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K Takeyama

Publications and source records attributed to K Takeyama.

139 records · Page 8Linked to original sources
PubMed1986

Antihypertensive mechanism of alacepril: effect on norepinephrine-induced vasoconstrictive response in vitro and in vivo.

To investigate the antihypertensive mechanism of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) a novel orally active angiotensin converting enzyme inhibitor, we studied the inhibitory activity of alacepril and DU-1227 (desacetyl-alacepril, a metabolite of alacepril) on the norepinephrine (noradrenaline, NA)-induced vasoconstrictive and pressor response in vitro and in vivo, and compared with that of captopril. Alacepril and captopril (3 X 10(-4) mol/l) attenuated slightly the NA-induced contractile response in isolated rat thoracic aorta and mesenteric artery, however, DU-1227 (3 X 10(-4) mol/l) inhibited more strongly the response in main artery and peripheral vascular bed. Orally given alacepril (18.7 mg/kg) inhibited the NA-induced pressor response in conscious normotensive rats, and the activity was more potent and long-lasting than that of an equimolar dose of captopril (10 mg/kg). After oral administration in hypertensive rats challenged with NA, alacepril (1.87 to 18.7 mg/kg) showed a dose-related antihypertensive effect which was slower in onset and longer lasting than that of equimolar dose of captopril (1.0 to 10.0 mg/kg). Consequently, the reduced sensitivity of the sympathetic nervous system in peripheral vasculature might contribute partly to the antihypertensive mechanism of alacepril.

Animals↗
PubMed1985

Antihypertensive activity of alacepril, an orally active angiotensin converting enzyme inhibitor, in renal hypertensive rats and dogs.

Alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine, DU-1219) showed a dose related and long lasting antihypertensive effect in renal hypertensive rats (two-kidney, one-clip), a typical renin dependent hypertensive model. The maximum hypotensive potency of alacepril (1-30 mg/kg) after single oral administration was slightly weaker than that of captopril (1-30 mg/kg). Judging from the AOC (area over the antihypertensive curve) value, the overall antihypertensive activity of alacepril was 3 times more potent than that of captopril on a weight basis. The long lasting antihypertensive effect of alacepril in renal hypertensive rats was also confirmed by once daily successive oral administration (1-2 mg/kg/d). In renal hypertensive dogs, alacepril (3 mg/kg) showed a stable and sustained hypotensive effect, and its duration of action was longer than that of captopril. Although alacepril did not possess a significant in vitro angiotensin converting enzyme (ACE) inhibitory activity, orally given alacepril (5.6-56.1 mg/kg) produced a potent and prolonged in vivo ACE inhibition which was estimated by suppression on angiotensin-I (310 ng/kg i.v.) induced pressor response in conscious normotensive rats. The prolonged in vivo ACE inhibitory activity of alacepril (5.6 mg/kg) was also observed in conscious normotensive dogs. These results suggest that the disposition and metabolism of orally given alacepril are responsible for the prolonged ACE inhibition and, concomitantly, for exerting the long lasting antihypertensive effect. Consequently, alacepril is a novel orally active ACE inhibitor having a potent and prolonged antihypertensive activity, and these properties suggest that alacepril is favorable for the treatment of hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

Antihypertensive activity of alacepril in spontaneously hypertensive rats and deoxycorticosterone acetate-salt hypertensive rats and dogs.

Antihypertensive activity of alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine, DU-1219), an orally active angiotensin converting enzyme (ACE) inhibitor, was investigated in hypertensive models with normal or low plasma renin activity (PRA). After single oral administration in spontaneously hypertensive rats (SHR), alacepril (1-30 mg/kg) showed a dose related antihypertensive effect with a gradual onset and long lasting action. The maximum hypotensive effect was about 3 times more potent than that of captopril (3-100 mg/kg) on a weight basis. When comparing the AOC (area over the antihypertensive curve) values, the overall antihypertensive activity of alacepril was 8 times stronger than that of captopril. In deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, alacepril (10-100 mg/kg) produced a significant and sustained hypotensive effect. The maximum hypotensive potency and the overall antihypertensive activity of alacepril were remarkably stronger than those of captopril (30, 100 mg/kg). During once daily successive oral administration for 10 days in SHR, alacepril (3-10 mg/kg/d) reduced dose relatedly the daily starting blood pressure. In DOCA-salt hypertensive rats and dogs, alacepril (30 mg/kg/d) produced a significant antihypertensive effect, while captopril (30 mg/kg/d) did not reduce daily starting blood pressure. Therefore, it may be expected that alacepril is a more effective antihypertensive agent than captopril in various hypertensions of different etiology.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1979

Effects of nonsteroidal anti-inflammatory drugs (NSAID) on renal excretion of sodium and water, and on body fluid volume in rats.

