Atsuhiro Kanda

Antihypertensive effects of MPC-1304, a novel calcium antagonist, in experimental hypertensive rats and dogs

Summary: Antihypertensive effects of a novel calcium antagonist, MPC-1304, (±)-methyl 2-oxopropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate and its active metabolites were investigated in experimental hypertensive rats and dogs and compared with those of other dihydropyridine derivatives (nifedipine, nisoldipine, nicardipine, and nitrendipine). MPC-1304 had a dose-related antihypertensive effect with a slight increase in heart rate (HR) in rats. The antihypertensive effects of MPC-1304 were more potent than those of other dihydropyridines, and its active metabolites had antihypertensive effects comparable to those of other dihydropyridines. The hypotensive effects of MPC-1304 were stronger in hypertensive rats than in normotensive rats. During repeated oral administration of MPC-1304 to spontaneously hypertensive rats (SHR, once daily for 4 weeks, 0.3-3 mg/kg), dose-response curves of the antihypertensive effect did not change and body weight gain was equal to that of the vehicle-treated group. When given orally to conscious renal hypertensive dogs, MPC-1304 0.1-0.3 mg/kg had a potency and duration of antihypertensive action comparable to that of nitrendipine (1-3 mg/kg). MPC-1304 increased coronary blood flow (CBF) and aortic blood flow (ABF) in conscious normotensive dogs. In conclusion, MPC-1304 and its active metabolites have potent antihypertensive effects and cause slight tachycardia, and they may be useful in treating hypertension

Cardiovascular profile of MPC-1304, a novel dihydropyridine calcium antagonist : comparison with other calcium antagonists

The cardiovascular profile of a novel calcium antagonist, MPC-1304 and its active metabolites were investigated in experimental animals in vitro and in vivo, and were compared with those of other calcium antagonists or nitroglycerin (NTG). The ratio of negative chronotropic/negative inotropic effect of MPC-1304 was 23 times higher than that of nifedipine in paced left and spontaneously beating right atria of guinea pigs. MPC-1304 and nifedipine did not change atrial-His (AH) conduction time or His-ventricular (HV) conduction time at hypotensive doses in open-chest dogs, whereas diltiazem prolonged AH time. MPC-1304 increased coronary blood flow, and strongly decreased myocardial oxygen consumption (MVO2) by decreasing blood pressure (BP) and heart rate (HR) in open-chest dogs. Left ventricular pressure (LVP) was not changed. Contractile force (dp/dt) was slightly increased by its action on afterload. MPC-1304 and nifedipine did not dilate the large coronary artery, but NTG did. MPC-1304 increased blood flow of the peripheral arteries, especially vertebral and CBF in anesthetized dogs. Cerebral blood flow (CBF) also increased. MPC-1304 decreased serum cholesterol levels and the plaque area of the aorta in cholesterol-fed rabbits. Because of this cardiovascular profile, MPC-1304 should be useful in treatment of hypertension as well as angina pectoris.

MPC-1304, another type of dihydropyridine, possessing highly potent vasodilating action

We investigated the vasodilating action of MPC-1304, one of the most potent dihydropyridines causing hypotension, in anesthetized dogs and compared this with its binding properties. After intraarterial injection, MPC-1304 was 3 times less potent than other dihydropyridines (nitrendipine, nifedipine, nicardipine and nisoldipine) in increasing femoral blood flow. After infusion of these drugs, however, MPC-1304 was the most potent in increasing femoral blood flow. The onset and recovery of the effect of MPC-1304 on femoral blood flow were slower than for nifedipine. Higher doses of Bay K 8644 were needed to antagonize the stimulating activity of MPC-1304 than for nifedipine. In a competition assay of [3H]nitrendipine binding, MPC-1304 and its metabolites bound to the dihydropyridine receptor with lower affinity than the other dihydropyridines. The binding affinity of [3H]MPC-1304 was lower than that of [3H]nitrendipine, consistent with the potency of this drug to increase femoral blood flow by bolus injection. The association and dissociation of [3H]MPC-1304 was slower than those of [3H]nitrendipine, which is consistent with the slow onset and long-lasting vasodilating effects of MPC-1304 on femoral blood flow. Moreover, diltiazem reduced a part of [3H]MPC-1304 binding in a competitive manner. In ex vivo binding assays with serum and aorta obtained after oral administration of the drug in spontaneously hypertensive rats, MPC-1304 inhibited [3H]nitrendipine binding to membrane preparations less potently than nifedipine. From these results, we conclude that MPC-1304 is a different type of dihydropyridine possessing the most potent vasodilating action of the representative dihydropyridines tested. Its activity cannot be explained solely by a slow interaction with voltage-dependent Ca2+ channels.

