CALCIUM ANTAGONIST PROPERTY OF CPU228, A DOFETILIDE DERIVATIVE, CONTRIBUTES TO ITS LOW INCIDENCE OF TORSADES DE POINTES IN RABBITS (English)

Clinical and Experimental Pharmacology and Physiology

Torsades de pointes (TDP) is a severe adverse effect during the clinical use of dofetilide, a selective blocker of the rapid component of the delayed rectifier potassium channel (IKr). The present study was designed to test whether CPU228, a derivative of dofetilide with calcium (Ca2+) antagonist properties, could reduce TDP without reducing the blockade of IKr.

The incidence of TDP in a rabbit model and the effective refractory period (ERP) were measured and compared for dofetilide and CPU228. Suppression of IKr and the L‐type Ca2+ current (ICa,L) and the Ca2+ transients of isolated cardiomyocytes were investigated by whole‐cell patch‐clamp and Fluo‐3 dye spectrophotometry.

The incidence of TDP was greatly reduced by CPU228 relative to dofetilide, occurring in only one of six rabbits compared with five of six rabbits following dofetilide (P <� 0.05). In isolated atria, prolongation of ERP by CPU228 was less than that of dofetilide and no reverse frequency dependence was observed. Negative inotropism by CPU228 was significant against positive inotropism by dofetilide. CPU228 inhibited both IKr and ICa,L currents and the IC50 for ICa,L inhibition was 0.909 µmol/L. At 3 µmol/L, CPU228 significantly suppressed the Ca2+ transients.

CPU228 is able to block ICa,L, contributing to decreased TDP, while also blocking IKr activity. By combined blockade of IKr and ICa,L, CPU228 shares the property of complex Class III anti‐arrhythmic agents.

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Table of contents – Volume 34, Issue 4

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Tables of content are generated automatically and are based on records of articles contained that are available in the TIB-Portal index. Due to missing records of articles, the volume display may be incomplete, even though the whole journal is available at TIB.

