Kiyoshi Ichikawa

The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide

Mitiglinide (KAD-1229), a new anti-diabetic drug, is thought to stimulate insulin secretion by closing the ATP-sensitive K+ (K(ATP)) channels in pancreatic beta-cells. However, its selectivity for the various K(ATP) channels is not known. In this study, we examined the effects of mitiglinide on various cloned K(ATP) channels (Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B) reconstituted in COS-1 cells, and compared them to another meglitinide-related compound, nateglinide. Patch-clamp analysis using inside-out recording configuration showed that mitiglinide inhibits the Kir6.2/SUR1 channel currents in a dose-dependent manner (IC50 value, 100 nM) but does not significantly inhibit either Kir6.2/SUR2A or Kir6.2/SUR2B channel currents even at high doses (more than 10 microM). Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentrations (1 microM). Binding experiments on mitiglinide, nateglinide, and repaglinide to SUR1 expressed in COS-1 cells revealed that they inhibit the binding of [3H]glibenclamide to SUR1 (IC50 values: mitiglinide, 280 nM; nateglinide, 8 microM; repaglinide, 1.6 microM), suggesting that they all share a glibenclamide binding site. The insulin responses to glucose, mitiglinide, tolbutamide, and glibenclamide in MIN6 cells after chronic mitiglinide, nateglinide, or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment. These results indicate that, similar to the sulfonylureas, mitiglinide is highly specific to the Kir6.2/SUR1 complex, i.e., the pancreatic beta-cell K(ATP) channel, and suggest that mitiglinide may be a clinically useful anti-diabetic drug.

Tranilast suppresses the vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet

Intimal hyperplasia is a serious problem after percutaneous transluminal coronary angioplasty. In this study, we assessed the effect of tranilast on vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet. In this animal model, intimal hyperplasia more severe than that in rabbits fed on a normal diet was observed. In addition, medial thickening and lipid deposits in both media and intima were also noted. These findings indicate that balloon injury caused intimal and medial hyperplasia and that this hyperplasia was accelerated by the high cholesterol load. Tranilast (300 mg/kg) significantly decreased the intimal area, medial area, and stenosis ratio, and increased the luminal/total area ratio, in the cholesterol-fed rabbits. These results suggest that tranilast may be useful for prevention of restenosis after percutaneous transluminal coronary angioplasty of patients, including those with a clinical risk of hypercholesterolemia.

Oxcarbazepine antinociception in animals with inflammatory pain or painful diabetic neuropathy.

1. Diabetic neuropathy is one of the most frequent complications of diabetes mellitus. However, the mechanisms underlying these disorders are not yet well defined and it has been reported that currently available analgesics have hardly any ameliorating effect on painful diabetic neuropathy.

Inhibitory effect of oxcarbazepine on high-frequency firing in peripheral nerve fibers.

We assessed the effects of oxcarbazepine, an antiepileptic derivative of carbamazepine, on discharges in single cutaneous afferent fibers produced by repetitive high-frequency stimulation (mimicking the abnormal excitation of peripheral nerves in neuropathic pain and paresthesia). After intravenous administration of oxcarbazepine, the later responses in the train dropped out without the earlier ones being affected and, thus, the total number of spikes decreased. The latency of the responses to an individual pulse was unchanged. These results, which indicate that oxcarbazepine inhibits the generation of high-frequency firing without affecting impulse conduction, suggest that this drug may be useful against neuropathic pain and paresthesia.

Participation of thromboxane A2 in the cough response in guinea-pigs: antitussive effect of ozagrel

The purpose of this study was to investigate the involvement of thromboxane A2 (TXA2) in the cough response in a guinea‐pig cough model. Here, we describe results obtained using a selective TXA2 synthetase inhibitor, ozagrel, and a selective TXA2 agonist, U‐46619. Guinea‐pigs were anaesthetized and exposed to an aerosol of capsaicin (100 μM) to elicit coughing. The number of coughs was 20.0±5.8 during capsaicin provocation (5 min), but only 2.8±0.4 during a 5‐min inhalation of phosphate‐buffered saline (PBS) (P<0.05). TXB2 levels in BAL were 101.4±8.0 and 58.4±8.7 pg ml−1 following capsaicin and PBS inhalation, respectively (P<0.01), but there was no intergroup difference in the cell populations in BAL. Inhalation of U‐46619 did not induce a cough response by itself at concentrations of 100 ng ml−1 to 10 μg ml−1. However, it caused a 2 fold increase in the number of capsaicin‐induced coughs. To explore the source of the TXA2, BAL cells were stimulated with capsaicin and the supernatants collected for analysis. The TXB2 concentration in BAL was increased dose‐dependently, indicating that TXA2 is released from BAL cells in response to capsaicin. Ozagrel was administered orally 1 h before a 5 min capsaicin provocation and the number of coughs was counted during the capsaicin inhalation. Ozagrel decreased the number of coughs dose‐dependently (ED50 value, 26.3 mg kg−1). These results show that TXA2 modulates the capsaicin‐induced cough response by increasing capsaicin‐sensitivity.

