Buichi Fujitani

Biochemical changes in unilateral brain injury in the rat: A possible role of free fatty acid accumulation

Cerebral energy metabolism was investigated in rats with the unilateral brain injury produced by the combination of left carotid artery ligation and systemic exposure to hypoxia. ATP and phosphocreatine levels in the left hemisphere were progressively reduced after the hypoxic-ischemic insult. The reduction of high-energy phosphate levels was accompained by an increase in sodium content and a decrease in potassium content. Mitochondria isolated from the damaged hemisphere showed a defect in ATP formation and oxygen uptake with a reduced ATP/O ratio. A large amount of free fatty acids (palmitic, stearic, oleic and arachidonic acids) accumulated in the injured hemisphere. The addition of unsaturated fatty acids (including oleic and arachidonic acids) to mitochondrial preparations caused an impairment of oxidative phosphorylation similar to that observed in mitochodria isolated from the damaged hemisphere.

Protective Effect of Zonisamide, an Antiepileptic Drug, Against Transient Focal Cerebral Ischemia with Middle Cerebral Artery Occlusion‐Reperfusion in Rats

Summary: Purpose: The antiepileptic effects of zonisamide (ZNS) have been well documented experimentally and clinically. The purpose of this study was to examine whether ZNS reduces cerebral damage after transient focal ischemia in rats.

Pharmacologic properties of a novel Ca2+ entry blocker, AJ-2615, in vitro

Summary: We studied the in vitro vascular relaxant properties of AJ-2615, (±)-/N-[6,11-dihydrodibenzo[b,e]-thiepin- 11-yl]-4-[4-fluorophenyl]-1-piperazinebutanamide monomaleate, a novel compound with long-lasting antihypertensive activity. AJ-2615 inhibited the high K + - induced contractile response in rat aorta with an IC50 of 2.08 x 10-8 M. It was 13 times less potent than nifedipine and 3, 10, and 15 times more potent than verapamil, diltiazem, and fluanarizine, respectively. AJ-2615 also inhibited the high K +-induced 45Ca influx in rat aorta at almost the same concentration as that for inhibition of the contractile response. The inhibition of 45Ca influx was reversed by Bay k 8644, a Ca2+ channel agonist. The effects of AJ-2615 on the contractile response and Ca2 + influx persisted for at least 120 min after AJ-2615 was removed from the medium. These results indicate that AJ-2615 acts directly on the potential-dependent Ca2 + channel in a long-lasting manner. AJ-2615 inhibited [3H]prazosin binding to dog aortic membranes (IC50=1.25 x 10-8 M) and phenylephrine-induced contractile response in superior mesenteric artery (SMA) of rabbits (IC50=3.87 x 10-8 M), indicating that AJ-2615 has potent α1-adrenoceptor blocking ctivity. AJ-2615 at 10-6 M did not inhibit the caffeine-induced contractile response in rabbit SMA in Ca2 + -free medium, nor did it inhibit calmodulin (CAM) activity. It had little effect on prostaglandin F2α (PGF2α)- and 5-hydroxytryptamine (5-HT)- induced contractile response in SMA, and on bindings of other vasoactive substances tested to their receptors such as α2 β-and -adrenergic, 5-HT1- and 5-HT2-serotonergic, endothelin-1 (ET-1) and AT1-angiotensin II (All) receptors. We conclude that AJ-2615 is a Ca2+ entry blocker with α1-adrenoceptor blocking activity built-in in the molecule

Synthesis and aldose reductase inhibitory activity of a new series of 5-[[2-(ω-carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine derivatives

Abstract Anew series of 5-[[2-(ω-carboxyalkoxy)aryl]methylene]-4-oxo-2-thioxothiazolidine derivatives was synthesized and evaluated for their potency as aldose reductase inhibitors (ARIs). Their activities were examined in terms of their inhibitory effect on rat lens aldose reductase in vitro and in terms of the preventive effect on sorbitol accumulation in the sciatic nerve of streptozotocin (STZ)-induced diabetic rats in vivo. Of these compounds, some of the naphthylmethylene thiazolidine derivatives were comparable to Zenarestat in the inhibitory potency in vitro and in vivo. In particular, compound 30 was 1.5 times more potent than Zenarestat in the in vivo activity, and had an adequate potency for clinical development.

Effect of OP-41483-α-CD, a prostacyclin analog, on a clamp-induced endothelial injury in rats

Abstract We studied the effect of OP-41483·α-CD, a stable prostacyclin analog, on clamp-induced endothelial injury in rats. The injury was assessed by vascular Evans blue leakage and using a scanning electron microscope. OP-41483·α-CD significantly reduced the Evans blue leakage at doses of 30 and 100ng/kg/min. PGE1·CD was also found to show an equipotent inhibitory action on the dye leakage. From scanning electron microscopic observations, a moderate degree of intimal defects, microvillous projections and platelet adhesions at the luminal surface were seen in the specimens from OP-41483·α-CD (30 and 100 ng/kg/min) treated rats. Furthermore, OP-41483·α-CD, PGE1·CD and Dibutyryl cyclic AMP (DbcAMP) were found to accelerate a proliferation of cultured bovine endothelial cells in a dose-dependent manner in vitro. Taken together, these data indicate that the endothelial regenerative effect of OP-41483·α-CD could contribute to healing of clamp-induce endothelial injury and it may be an important therapeutic drug to protect vascular intimal injury.