255
DIFFERENCES BETWEEN PATHOLOGICAL AND PHYSIOLOGICAL CARDIAC HYPERTROPHY: NOVEL THERAPEUTIC STRATEGIES TO TREAT HEART FAILURE
McMullen, Julie R / Jennings, Garry L | 2007
263
INVESTIGATION OF THE MICROCIRCULATION AND THE STATE OF OXIDATIVE STRESS IN THE RAT AFTER SCORPION ENVENOMATION
Sahnoun, Z / Chaker‐Krichen, S / Kassis, M / Hakim, A / Hammami, S / Ghozzi, H / Bouayed, N / Bellasfar, Z / Zeghal, KM / Rebai, T | 2007
269
SPATIAL PULMONARY FLOW DISTRIBUTION IN RABBIT ISOLATED LUNGS IS A POOR REPRESENTATION OF THE SITUATION IN VIVO*
Hübler, M / Heller, AR / Bleyl, JU / Rössel, T / Stehr, SN / Koch, T | 2007
274
EFFECT OF HIGH SALT INTAKE ON LOCAL RENIN–ANGIOTENSIN SYSTEM AND VENTRICULAR DYSFUNCTION FOLLOWING MYOCARDIAL INFARCTION IN RATS
De Resende, Micheline M / Mill, José G | 2007
280
INVOLVEMENT OF THE ENDOTHELIN ETB RECEPTOR IN GENDER DIFFERENCES IN DEOXYCORTICOSTERONE ACETATE‐SALT‐INDUCED HYPERTENSION
Kawanishi, Hideaki / Hasegawa, Youichi / Nakano, Daisuke / Ohkita, Mamoru / Takaoka, Masanori / Ohno, Yukihiro / Matsumura, Yasuo | 2007
286
IDENTIFICATION OF LIGANDS BINDING SPECIFICALLY TO INFLAMMATORY INTESTINAL MUCOSA USING PHAGE DISPLAY
Takagi, Tamaki / Arisawa, Tomiyasu / Yamamoto, Kazumasa / Hirata, Ichiro / Nakano, Hiroshi / Sawada, Makoto | 2007
290
PHARMACOKINETICS AND PHARMACODYNAMICS OF A NITRIC OXIDE‐RELEASING DERIVATIVE OF ENALAPRIL IN MALE BEAGLES
Okuyama, Cristina E / Mendes, Gustavo Duarte / Faro, Renato / Rezende, Vinicius M / Lagos, Rodolfo Monaco / Astigarraga, Rafael E B / Antunes, Edson / De Nucci, Gilberto | 2007
296
MORPHOLOGICAL AND FUNCTIONAL CHANGES IN P‐GLYCOPROTEIN DURING DEXAMETHASONE‐INDUCED HEPATOMEGALY
Micuda, Stanislav / Fuksa, Leos / Mundlova, Lucie / Osterreicher, Jan / Mokry, Jaroslav / Cermanova, Jolana / Brcakova, Eva / Staud, Frantisek / Pokorna, Pavla / Martinkova, Jirina | 2007
304
INHIBITION OF NAD(P)H OXIDASE REDUCES FIBRONECTIN EXPRESSION IN STROKE‐PRONE RENOVASCULAR HYPERTENSIVE RAT BRAIN
Cui, Chunmei / Chen, Alex F / Jiang, Zongpei / Wu, Qingqing / Lin, Jianwen / Wen, Hongmei / Zeng, Jinsheng | 2007
310
CALCIUM ANTAGONIST PROPERTY OF CPU228, A DOFETILIDE DERIVATIVE, CONTRIBUTES TO ITS LOW INCIDENCE OF TORSADES DE POINTES IN RABBITS
Huang, Zhi‐Jiang / Dai, De‐Zai / Li, Na / Na, Tao / Ji, Min / Dai, Yin | 2007
318
DOES NITRIC OXIDE MODULATE TRANSMITTER RELEASE AT THE MAMMALIAN NEUROMUSCULAR JUNCTION?
Nickels, Travis J / Reed, Grant W / Drummond, Justin T / Blevins, Dustin E / Lutz, Megan C / Wilson, David F | 2007
327
NITRIC OXIDE, ERECTILE DYSFUNCTION AND BETA‐BLOCKER TREATMENT (MR NOED STUDY): BENEFIT OF NEBIVOLOL VERSUS METOPROLOL IN HYPERTENSIVE MEN
Brixius, K / Middeke, M / Lichtenthal, A / Jahn, E / Schwinger, R H G | 2007
332
EFFECTS OF HYPOXIA/REPERFUSION INJURY ON DRUG DISPOSITION IN THE RAT ISOLATED PERFUSED LIVER
Arab, HA / Cheung, K / Hickman, PE / Potter, JM / Kadkhodaee, M / Roberts, MS | 2007
339
INHIBITION OF INDUCIBLE NITRIC OXIDE SYNTHASE ATTENUATES ACUTE ENDOTOXIN‐INDUCED LUNG INJURY IN RATS
Su, Chain Fa / Yang, Fwu Lin / Chen, Hsing I | 2007
347
ADMINISTRATION OF EXOGENOUS ERYTHROPOIETIN b AFFECTS LIPID PEROXIDATION AND SERUM PARAOXONASE-1 ACTIVITY AND CONCENTRATION IN PREDIALYSIS PATIENTS WITH CHRONIC RENAL DISEASE AND ANAEMIA:
Marsillach, J. / Martinez-Vea, A. / Marcas, L. / Mackness, B. / Mackness, M. / Ferre, N. / Joven, J. / Camps, J. | 2007
347
ADMINISTRATION OF EXOGENOUS ERYTHROPOIETIN β AFFECTS LIPID PEROXIDATION AND SERUM PARAOXONASE‐1 ACTIVITY AND CONCENTRATION IN PREDIALYSIS PATIENTS WITH CHRONIC RENAL DISEASE AND ANAEMIA
Marsillach, Judit / Martínez‐Vea, Albert / Marcas, Luis / Mackness, Bharti / Mackness, Michael / Ferré, Natàlia / Joven, Jorge / Camps, Jordi | 2007
350
METHODS OF ANALYSIS AND PHYSIOLOGICAL RELEVANCE OF RHYTHMS IN SYMPATHETIC NERVE DISCHARGE
Barman, Susan M / Kenney, Michael J | 2007
356
SYMPATHETIC RHYTHMS AND NERVOUS INTEGRATION
Gilbey, Michael P | 2007
362
IDENTIFICATION OF BLOOD PRESSURE CONTROL MECHANISMS BY POWER SPECTRAL ANALYSIS
Stauss, Harald M | 2007
369
DIFFERENTIAL EFFECTS OF VASOPRESSINERGIC AND OXYTOCINERGIC PRE‐AUTONOMIC NEURONS ON CIRCULATORY CONTROL: REFLEX MECHANISMS AND CHANGES DURING EXERCISE
Michelini, Lisete Compagno | 2007
377
EXERCISE TRAINING AND SYMPATHETIC NERVOUS SYSTEM ACTIVITY: EVIDENCE FOR PHYSICAL ACTIVITY DEPENDENT NEURAL PLASTICITY
Mueller, Patrick J | 2007
385
CORRIGENDUM
| 2007

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