Objectives: The drug K201 (JTV-519) increases inotropy and suppresses arrhythmias in failing hearts, but the effects of K201 on normal hearts is unknown. Methods: The effect of K201 on excitation-contraction (E-C) coupling in normal myocardium was studied by using voltage-clamp and intracellular Ca 2+ measurements in intact cells. Sarcoplasmic reticulum (SR) function was assessed using permeabilised cardiomyocytes. Results: Acute application of b1 μmol/L K201 had no significant effect on E-C coupling. K201 at 1 μmol/L
Three-dimensional reconstruction of the human heart was performed to define the structure of the intramyocardial microvasculature. A total of 200 consecutive serial sections of 6 μm each were prepared from the left ventricular tissue of an autopsied human heart with normal coronary arteries. The corresponding arteriole, venule, and all capillaries were reconstructed using three-dimensional software. The capillary network extended right and left along the cardiomyocyte with major and minor axes of about 130 and 120 μm, respectively. The capillary length from an arteriole to an adjacent venule was about 350 μm. Two types of sack-like structures, the precapillary sinus and the capillary sinus, were present in the capillary network, and many capillaries diverged from these sinuses. The cardiomyocytes were covered with reticular capillaries. In contrast, the precapillary and capillary sinuses were surrounded by many cardiomyocytes. The arterial and venous capillaries were positioned alternately, forming a lattice pattern. Intramyocardial microcirculatory units forming a capillary network from an arteriole to adjacent venules on both sides were present. The sizes of myocardial micronecroses corresponded to that of the intramyocardial microcirculatory unit. These results show that the capillary network is an ordered and anatomically regulated structure and that the microcirculatory unit and the precapillary and capillary sinuses may play an important role in maintaining the intramyocardial microcirculation during contraction and relaxation.
K201 is a 1,4-benzothiazepine derivative that is a promising new drug with a strong cardioprotective effect. We initially discovered K201 as an effective suppressant of sudden cardiac cell death due to calcium overload. K201 is a nonspecific blocker of sodium, potassium and calcium channels, and its cardioprotective effect is more marked than those of nicorandil, prazosine, propranolol, verapamil and diltiazem. Recently, K201 has also been shown to have activities indicated for treatment of atrial fibrillation, ventricular fibrillation, heart failure and ischemic heart disease, including action as a multiple-channel blocker, inhibition of diastolic Ca2+ release from the sarcoplasmic reticulum, suppression of spontaneous Ca2+ sparks and Ca2+ waves, blockage of annexin V and provision of myocardial protection, and improvement of norepinephrine-induced diastolic dysfunction. Here, we describe the pharmacological characteristics and clinical applications of K201.
arge-scale clinical studies have recently shown an inhibitory effect on cardiovascular events of lipidlowering therapy with HMG-CoA reductase inhibitors (statins), indicating the usefulness of this therapy. [1][2][3][4][5][6][7][8] The benefit is particularly marked in patients with coronary heart disease (CHD), and the guidelines of the American National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III positively state the utility of lipid-lowering therapy in reducing low-density lipoprotein (LDL)-cholesterol (C) to below 70 mg/dl in patients with coronary artery disease. 9 In Japan, the guidelines for prevention of arteriosclerotic diseases specify a target value of LDL-C of less than 100 mg/dl for control of CHD patients in category C. 10 Evaluation of coronary arterial plaques by imaging diagnosis has progressed markedly in recent years. In the REVERSAL study, intravascular ultrasonography (IVUS) was used to compare the effect of lipid-lowering therapy between CHD patients treated with standard and active regimens, with the latter found to inhibit expansion of coronary plaques. 11 Size reduction of coronary plaques on IVUS by statin treatment in patients with acute coronary syndrome (ACS) has also been reported in Japan (the ESTABLISH study). 12 Subsequent multicenter studies such as the JAPAN-ACS study have verified the ESTABLISH results through investigation of strong statin-induced volume reduction of coronary plaques. [13][14][15] However, these studies have all evaluated quantitative changes of the plaques, and there have been fewer qualitative evaluations. 16 Spectral analysis of IVUS radiofrequency (RF) data can provide detailed quantitative and qualitative information on coronary plaque composition in vivo. [17][18][19][20][21] Nasu et al found that in vivo characterization of coronary plaques by 'virtual histology (VH)' correlated favorably with the results of in vitro histopathological examination of tissue samples obtained by directional coronary atherectomy. 22 In this study, we used VH-IVUS to evaluate short-term quantitative and qualitative changes in non-culprit lesions in a comparison of pitavastatin, a new strong statin, with atorvastatin after administration in the early stage (2-3 weeks) after onset of ACS. The follow-up period of 2-3 weeks was chosen to evaluate the inhibition of short-term events within 1 month by early statin administration after ACS onset, and to examine if the statin effect starts to appear in this period. Methods Study Design and Patient PopulationThe study was performed as a prospective, randomized, single-center trial to assess the effect of 2-to 3-weeks of (Received November 5, 2008 Patients with acute coronary syndrome who underwent emergency percutaneous coronary intervention (PCI) were randomly assigned to receive pitavastatin (n=80; 2 mg/day) or atorvastatin (n=80; 10 mg/day) immediately after PCI. All patients underwent a blood lipid test and VH-IVUS evaluation of non-PCI lesions at admission and after 2-3 weeks of statin administration. A...
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