Effect of Ozagrel on Locomotor and Motor Coordination after Transient Cerebral Ischemia in Experimental Animal Models

The effect of ozagrel, a selective thromboxane A2 (TXA2) synthetase inhibitor, on the obstruction after cerebral ischemia-reperfusion was studied in experimental animal models. The reduced spontaneously locomotor activity and the obstruction of motor coordination were improved by the administration of ozagrel in the conscious cerebral ischemia-reperfusion mouse model. Ozagrel suppressed the decrease in specific gravity of the brain tissue induced by the occlusion-reperfusion in the conscious cerebral ischemia-reperfusion SHR model, and recovered the postischemic decrease in cortical PO2 after middle cerebral artery occlusion-reperfusion in cats. The level of TXB2, a metabolite of TXA2, in the brain increased after the cerebral ischemia-reperfusion, and ozagrel prevented this increase. Additionally, ozagrel also increased the level of 6-keto-PGF1α, a metabolite of prostaglandin I2 (PGI2), in the brain tissue after cerebral ischemia-reperfusion, and the administration of PGI2 improved the reduced spontaneous locomotor activity in the conscious cerebral ischemia-reperfusion mouse model. Our data suggest that ozagrel suppressed the obstruction following cerebral ischemia-reperfusion by preserving the cerebral blood flow via preventing the increase in TXA2 and causing an increase in the PGI2 level.

Effect Of Kad-1229, A Novel Hypoglycaemic Agent, On Plasma Glucose Levels After Meal Load In Type 2 Diabetic Rats

1. The effects of KAD‐1229 (a novel non‐sulphonylurea agent), voglibose (an α‐glucosidase inhibitor) and nateglinide (a non‐sulphonylurea antihyperglycaemic agent) on hyperglycaemia induced by a meal load were assessed in diabetic rats.

Suppressive Effects Of Oxcarbazepine On Tooth Pulp-Evoked Potentials Recorded At The Trigeminal Spinal Tract Nucleus In Cats

1. The purpose of the present study was to evaluate the antinociceptive effect of oxcarbazepine, a keto derivertive of carbamazepine (an anticonvulsant), in an animal model. To evoke a nociceptive response, we electrically stimulated the maxillary canine tooth pulp (MCTP) in anaesthetized (allobarbital–urethane), spontaneously breathing cats.

Effect of KAD-1229, a nonsulfonylurea hypoglycemic agent, on plasma glucose and insulin in streptozotocin-induced diabetic dogs.

Hypoglycemic agents with a rapid onset and short duration of action should be useful for controlling postprandial hyperglycemia. Our aim was to establish a diabetes mellitus model in dogs, and then during an oral glucose tolerance test to compare the hypoglycemic effect and insulinotropic action of KAD-1229, a new hypoglycemic agent, with that of gliclazide, a conventional sulfonylurea. In this model, KAD-1229 reduced the increase in plasma glucose level without producing hypoglycemia. Gliclazide had a weaker effect on reduction of the glucose increase and caused hypoglycemia via a significantly raised insulin secretion in the late phase. A rapid insulinotropic action of KAD-1229 was clearly observed in the portal venous blood. The results suggest that in type 2 diabetes caused by, at least, insulin deficiency, KAD-1229 may improve impaired insulin secretion in the early phase and attenuate hyperglycemia without causing a sustained hypoglycemia.

Absence of exacerbation of myocardial stunning in anesthetized dogs treated with KAD-1229, a novel hypoglycemic agent

The effect of (+)-momocalcium bis[(2S,3a,7a-cis)-alpha-benzylhexahydro-gamma-oxo-2-isoindolinebutyrate]dihydrate (KAD-1229), a novel hypoglycemic agent with a chemical structure different from that of the sulfonylureas, on myocardial stunning was assessed in anesthetized dogs by comparison with that of glibenclamide, a sulfonylurea. Even though their hypoglycemic effects were of similar magnitude, glibenclamide (1 mg/kg, i.v.), but not KAD-1229, exacerbated the myocardial stunning induced by occlusion/reperfusion of the descending coronary artery. In a receptor-binding experiment, unlabeled glibenclamide completely inhibited [(3)H]glibenclamide binding to the myocardium, but KAD-1229 did not. These results suggest that the difference in binding properties of KAD-1229 and glibenclamide toward cardiac sulfonylurea receptors is one of the causes of their different effects on myocardial stunning. It is likely that KAD-1229 is highly specific for pancreatic sulfonylurea receptors and is speculated to be a safer hypoglycemic agent than, at least, glibenclamide.