Kengo Harada

Selective effect of KB-2796, a new calcium entry blocker, on cerebral circulation : a comparative study of the effects of calcium entry blockers on cerebral and peripheral arterial blood flows

The effects of a new calcium entry blocker, KB-2796, on cerebral and peripheral circulation were compared with those of four other calcium entry blockers (flunarizine, cinnarizine, nicardipine, and diltiazem) and also papaverine in anesthetized dogs. KB-2796 increased the vertebral blood flow to the same extent as the other drugs. KB-2796 and the other drugs increased the coronary blood flow, although the effect of KB-2796 was obviously weaker than that of the other drugs. The dose of KB-2796 producing a 30% increase in coronary blood flow was about 20 times higher than that producing an equivalent increase in vertebral blood flow. KB-2796 and the other calcium entry blockers caused a moderate increase in both femoral and common carotid blood flow. The renal artery showed a biphasic response to all drugs, which consisted of an initial decrease and a subsequent increase in the flow. From these results, it is suggested that KB-2796 is a new type of calcium entry blocker that selectively affects the cerebral circulation. It is also concluded that calcium entry blockers have a different spectrum of vasodilatory action on coronary and cerebral vascular beds and that a selective coronary vasodilatory action is not a common feature among all calcium entry blockers.

Focal brain ischemia model in rats. an experimental study

Using 74 male rats, anatomical variations of branching of the proximal segment of the middle cerebral artery were studied. In 36 rats (28 Sprague-Dawley rats and eight spontaneously hypertensive rats), the middle cerebral artery and/or its branches were occluded at various sites. Occlusion of the middle cerebral artery at the lateral border of the olfactory tract with or without simultaneous ligation of the ipsilateral common carotid artery rarely caused cerebral infarction in Sprague-Dawley rats. Occlusion of the olfactory branch in addition to the trunk of the middle cerebral artery caused large infarction of the pallium in five of eight Sprague-Dawley rats. Occlusion of the middle cerebral artery at the medial border of the olfactory tract caused infarction in the pallium and/or basal ganglia in five of six rats, and neurologic deficits were severe and persistent. Occlusion of the middle cerebral artery at the lateral border of the olfactory tract in spontaneously hypertensive rats caused large infarction with severe neurologic deficits in all eight animals. Possible factors responsible for such diverse differences and the relative value of each group as an experimental model of focal cerebral ischemia in rats were discussed.

Effects of a new Ca2+ antagonist, KB-2796, on the regional cerebral blood flow and somatosensory evoked potentials in the ischemic brain in cats

Effects of a new Ca2+ antagonist, 1-[bis(4-fluorophenyl) methyl]-4-(2,3,4-trimethoxybenzyl) piperazine dihydrochloride (KB-2796), on the regional cerebral blood flow (rCBF) and somatosensory evoked potentials (SEPs) were investigated using a model of focal cerebral ischemia in cats. In experiment 1, an occlusion of the middle cerebral artery for 4 hours persistently reduced the ipsilateral rCBF in both the control and the KB-2796-treated groups. However, the flow reduction was much milder in the treatment group than in the control group. Amplitudes of the SEPs diminished in both groups but the rate of deterioration was much slower in the treatment group than in the control group. In experiment 2, an occlusion of the middle cerebral artery for 1 hour was followed by reperfusion for 3 hours. The ipsilateral rCBF decreased during occlusion in both the control and the treatment groups. In the control group, postischemic hyperperfusion was seen in the ectosylvian gyrus after reperfusion, whereas the ipsilateral rCBF recovered rapidly to the control values without showing a phase of hyperperfusion in the treatment group. The rate of recovery of the SEPs was also much more rapid in the treatment group.

Effects of a novel calcium antagonist, KB-2796, on neurologic outcome and size of experimental cerebral infarction in rats.

Effects of a novel calcium 2+ antagonist, KB-2796, on neurologic outcome and size of infarction were studied in the rat model of focal cerebral ischemia. Neurologic deficits were examined from 1 to 24 hours after occlusion of the middle cerebral artery and size of infarction was measured at 24 hours postocclusion. When KB-2796 (10 mg/kg, IP) was given immediately after, or 1 hour after, middle cerebral artery occlusion, marked improvement in neurologic score was seen 1 to 3 hours postocclusion. When given immediately after middle cerebral artery occlusion, size of infarction was also markedly smaller when compared with the control rat. The present study suggests that the calcium 2+ antagonist KB-2796 has brain-protective effects against ischemia even with its administration after induction of ischemia.

Effects of ouabain on muscle tension and intracellular Ca2+ level in guinea-pig aorta

The effects of ouabain on muscle tension and the intracellular Ca2+ level ([Ca2+]i) were examined in guinea-pig aorta loaded with fura-2. Ouabain caused a gradual and sustained increase in both [Ca2+]i and muscle tension. There was a positive correlation between these two parameters. In Ca(2+)-free solution, ouabain did not affect either [Ca2+]i or muscle tension, suggesting that the ouabain-induced increase in [Ca2+]i was not due to Ca2+ release from storage sites. The ouabain-induced increase in [Ca2+]i and muscle tension was inhibited by Ni2+, which inhibits the Na+/Ca2+ exchanger, but not by verapamil. Furthermore, anionic and cationic amphiphiles were used as modulators of the Na+/Ca2+ exchanger. Sodium dodecyl sulfate accelerated the responses to ouabain, whereas dodecyltrimethylammonium bromide inhibited them. These results suggest that in the guinea-pig aorta, ouabain induces contraction by increasing the Ca2+ influx through the Na+/Ca2+ exchanger on the plasma membrane, but not through verapamil-sensitive Ca2+ channels.