Andreas Busch

Combined Tyrosine and Serine/Threonine Kinase Inhibition by Sorafenib Prevents Progression of Experimental Pulmonary Hypertension and Myocardial Remodeling

Background— Inhibition of tyrosine kinases, including platelet-derived growth factor receptor, can reduce pulmonary arterial pressure in experimental and clinical pulmonary hypertension. We hypothesized that inhibition of the serine/threonine kinases Raf-1 (also termed c-Raf) and b-Raf in addition to inhibition of tyrosine kinases effectively controls pulmonary vascular and right heart remodeling in pulmonary hypertension. Methods and Results— We investigated the effects of the novel multikinase inhibitor sorafenib, which inhibits tyrosine kinases as well as serine/threonine kinases, in comparison to imatinib, a tyrosine kinase inhibitor, on hemodynamics, pulmonary and right ventricular (RV) remodeling, and downstream signaling in experimental pulmonary hypertension. Fourteen days after monocrotaline injection, male rats were treated orally for another 14 days with sorafenib (10 mg/kg per day), imatinib (50 mg/kg per day), or vehicle (n=12 to 16 per group). RV systolic pressure was decreased to 35.0±1.5 mm Hg by sorafenib and to 54.0±4.4 mm Hg by imatinib compared with placebo (82.9±6.0 mm Hg). In parallel, both sorafenib and imatinib reduced RV hypertrophy and pulmonary arterial muscularization. The effects of sorafenib on RV systolic pressure and RV mass were significantly greater than those of imatinib. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of the downstream ERK1/2 signaling pathway in RV myocardium and the lungs. In addition, sorafenib but not imatinib antagonized vasopressin-induced hypertrophy of the cardiomyoblast cell line H9c2. Conclusions— The multikinase inhibitor sorafenib prevents pulmonary remodeling and improves cardiac and pulmonary function in experimental pulmonary hypertension. Sorafenib exerts direct myocardial antihypertrophic effects, which appear to be mediated via inhibition of the Raf kinase pathway. The combined inhibition of tyrosine and serine/threonine kinases may provide an option to treat pulmonary arterial hypertension and associated right heart remodeling.

KVLQT channels are inhibited by the K+ channel blocker 293B.

Abstract Previous data have indicated that the chromanol 293B blocks a cAMP activated K+ conductance in the colonic crypt, a K+ conductance in pig cardiac myocytes and the K+ conductance induced by IsK protein expression in Xenopus oocytes. We have also shown that cAMP-activated cystic fibrosis transmembrane conductance regulator (CFTR) up-regulates, apart from the typical Cl–current, a 293B- inhibitable K+ current. Very recently it has been shown that the IsK protein interacts with KVLQT subunits to produce a K+ channel. These data have prompted us to ask the following questions: Is the 293B-inhibitable current in oocytes expressing CFTR and activated by cAMP caused by an endogenous Xenopus KVLQT (XKVLQT), and is mouse KVLQT (mKVLQT) expressed in oocytes inhibited by 293B? Antisense and sense probes for XKVLQT were coinjected with CFTR cRNA into oocytes. After 3–4 days the oocytes were examined by two electrode voltage clamp. It was found that in control oocytes expressing CFTR and stimulated by isobutylmethylxanthine (IBMX, 1 mmol/l) 293B (10 μmol/l) reduced the conductance (Gm). In oocytes coinjected with the sense probe for XKVLQT and pretreated with IBMX 293B still reduced Gm, whilst the 293B-inhibitable Gm was almost completely absent in oocytes coinjected with XKVLQT antisense. In another series a full length clone for mKVLQT was generated by PCR techniques and the cRNA was injected into oocytes. After several days these oocytes, unlike water injected ones, were found to be strongly hyperpolarized and their Gm was increased significantly. The oocytes were depolarized significantly and their Gm was reduced reversibly by 10 μmol/l 293B. These data indicate that CFTR activation by IBMX indeed co-activates an endogenous oocyte XKVLQT channel and that this channel is inhibited by a new class of channel blockers, of which 293B is the prototype.