Lafutidine inhibits Helicobacter pylori-induced interleukin-8 production in human gastric epithelial cells

Background and Aim:  Attachment of Helicobacter pylori to gastric epithelial cells leads to the production of chemokines, such as interleukin‐8 (IL‐8), which in turn activate and recruit neutrophils to the site of infection. Lafutidine [(+/–)‐2‐(furfurylsulfinyl)‐N‐(4‐(4‐(piperidinomethyl)‐2‐pyridyl)oxy‐(Z)‐2‐butenyl)acetamide] is a new type of antiulcer drug that possesses an antisecretory action as well as gastroprotective activity, independent of its antisecretory action. In the present study, we examined the effects of lafutidine on H. pylori‐induced IL‐8 release and H. pylori adhesion to MKN45 cells.

Renal effects of the calcium channel blocker aranidipine and its active metabolite in anesthetized dogs and conscious spontaneously hypertensive rats

The purpose of this study was to investigate the renal effects of aranidipine, a novel calcium channel blocker of the dihydropyridine type, and its active metabolite in anesthetized dogs and conscious spontaneously hypertensive rats (SHRs). When infused into the renal artery in anesthetized dogs, aranidipine (0.03 microg/kg/min) induced sustained increases in urine volume and urinary excretion of sodium and of potassium. This effect was greater than that elicited by nifedipine (0.1 microg/kg/min). The aranidipine metabolite, M-1 (0.1 microg/kg/min), also caused diuresis and natriuresis almost equal to those of nifedipine. The stop-flow experiment using the anesthetized dog showed that intrarenal infusion of aranidipine (0.03 microg/kg/min), as well as nifedipine (0.1 microg/kg/min), produced natriuresis at the distal tubular site rather than at the proximal site. Aranidipine (0.3, 1, and 3 mg/kg), when administered orally, dose-dependently increased urine volume and urinary excretion of electrolytes in conscious saline-loaded SHRs. M-1 (10 mg/kg, p.o.) also showed diuretic and natriuretic effects comparable to those of nifedipine (10 mg/kg) in SHRs. In addition, after repeated oral administration of aranidipine for 7 days, short-term tolerance was not found for its diuretic and natriuretic effects in SHRs. These results suggest that, apart from antihypertensive efficiency, aranidipine may offer a therapeutic advantage by producing diuresis and natriuresis in hypertensive patients. The metabolite of aranidipine may contribute, in part, to the diuretic, natriuretic, and antihypertensive effects of aranidipine.

Tas-301, a new synthetic inhibitor of neointimal thickening after balloon injury, inhibits calcium-dependent signal transduction and cytoskeletal reorganization.

We previously demonstrated that a recently synthesized drug, TAS-301 [3-bis(4-methoxyphenyl)methylene-2-indolinone], inhibited neointimal thickening after single-balloon injury to the rat common carotid artery by inhibiting both the migration and proliferation processes of vascular smooth muscle cells (VSMCs). The purpose of this current study was to elucidate the possible mechanism of action for its inhibition of the migration process of VSMCs. We also determined the efficacy of TAS-301 on second neointimal formation 14 days after a double-balloon injury to the rat common carotid artery. Neointimal thickening, 14 days after second balloon injury, was reduced by the oral administration of TAS-301 in a dose-dependent manner. In in vitro assays using rat VSMCs, Western blot analysis showed that TAS-301 inhibited platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of both focal adhesion kinase and paxillin. Tyrosine phosphorylation of these proteins depended on the increment of intracellular calcium concentration ([Ca2+]i). The PDGF-induced elevation of [Ca2+]i and activation of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) were also inhibited by TAS-301. Additionally, TAS-301 at 10 µmol/l reduced the extent of F-actin stress fiber depolymerization observed in response to PDGF. These results indicate that TAS-301 reduced the intimal thickening after denudation to a pre-existing lesion to the same extent as it reduced that after a single-balloon injury to the normal artery. Furthermore, the results of our in vitro experiments suggest that antimigratory mechanisms of TAS-301 that contribute to preventing the intimal thickening might be mediated by drug inhibition of Ca2+-dependent signal molecules and the following cytoskeletal depolymerization.

Effect of lafutidine on CGRP release from cultured rat dorsal root ganglion cells

Lafutidine increased capsaicin-stimulated CGRP release from isolated rat stomach without changing basal CGRP levels. In order to clarify the mechanism of this effect, we used cultured rat DRG cells and measured CGRP release. (1) DRG cells were treated with each drug, and the CGRP content of the supernatant was determined by EIA. (2) RGM-1 cells were co-cultured with DRG cells through a cell culture insert, and capsaicin-evoked CGRP release from the DRG cells was determined when lafutidine or PGE2 was added to the RGM-1 cells. (3) The supernatant of isolated rat stomach incubated with lafutidine was added to cultured DRG cells, and capsaicin-evoked CGRP release was determined. PGE2, but not lafutidine, augmented capsaicin-evoked CGRP release from DRG cells. Lafutidine did not modulate CGRP release from DRG cells, even though it sensitized CGRP-containing afferent nerves in the rat stomach. Lafutidne and PGE2 may have different mechanisms of sensitization.