2 rat ventricular cells during the exposure, triggered an intracellular death cascade leading to delayed time-dependent cell death starting from 1 h after the insult had been withdrawn, and this post-H2O2 cell death cumulated gradually, reaching a maximum level 8 h after H2O2 withdrawal. By comparison, sustained exposure to H2O2 caused complete cell death within a narrow time frame (2 h). The time-dependent post-H2O2 cell death was typical of apoptosis, both morphologically (cell shrinkage and nuclear condensation) and biochemically (DNA fragmentation, extracellular exposure of phosphatidylserines, and caspase-3 activation). A dichlorofluorescein fluorescent signal showed a time-dependent endogenous increase of reactive oxygen species (ROS) production, which was almost abolished by inhibition of the mitochondrial electron transport chain. Application of antioxidants (vitamin E or DTT) before H2O2 addition or after H2O2 withdrawal prevented the H2O2-triggered progressive ROS production and apoptosis. Sequential appearance of events associated with activation of the mitochondrial death pathway was found, including progressive dissipation of mitochondrial membrane potential, cytochrome c release, and late activation of caspase-3. In conclusion, transient oxidative stress triggers an intrinsic program leading to self-sustained apoptosis in H9c2 cells via cumulative production of mitochondrial ROS and subsequent activation of the mitochondrial death pathway. This pattern of apoptosis may contribute to the progressive and long-lasting cell loss in some degenerative diseases.
Inhibition of PKC phosphorylation of cTnI improves cardiac performance in vivo
Authors: Roman Brian B. , Goldspink Paul H. , Spaite Elyse , Urboniene Dalia , McKinney Ron , Geenen David L. , Solaro R. John , Buttrick Peter M.
Published: May 2004

Protein kinase C (PKC) modulates cardiomyocyte function by phosphorylation of intracellular targets including myofilament proteins. Data generated from studies on in vitro heart preparations indicate that PKC phosphorylation of troponin I (TnI), primarily via PKC-ε, may slow the rates of cardiac contraction and relaxation (+dP/d t and −dP/d t). To explore this issue in vivo, we employed transgenic mice [mutant TnI (mTnI) mice] in which the major PKC phosphorylation sites on cardiac TnI were mutated by alanine substitutions for Ser43and Ser45and studied in situ hemodynamics at baseline and increased inotropy. Hearts from mTnI mice exhibited increased contractility, as shown by a 30% greater +dP/dt and 18% greater −dP/d t than FVB hearts, and had a negligible response to isoproterenol compared with FVB mice, in which +dP/d t increased by 33% and −dP/d t increased by 26%. Treatment with phenylephrine and propranolol gave a similar result; FVB mouse hearts demonstrated a 20% increase in developed pressure, whereas mTnI mice showed no response. Back phosphorylation of TnI from mTnI hearts demonstrated that the mutation of the PKC sites was associated with an enhanced PKA-dependent phosphorylation independent of a change in basal cAMP levels. Our results demonstrate the important role that PKC-dependent phosphorylation of TnI has on the modulation of cardiac function under basal as well as augmented states and indicate interdependence of the phosphorylation sites of TnI in hearts beating in situ.
Thoracic vein ablation terminates chronic atrial fibrillation in dogs
Authors: Park Angela M. , Chou Chung-Chuan , Drury Paul C. , Okuyama Yuji , Peter Anish , Hamabe Akira , Miyauchi Yasushi , Kass Robert M. , Karagueuzian Hrayr S. , Fishbein Michael C. , Lin Shien-Fong , Chen Peng-Sheng
Published: May 2004

