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1. 1. KC-404 prevented mice from death and rats from A-V block, both induced by rapid i.v. injection of adenosine diphosphate (ADP), at high doses (5–100 mg/kg, i.v.). 2. 2. KC-404, at relatively lower doses (0.5–2 mg/kg, i.v.), inhibited the electroencephalographic (EEG) change in rat rapidly administered with arachidonic acid (AA) into the internal carotid artery. 3. 3. KC-404 (0.3–3 mg/kg, p.o.) inhibited the necrotic change of lower leg, paw or finger of rat when injected with sodium laurate into the femoral artery. 4. 4. KC-404 at doses up to 100 mg/kg, p.o. did not alter bleeding time in rat. 5. 5. Thus, KC-404 is expected to be of therapeutic value in cerebrovascular disorders accompanying thrombus in cerebral vasculature.

The effcts of sodium nitroprusside (NaNP) and diltiazem on CaCl2-, KCl- and histamine-induced contractile responses were studied in isolated rabbit basilar artery, aorta, taenia coli and trachea. NaNP reduced CaCl2-induced maximal contractions in basilar artery and aorta, but little affected those in taenia coli and trachea. NaNP reduced histamine-induced maximal contraction markedly in aorta but slightly in basilar artery and taenia coli. The reduction in aorta was reversed by increasing CaCl2 concentration in bathing medium. NaNP inhibited histamine-induced contractions of basilar artery, aorta and taeniacoli in Ca-free medium. Diltiazem reduced CaCl2-induced maximal contractions in basilar coli in Ca-free medium. Diltiazem reduced CaCl2-induced maximal contractions in basilar artery and aorta, whilst it caused a parallel shift of concentration-response curves for CaCl2 to the right in taenia coli and trachea. Diltiazem reduced histamine-induced maximal contractions in basilar artery and taenia coli. These reductions were reversed by increasing CaCl2 concentration in bathing medium. Diltiazem strongly inhibited histamine-induced contraction of taenia coli in Ca-free medium. The effects of NaNP and diltiazem on KCl-induced contractions both in normal (Ca;2.5 mM) and in high Ca (Ca;12.5 mM) media were also studied. From the results obtained in this study, the actions of NaNP and diltiazem were considered to vary with the type of smooth muscle or the condition eliciting contraction. Their possible mechanisms were discussed in this paper.

1. 1. The effect of KC-404 on vertebral blood flow in the absence and presence of indomethacin was investigated in an anesthetized dog. 2. 2. KC-404 (0.2 mg/kg, i.v.) showed a significant and long lasting increase in vertebral blood flow. This was markedly diminished by pretreatment of the animal with indomethacin. 3. 3. The increase in heart rate due to KC-404 administration was also diminished, though moderately, by pretreatment with indomethacin. 4. 4. From these results, the possible mechanism of action of KC-404 was discussed, particularly in reference to cerebral vasodilating prostaglandins.

An interaction of Ca entry blockers, D600 and diltiazem, with histamine receptors was tested in rabbit aorta and basilar artery. D600 caused a parallel rightward shift of the concentration response curve for histamine. The slope values from Schild plot analysis in aorta were not different from unity. Dibenamine pretreatment caused reduction of maximum response to histamine in aorta. Such reduction was diminished markedly by the presence of D600 or chlorpheniramine in aorta but not in basilar artery. However, diltiazem did not influence the concentration response curve for histamine. These findings suggest that pharmacological property of histamine receptors in rabbit aorta is distinct from that in basilar artery. Furthermore diltiazem seems not to interact with histamine receptors in both vascular tissues.