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.

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Examination was made of the effect of annexin V on Ca2+ movement into large unilamellar vesicles (LUV) using fura-2, a calcium-sensitive fluorescent dye. To avoid the possible difficulties relating to the addition of annexin V and/or Ca2+ in fura-2-loaded LUV, the burst method was used. LUV, preincubated with rat annexin V in the presence of Ca2+, were collected by centrifugation and resuspended, and then burst with Triton X-100 in the presence of fura-2. Inward Ca2+ movement across the artificial lipid membrane was measured by determination of fura-2 fluorescence due to the leaked Ca2+ from ruptured LUV. The observed Ca2+ signal increased dependent on annexin V and Ca2+ concentrations, whereas bovine serum albumin did not affect this signal up to 1 microM. Thus, annexin V shows Ca2+ channel activity in LUV. K201, a novel 1,4-benzothiazepine, inhibited inward Ca2+ movement into LUV caused by annexin V in a dose-dependent manner. In the presence of 50 nM annexin V and 400 microM Ca2+, 3 microM K201 showed significant inhibition of Ca2+ movement due to annexin V, and 50% inhibition was achieved at 25 microM K201. On the other hand, diltiazem had no such effect even at 30 microM. K201 is thus shown to have inhibitory activity on inward Ca2+ movement due to annexin V in artificial vesicles and may prove useful as a probe for elucidating the functions of annexin V in vivo.

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