Effects of nonsteroidal anti-inflammatory drugs (NSAID) on urine volume and urinary sodium excretion, and on plasma volume and extracellular fluid volume were examined in conscious rats. The basal urine volume and urinary sodium excretion were decreased and the increased urine volume and urinary sodium excretion elicited by saline load (25 ml/kg) and by hydrochlorothiazide (10 mg/kg) were inhibited after oral administration of NSAID in doses which inhibited the rat carrageenin-induced hind paw edema (indomethacin, 1--10 mg/kg; tolmetin, 3--30 mg/kg; phenylbutazone, 3--30 mg/kg; aspirin, 30--300 mg/kg), but aminopyrine (30--300 mg/kg) did not show such an effect. The inhibitory activity on renal function was diminished gradually with repeated administration of NSAID. NSAID (indomethacin, 3 mg/kg; tolmetin, 10 mg/kg; phenoxybenzamin, 10 mg/kg; aspirin, 100 mg/kg) increased plasma volume and extracellular fluid volume of rats after repeated medication for 3 or 5 days, but the body fluid volume expansion disappeared with further repeated administration of NSAID. These results suggest that NSAID may inhibit the intrarenal role of prostaglandins and decrease sodium and water excretion in urine with resulting increased body fluid volume. Tolerance to these actions of NSAID developed after repeated administration.

Animals↗
PubMedDate not supplied

In vivo function of VDR in gene expression-VDR knock-out mice.

Vitamin D exerts many biological actions through nuclear vitamin D receptor (VDR)-mediated gene expression. The transactivation function of VDR is activated by binding 1alpha,25-dihydroxyvitamin D3[1alpha,25(OH)2D3], an active form of vitamin D. Conversion from 25(OH)D3 is finely regulated in kidney by 25(OH)D3 1alpha-hydroxylase[25(OH)D 1alpha-hydroxylase], keeping serum levels of 1alpha,25(OH)2D3 constant. Deficiency of vitamin D and mutations in the genes like VDR (type II genetic rickets) are known to cause rickets like lowered serum calcium, alopecia and impaired bone formation. However, the molecular basis of vitamin D VDR system in the vitamin D action in intact animals remained to be established. In addition, the 1alpha-hydroxylase gene from any species had not yet been cloned, irrespective of its biological significance and putative link to the type I genetic rickets. We generated VDR-deficient mice (VDR KO mice). VDR KO mice grew up normally until weaning, but after weaning they developed abnormality like the type II rickets patients. These results demonstrated indispensability of vitamin D-VDR system in mineral and bone metabolism only in post-weaning life. Using a newly developed cloning system, we cloned the cDNA encoding a novel P450 enzyme, mouse and human 1alpha-hydroxylase. The study in VDR KO mice demonstrated the function of liganded VDR in the negative feed-back regulation of 1alpha,25(OH)2D3 production. Finally, from the analysis of type I rickets patients, we found missense genetic mutations in 1alpha-hydroxylase, leading to the conclusion that this gene is responsible for the type I rickets.

Animals↗
PubMedDate not supplied

Antihypertensive activity of cadralazine in experimental hypertensive rats.

Antihypertensive and tachycardic activities of cadralazine were examined in experimental hypertensive rats (spontaneous, renal and deoxycorticosterone acetate-salt hypertension) after single or repeated oral administration, and compared with those of hydralazine. In single oral administration, cadralazine (0.3-5 mg/kg) produced a dose-related hypotensive effect and its maximum activity was equipotent to or more potent than that of hydralazine (1-5 mg/kg) in these hypertensive rats. The hypotensive effect of cadralazine appeared gradually and reached a maximum at 5-7 hr, while the maximum effect of hydralazine was observed at 1 hr after dosing. In SHR, the significant hypotensive effect of cadralazine persisted for 9-24 hr, but that of hydralazine lasted for only 1-12 hr. Therefore, there were marked differences in onset and duration of the hypotensive effect between cadralazine and hydralazine. Both drugs produced a dose-related tachycardic effect concomitant with the hypotensive effect. The separation ratios of cadralazine on these effects were equivalent to those of hydralazine. In repeated oral administration for 7 days, cadralazine (3 mg/kg/once a day) significantly reduced the daily starting blood pressure. The same response was obtained by 3 times daily repeated administration of hydralazine (3 mg/kg). Tolerance to the hypotensive and tachycardic effects was not observed during successive dosings of cadralazine or hydralazine. The potent and long lasting hypotensive effect of cadralazine might be useful for the treatment of arterial hypertension.

Animals↗