Rate- and Site-Dependent Effects of Propafenone, Dofetilide, and the New IKs-Blocking Agent Chromanol 293b on Individual Muscle Layers of the Intact Canine Heart

BACKGROUND Recent in vitro studies have demonstrated regional differences in electrophysiological properties of individual left ventricular muscle layers. Controversy exists on the relevance of these findings for the situation in vivo. Thus, this study was designed to determine whether the in vivo canine heart exhibits regional differences in left ventricular refractoriness and in the susceptibility to sodium and potassium channel blockers. METHODS AND RESULTS In 16 dogs, 36 needle electrodes (12 mm long, 4 bipolar electrodes, interelectrode distance 2.5 mm) were inserted into the left ventricular wall. By use of a computerized multiplexer-mapping system, the spread of activation in epicardial, endocardial, and midmyocardial muscle was reconstructed during ventricular pacing at 300- and 850-ms basic cycle length (BCL). Effective refractory periods (ERPs) were determined at baseline and after application of propafenone (2 mg/kg), dofetilide (30 microg/kg), or chromanol 293b (10 mg/kg) by the extrastimulus technique (BCL 300 and 850 ms). At baseline, activation patterns and ERPs were uniform in all muscle layers. Propafenone homogeneously decreased conduction velocity and moderately prolonged ERPs without any regional differences. Dofetilide and chromanol 293b did not affect the spread of activation. Dofetilide exhibited reverse use-dependent effects on ERP, still preserving transmural homogeneity of refractoriness. Chromanol 293b led to a regionally uniform but more pronounced increase in local ERPs at faster than at slower pacing rates. CONCLUSIONS At the heart rates applied, the in vivo canine heart does not exhibit regional differences in electrophysiological properties. Given the homogeneity of antiarrhythmic drug effects, induction of local gradients of refractoriness is obviously not a common mechanism of proarrhythmia in normal hearts.

National Filters: Europeanisation, Institutions, and Discourse in the Case of Banking Regulation

confronted with substantial challenges and undergone momentous changes in the last three decades. While the post-World War II system (also known as the Bretton Woods system) in most countries had – in line with then prevailing economic policy dogma – imposed capital controls in order to regulate interest rates and manage the domestic economy (as well as protect the new welfare state from capital flight), the 1970s saw stark changes after decades of stability. Technological change in the areas of computerisation, a telecommunications revolution, but above all changes in international markets and politics – such as the breakdown of the system of fixed exchange rates and the two oil-shocks of the 1970s – substantially altered the conditions under which financial markets operated. As most economies were confronted with deep economic crises (spiralling inflation, rising unemployment and sluggish economic growth), economic policy concepts changed. Keynesian ideas, which had guided many countries through the decades following World War II (Hall 1989), were increasingly replaced by economic concepts that focused on supplyside policies rather than the attempt to steer national economies by means of demand-side management. As an increased reliance on markets came to be seen as an antidote to the recessionary environment that had followed the end of the golden age of capitalism in the early 1970s, liberalisation and the abolition of the many barriers that separated national markets were the logical complement in the international sphere. Indeed, governments actively encouraged and engineered the lowering of national barriers, above all in financial markets and banking, for a variety of reasons (Kapstein 1994), for example, by lowering and eventually abolishing capital controls that had relied on the logic of a system of fixed exchange rates. These changes had enormous consequences – indeed, it has been claimed that the ‘internationalization and integration of capital markets has been the most National Filters: Europeanisation, Institutions, and Discourse in the Case of Banking Regulation

Protein Kinase C Pathway Is Involved in Transcriptional Regulation of C-Reactive Protein Synthesis in Human Hepatocytes

Objective— C-Reactive protein (CRP) is the prototype acute phase protein and a cardiovascular risk factor. Interleukin-1&bgr; (IL-1&bgr;) and IL-6 stimulate CRP synthesis in hepatocytes. We searched for additional pathways regulating CRP expression. Methods and Results— Primary human hepatocytes (PHHs) were treated with IL-1&bgr;, IL-6, and protein kinase C (PKC) activator phorbol 12,13-dibutyrate (PDBu). CRP was analyzed by quantitative RT-PCR and ELISA. PDBu significantly induced CRP transcription by 21.0±9.24-fold and protein release by 2.9±0.5-fold. Transcriptional regulation was studied in detail in hepatoma G2 (HepG2) cells stably transfected with the 1-kb CRP promoter (HepG2–ABEK14 cells). In these cells, PDBu significantly induced CRP transcription by 5.39±0.66-fold. Competetive inhibition with bisindolylmaleimide derivative LY333531 abolished PDBu-mediated promoter activation. Competetive inhibition with I&kgr;B kinase inhibitor I229 also inhibited PDBu effects. Importantly, IL-8 significantly induced CRP release in PHHs by 58.675±19.1-fold, which was blockable by LY333531. Conclusions— This study describes a novel PKC-dependent transcriptional regulation of CRP gene expression, which, in analogy to the classical IL-1&bgr; and IL-6 pathways, is operational in hepatocytes only. It also identifies IL-8 as a potential physiological PKC activator. HepG2–ABEK14 cells may be useful for high throughput screening to identify inhibitors of CRP synthesis for the prevention of cardiovascular disease.