Prevention by the new Ca2+ channel antagonist, AJ-3941, of loss of endothelium-dependent relaxation after subarachnoid hemorrhage in rats

AJ-3941 ((+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]-oxepine-11-yl ) -4-(3-phenyl-2-propenyl)-piperazine dimaleate; CAS No. 143110-70-7), a cerebrovascular-selective Ca2+ channel antagonist having anti-lipid peroxidative action, was reported to prevent cerebral vasospasm following subarachnoid hemorrhage in rats. The present study was undertaken to determine whether AJ-3941 protects the impairment of cerebroarterial endothelium-dependent relaxation which is concomitantly induced with cerebral vasospasm. Subarachnoid hemorrhage biphasically suppressed the response to acetylcholine in rat basilar artery, at 0.5 h (n = 4; P < 0.06) and 1 day (n = 5; P < 0.05) after subarachnoid hemorrhage. The reduction of the responses was correlated significantly to the degree of vasospasm determined angiographically. This reduction was accompanied by a 49% increase of arterial lipid peroxide contents. Endothelium-independent relaxation in subarachnoid hemorrhage rats was preserved in response to 3-morpholinosydnonimine, sodium nitroprusside and papaverine. AJ-3941 prevented (n = 6-8, P < 0.05) the suppression of the acetylcholine-induced response and the increase in lipid peroxide content in subarachnoid hemorrhage rats. These results suggest that AJ-3941 could exert its vasospasmolytic effect by preserving endothelial function through its anti-lipid peroxidative action, in addition to its inhibition of vasospasmogen-induced vasoconstriction related to intracellular Ca2+ mobilization.

Effects of OP-41483·α-CD, a stable prostacyclin analog, on cultured endothelial cell dysfunction caused by 15(S)-hydroperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE) in vitro

We studied the effect of OP-41483.alpha-CD, a stable prostacyclin analog, on, 15-HPETE induced bovine endothelial cell dysfunction, which was assessed by measuring a number of endothelial cells attached to plastic plates. 15-HPETE decreased the number of attached endothelial cells in a concentration- and time-dependent manner. OP-41483.alpha-CD and PGI2 significantly inhibited 15-HPETE induced dysfunction of the cells at a concentration of more than 10(-9)M. Besides, DDA (10(-6) - 10(-4)M) an adenylate cyclase inhibitor, diminished the inhibitory effect of OP-41483.alpha-CD on 15-HPETE induced cell dysfunction in a concentration-dependent manner. Furthermore, OP-41483.alpha-CD increased cAMP levels in the endothelial cells in the range of 10(-10) to 10(-8)M in a dose-dependent manner. These data suggest that OP-41483.alpha-CD could exert an inhibitory action on 15-HPETE induced endothelial cell dysfunction via partly increasing its effect on the intracellular cAMP level.

Inhibitory Effect of Monatepil Maleate on Acyl-CoA:Cholesterol Acyltransferase Activity in the Liver of Cholesterol-Fed Japanese Monkeys

We have previously demonstrated that monatepil maleate, AJ-2615, a new calcium antagonist endowed with alpha1-adrenoceptor blocking property, has antiatherosclerotic and plasma lipid-lowering effects in Japanese monkeys fed on a cholesterol-rich diet. To clarify the mechanisms on plasma lipid-lowering action, we investigated the effect of monatepil maleate in these monkeys on hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activity. Both ACAT activity and esterified cholesterol content in the livers of monkeys fed on a cholesterol-rich diet for 6 months significantly increased about 7- and 16-fold, respectively, as compared with those in monkeys fed on a standard diet. Monatepil maleate (30 mg/kg/day for 6 months, orally) inhibited the increases of ACAT activity and esterified cholesterol content by 51% and 71%, respectively. In in vitro experiments, monatepil maleate inhibited ACAT activity in a concentration-dependent manner, whereas it did not affect 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity. A kinetic analysis revealed that monatepil maleate was a noncompetitive type inhibitor of ACAT. Hepatic ACAT activity was significantly correlated to hepatic esterified cholesterol content (r = 0.775, P < .0001), to plasma very low density lipoprotein (VLDL) content (r = 0.765, P < .0001) and to plasma total cholesterol content (r = 0.573, P < .005) in the monkeys. These results suggest that ACAT-inhibiting effect of monatepil maleate plays an important role in the reduction of hyperlipidemia.