The thoracic vein hypothesis of chronic atrial fibrillation (AF) posits that rapid, repetitive activations from muscle sleeves within thoracic veins underlie the mechanism of sustained AF. If this is so, thoracic vein ablation should terminate sustained AF and prevent its reinduction. Six female mongrel dogs underwent chronic pulmonary vein (PV) pacing at 20 Hz to induce sustained (>48 h) AF. Bipolar electrodes were used to record from the atria and thoracic veins, including the vein of Marshall, four PVs, and the superior vena cava. Radio frequency (RF) application was applied around the PVs and superior vena cava and along the vein of Marshall until electrical activity was eliminated. Computerized mapping (1,792 electrodes, 1 mm resolution) was also performed. Sustained AF was induced in 30.6 ± 6.5 days, and ablation was done 17.3 ± 8.5 days afterward. Before ablation, the PVs had shorter activation cycle lengths than the atria, and rapid, repetitive activations were observed in the PVs. All dogs converted to sinus rhythm during ( n = 4 dogs) or within 90 min of completion of RF ablation. Rapid atrial pacing afterward induced only nonsustained (<60 s) AF in all dogs. Average AF cycle lengths after reinduction were significantly ( P = 0.01) longer (183 ± 31.5 ms) than baseline (106 ± 16.2 ms). There were no activation cycle length gradients after RF application. We conclude that thoracic vein ablation converts canine sustained AF into sinus rhythm and prevents the reinduction of sustained AF. These findings suggest that thoracic veins are important in the maintenance of AF in dogs.
Platelet-derived growth factor-BB and Ets-1 transcription factor negatively regulate transcription of multiple smooth muscle cell differentiation marker genes
Authors: Dandré Frédéric , Owens Gary K.
Published: May 2004

Platelet-derived growth factor (PDGF)-BB, a potent mitogen for mesenchymal cells, also downregulates expression of multiple smooth muscle (SM) cell (SMC)-specific markers. However, there is conflicting evidence whether PDGF-BB represses SMC marker expression at a transcriptional or posttranscriptional level, and little is known regarding the mechanisms responsible for these effects. Results of the present studies provide clear evidence that PDGF-BB treatment strongly repressed SM α-actin, SM myosin heavy chain (MHC), and SM22α promoters in SMCs. Of major significance for resolving previous controversies in the field, we found PDGF-BB-induced repression of SMC marker gene promoters in subconfluent, but not postconfluent, cultures. Treatment of postconfluent SMCs with a tyrosine phosphatase inhibitor restored PDGF-BB-induced repression, whereas treatment of subconfluent SMCs with a tyrosine kinase blocker abolished PDGF-BB-induced repression, suggesting that a tyrosine phosphorylation event mediates cell density-dependent effects. On the basis of previous observations that Ets-1 transcription factor is upregulated within phenotypically modulated neointimal SMCs, we tested whether Ets-1 would repress SMC marker expression. Consistent with this hypothesis, results of cotransfection experiments indicated that Ets-1 overexpression reduced transcriptional activity of SMC marker promoter constructs in SMCs, whereas it increased activity of SM α-actin promoter in endothelial cells. PDGF-BB treatment increased expression of Ets-1 in cultured SMCs, and SM α-actin mRNA expression was reduced in multiple independent clones of SMCs stably transfected with an Ets-1-overexpressing construct. Taken together, results of these experiments provide novel insights regarding possible mechanisms whereby PDGF-BB and Ets-1 may contribute to SMC phenotypic switching associated with vascular injury.
Individual differences in respiratory sinus arrhythmia
Authors: Lamine Samia Ben , Calabrese Pascale , Perrault Hélène , Dinh Tuan Pham , Eberhard André , Benchetrit Gila
Published: May 2004