Globalisation and national varieties of capitalism: The contested viability of the ‘german model’

It is often argued that globalisation is eroding differences between national varieties of capitalism and enforcing convergence. This study takes up the debate – triggered by declining economic performance – about the viability of the ‘German model’ of a coordinated market economy, examining the arguments about its alleged seminal transformation over the last decade. It goes on to identify a number of flaws in the literature and questions whether the case for fundamental change in Germany has really been made in a credible and convincing way. In addition, it points to significant elements of continuity in areas such as industrial relations and emphasises the importance of political decisions in determining the fate of national economic models.

Central bank independence and the Westminster model

The article deals with and traces the current emergence of a ‘Continental European’ model of central bank independence in several European countries as well as in the Maastricht Treaty (modelled along the lines of the Bundesbanks constitution) and juxtaposes this with outright rejection of central bank independence in the UK. It is then asked why this is the case, the answer being provided by particular British constitutional traditions, most notably the doctrine of parliamentary sovereignty. This is followed by the presentation of a model of central bank independence compatible with the requirements of British constitutional thought while still capable of providing the advantages of removing day‐to‐day monetary policy from the hands of the administration. Experiences from New Zealand with a similar model and an outlook on the consequences of recent turbulences in the EMS conclude the article.

Verfassungspolitik: Stabilität und permanentes Austarieren

Verfassungspolitik unterscheidet sich von den anderen in diesem Band behandelten Politikfeldern dadurch, dass in ihr die Bedingungen fur die Entscheidungen in letzteren festgelegt werden: Da Verfassungen die Regeln fur das Treffen legitimer politischer Entscheidungen bestimmen, konnen durch Anderungen der Verfassung auch jene Regeln geandert werden. Dies ist zwar ein zentraler, doch nicht der einzige Unterschied: Wahrend in anderen Politikbereichen eine rasche inhaltliche Anpassung an geanderte Rahmenbedingungen gemeinhin als ein Positivum betrachtet wird, beruht die Legitimitat von Verfassungsregeln zu einem erheblichen Teil auf ihrer Stabilitat und Verlasslichkeit; rasche und haufige Anderungen konnen daher hier kontraproduktiv wirken und die Anerkennung der Verfassung durch die Bevolkerung beschadigen.

Kontinuität statt Wandel: Die Innen- und Rechtspolitik der Großen Koalition

Grose Koalitionen werden in der Politik im Allgemeinen, sicher aber in der Bundesrepublik Deutschland, als Notlosungen angesehen. Sie kommen nur dann zu Stande, wenn andere, eigentlich praferierte Koalitionen aus welchen Grunden auch immer nicht realisierbar sind. Entsprechend gering ist die Einschatzung der Losungsfahigkeit solcher Koalitionen in der allgemeinen Wahrnehmung, da sie als eine erzwungene Kooperation hochst unterschiedlicher Konzepte und Politikpraferenzen wahrgenommen werden. Deshalb wird solchen Koalitionen oft eine geringe Lebensdauer vorausgesagt, und man nimmt an, dass sie durch andauernde Streitigkeiten auch nicht in der Lage sind, wirkliche Losungen – zumal fundamentaler Art – zu Stande zu bringen. Das offentliche Echo auf die Begrundung der Grosen Koalition im Jahr 2005 war jedenfalls entsprechend, vor allem im Ausland, wo man mit den Details der deutschen Politik nicht so vertraut ist.

Governance in Contemporary Germany: Shock-Absorbers Under Stress: Parapublic Institutions and the Double Challenges of German Unification and European Integration

The paper focuses on a specific category of institutions that are, it has been suggested, characteristic of Germany’s ”semisovereign state”, namely ”parapublic institutions”. Parapublic institutions are a heterogeneous group, united by the fact that they bridge the gap between the public and private sectors, and that they carry out important policy functions. Furthermore, they combine a high degree of autonomy in policy making (under a general supervision of the government, which rules out interfering in details), with a high level