Mitsuo Ohashi

Anti-thrombotic effect of KC-404, a novel cerebral vasodilator

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.). 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. 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. KC-404 at doses up to 100 mg/kg, p.o. did not alter bleeding time in rat. Thus, KC-404 is expected to be of therapeutic value in cerebrovascular disorders accompanying thrombus in cerebral vasculature.

Effect of Ibudilast, a Novel Antiasthmatic Agent, on Anaphylactic Bronchoconstriction: Predominant Involvement of Endogenous Slow Reacting Substance of Anaphylaxis

The effect of ibudilast on anaphylactic bronchoconstriction was studied in guinea pigs sensitized actively with ovalbumin (OA). Animals were treated with indomethacin, tripelennamine and propranolol prior to the antigen challenge. Anaphylactic bronchoconstriction was prevented by ibudilast (1-4 mg/kg i.v. and 5-20 mg/kg p.o.) dose-dependently. FPL55712 and phenidone were also effective. Even when administered at the maximum development of bronchoconstriction, ibudilast (0.5 and 2 mg/kg i.v.) and FPL 55712 caused significant reduction of the increased airway tone, while phenidone did not. Ibudilast (1-4 mg/kg i.v.) and FPL55712 inhibited leukotriene D4-induced airway responses in nonsensitized guinea pigs pretreated with indomethacin and propranolol. Ibudilast (1.6 and 4 mg/kg i.v.) inhibited platelet-activating-factor (PAF)-induced airway responses in nonsensitized guinea pigs pretreated with indomethacin and propranolol, however, FPL 55712 inhibited PAF-induced airway responses only at a high dose such as 10 mg/kg i.v. Ibudilast (4 mg/kg i.v.) did not inhibit acetylcholine-induced airway response. Ibudilast showed inhibition of the release of slow-reacting substance of anaphylaxis (SRS-A) from guinea pig chopped lung sensitized with OA, which was significantly diminished by indomethacin. The drug little affected the activity of phospholipase A2 and 5-lipoxygenase in guinea pig polymorphonuclear leukocytes. These results indicate that ibudilast inhibits anaphylactic bronchoconstriction which is considered to be largely mediated by endogenously released SRS-A. The inhibitory effect of ibudilast on anaphylactic bronchoconstriction in the presence of indomethacin is considered to be exerted through its antagonism to SRS-A.

Anti-leukotriene D4 action of a new anti-asthmatic drug (KC-404) on the guinea-pig isolated trachea

Anti-asthmatic drug, KC-404, inhibited specifically spontaneous contraction and leukotriene (LT) D4-induced contraction of guinea-pig trachea. Relaxation of spontaneous contraction by KC-404 was reduced by the treatment of the guinea-pig trachea with a cyclooxygenase inhibitor, flurbiprofen. Some parallel shift of the concentration-action curve of LTD4 by KC-404 was still observed in the presence of flurbiprofen. Specific binding of [3H]LTD4 to the microsomal fraction of guinea-pig trachea was partially inhibited by KC-404. These results suggest that the relaxing action of trachea of KC-404 is due to the interference of interaction between LTD4 and its receptor and to the product(s) via cyclooxygenase pathway.

Ca-entry blockers, verapamil and diltiazem, on α1-adrenoceptors in thoracic aorta, renal artery and portal vein from rabbit

1. Verapamil caused a parallel shift of the concentration-response curve for norepinephrine in rabbit thoracic aorta and the reduction in norepinephrine-induced maximum response with shifts of the concentration-response curve for norepinephrine in renal artery and portal vein. 2. Diltiazem was without any effects on the response of thoracic aorta to norepinephrine, while the responses of renal artery and portal vein to norepinephrine were inhibited noncompetitively by diltiazem. 3. Verapamil but not diltiazem diminished markedly dibenamine-induced inhibition of maximum response to norepinephrine in all the preparations used. 4. Specific bindings of [3H]prazosin to both the membrane fractions derived from thoracic aorta and renal artery were displaced concentration-dependently by verapamil and diltiazem, but the effective concentrations of diltiazem were more than those for Ca-entry blocking activity. 5. These results suggest that verapamil might antagonize norepinephrine at alpha 1-adrenoceptors and the effective concentration for Ca-entry blocking activity of diltiazem were less than those for the interaction of diltiazem with alpha 1-adrenoceptors.

Influence of indomethacin on an increase in cerebral blood flow induced by KC-404, a novel cerebral vasodilator, in an anesthetized dog

The effect of KC-404 on vertebral blood flow in the absence and presence of indomethacin was investigated in an anesthetized dog. 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. The increase in heart rate due to KC-404 administration was also diminished, though moderately, by pretreatment with indomethacin. From these results, the possible mechanism of action of KC-404 was discussed, particularly in reference to cerebral vasodilating prostaglandins.