To investigate the interindividual differences in respiratory sinus arrhythmia (RSA), recordings of ventilation and electrocardiogram were obtained from 12 healthy subjects for five imposed breathing periods ( TTOT) surrounding each individual's spontaneous breathing period. In addition to the spectral analysis of the R-R interval signal at each breathing period, RSA characteristics were quantified by using a breath-by-breath analysis where a sinusoid was fitted to the changes in instantaneous heart rate in each breath. The amplitude and phase (or delay = phase × TTOT) of this sinusoid were taken as the RSA characteristics for each breath. It was found that for each subject the RSA amplitude- TTOT relationship was linear, whereas the delay- TTOT relationship was parabolic. However, the parameters of these relationships differed between individuals. Linear correlation between the slopes of RSA amplitude versus TTOT regression lines and 1) mean breathing period and 2) mean R-R interval during spontaneous breathing were calculated. Only the correlation coefficient with breathing period was significantly different from zero, indicating that the longer the spontaneous breathing period the lesser the increase in RSA amplitude with increasing breathing period. Similarly, only the correlation coefficient between the curvature of the RSA delay- TTOT parabola and mean breathing period was significantly different from zero; the longer the spontaneous breathing period the larger the curvature of RSA delay. These results suggest that the changes in RSA characteristics induced by changing the breathing period may be explained partly by the spontaneous breathing period of each individual. Furthermore, a transfer function analysis performed on these data suggested interindividual differences in the autonomic modulation of the heart rate.
Relationship between arterial diameter and perfused tissue volume in myocardial microcirculation: a micro-CT-based analysis
Authors: Malyar Nasser M. , Gössl Mario , Beighley Patricia E. , Ritman Erik L.
Published: May 2004

The volume of myocardial tissue that is perfused by an epicardial coronary artery has been shown to be predictably related to the diameter of the epicardial arterial lumen. However, to what extent the intramyocardial microvasculature follows the epicardial rules remains unclear. To explore the relationship between the diameter of coronary arterioles and their subsequent perfused myocardial volumes, we quantified the volume of nonperfused myocardium resulting from an embolized arteriole of a certain diameter. We injected a single dose of microspheres selected from one of nine possible microsphere combinations (10, 30, and 100 μm diameter, each at three possible doses) into the left anterior descending coronary and/or left circumflex arteries of seven anesthetized pigs. At postmortem, the coronary arteries were infused with a radiopaque silicon polymer. Embolized myocardium (1 cm3) was scanned with a microcomputerized tomography scanner and resulted in three-dimensional images that consisted of 20 μm/side cubic voxels and a subvolume of the specimen with 4 μm/side cubic voxels. Image analysis provided the number and volumes of myocardial perfusion defects for each size and dose of microspheres. The smallest individual myocardial perfusion defects, which correspond to the volume of myocardium perfused by a single embolized arteriole, were found to be 0.0004 ± 0.0002, 0.02 ± 0.004, and 0.62 ± 0.099 mm3 for the 10-, 30-, and 100-μm microspheres, respectively. The number of myocardial perfusion defects in the embolized myocardium was inversely related to the dose of the injected microspheres. This reflects a clustering behavior that is consistent with a random distribution process of the individual embolized perfusion defects.
Suppression of alternans and conduction blocks despite steep APD restitution: electrotonic, memory, and conduction velocity restitution effects
Authors: Cherry Elizabeth M. , Fenton Flavio H.
Published: May 2004

We examine the utility of the action potential (AP) duration (APD) restitution curve slope in predicting the onset of electrical alternans when electrotonic and memory effects are considered. We develop and use two ionic cell models without memory that have the same restitution curve with slope >1 but different AP shapes and, therefore, different electrotonic effects. We also study a third cell model that incorporates short-term memory of previous cycle lengths, so that it has a family of S1-S2 restitution curves as well as a dynamic restitution curve with slope >1. Our results indicate that both electrotonic and memory effects can suppress alternans, even when the APD restitution curve is steep. In the absence of memory, electrotonic currents related to the shape of the AP, as well as conduction velocity restitution, can affect how alternans develops in tissue and, in some cases, can prevent its induction entirely, even when isolated cells exhibit alternans. When short-term memory is included, alternans may not occur in isolated cells, despite a steep APD restitution curve, and may or may not occur in tissue, depending on conduction velocity restitution. We show for the first time that electrotonic and memory effects can prevent conduction blocks and stabilize reentrant waves in two and three dimensions. Thus we find that the slope of the APD restitution curve alone does not always well predict the onset of alternans and that incorporating electrotonic and memory effects may provide a more useful alternans criterion. A Data Supplement containing movies and JAVA applets is available online at http://ajpheart.physiology.org/cgi/content/full/00747.2003/DC1 .