[Evaluation of efficacy of amiodarone by electrophysiologic studies in patients with sustained ventricular tachycardia].
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Amiodarone↗
Biomedical subjects
I Yamaguchi
Publications and source records attributed to I Yamaguchi.
Effect of nilvadipine on balloon catheterization-induced intimal thickening of the coronary artery in miniature pigs.
The effect of nilvadipine on balloon catheterization-induced intimal thickening of the coronary artery was examined in miniature pigs. A diffuse intimal thickening was observed in vehicle-treated controls 6 weeks after balloon catheterization. The histologic features of the intimal thickening resembled those of early atherosclerotic lesions and restenosis after percutaneous transluminal coronary angioplasty (PTCA). Nilvadipine given in a daily dose of 10 mg/kg (subcutaneously, s.c.) for 6 weeks significantly inhibited intimal thickening. The ratio of the cross-sectional area of the intima to the cross-sectional area of the media was significantly reduced by 62% in nilvadipine-treated animals. These results suggest that nilvadipine may prevent or exert beneficial effects on coronary arterial injuries such as atherosclerosis and restenosis after PTCA.
Angioplasty, Balloon, Coronary↗
Effects of the new angiotensin-converting enzyme inhibitor imidapril on renal hemodynamics and function in anesthetized dogs.
The effects of a new angiotensin-converting enzyme (ACE) inhibitor, imidapril hydrochloride ((-)-(4S)-3-[(2S)-2- [[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino]propionyl]- 1-methyl-2-oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1) and of its active metabolite, 6366 A (CAS 89371-44-8) on renal function were studied in anesthetized dogs and compared to the effects of enalapril and its active metabolite, enalaprilat. Intravenous (i.v.) administration of 6366 A at 30 micrograms/kg strongly inhibited angiotensin I-induced renal vasoconstrictive and pressor responses. 6366 A promptly lowered blood pressure and renal vascular resistance, and caused clear increases in renal blood flow and glomerular filtration rate. It also increased urine volume and urinary excretion of sodium and chloride. These renal effects were also produced by intraduodenal (i.d.) administration of 2 mg/kg of imidapril. However, the effects of i.d. imidapril began later, developed gradually and reached a plateau after 2 to 3 h. Enalaprilat (30 micrograms/kg i.v.) and enalapril (2 mg/kg i.d.) had renal effects similar to 6366 A and imidapril. In conclusion, the ACE inhibitor imidapril has beneficial effects on renal function via its active metabolite, and the effects appear to be essentially identical to those of enalapril.
Anesthesia↗
Acute hemodynamic effects of the active metabolite of imidapril, (4S)-3-((2S)-2-[N-((1S)-1-carboxy-3-phenyl-propyl)amino]propionyl)-1- methyl-2-oxoimidazolidine-4-carboxylic acid, and enalaprilat in anesthetized dogs.
The hemodynamic effects of imidapril, a novel nonsulfhydryl angiotensin-converting enzyme inhibitor, were examined in anesthetized dogs by the intravenous injection of its active metabolite 6366A ((4S)-3-((2S)-2-[N-((1S)-1-carboxy-3- phenylpropyl)amino]propionyl)-1-methyl-2-oxoimidazolidine-4-carboxylic acid, CAS 89371-44-8) and were compared to those of enalaprilat. 6366A (1-100 micrograms/kg) reduced the blood pressure and total peripheral resistance in a dose-dependent manner, while causing no marked changes in heart rate, LV dp/dtmax, and pulmonary arterial pressure. The cardiac output and stroke volume were slightly increased. Blood flow in the common carotid artery, the vertebral artery, and the femoral artery was reduced or tended to decrease, while the superior mesenteric arterial blood flow was increased. These effects were similar to those of enalaprilat. 6366A did not inhibit the pressor response of angiotensin II, but markedly inhibited that of angiotensin I, and the effects of 6366A on regional blood flow were opposite to those of angiotensin II. Thus, 6366A appears to produce its hemodynamic effects by angiotensin converting enzyme inhibition, as does enalaprilat. 6366A also tended to decrease myocardial oxygen consumption. These results suggested that the hemodynamic effects of imidapril on the heart and on regional blood flow are similar to those of enalapril.
Anesthesia↗
Effect of FR121196, a novel cognitive enhancer, on the memory impairment of rats in passive avoidance and radial arm maze tasks.
Passive avoidance performance was impaired in young rats by scopolamine (1.0 mg/kg) or by nucleus basalis magnocellularis lesions and in aged rats (24-26 months old). FR121196[N-(4-acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide+ ++], a newly introduced cognitive enhancer, ameliorated the failure in memory retention with bell-shaped dose-response curves in doses ranging from 0.1 to 10 mg/kg. Similar dose-response curves also were obtained with methamphetamine (0.1-10 mg/kg), whereas physostigmine (0.01-1.0 mg/kg) attenuated the amnesia in scopolamine-treated rats, but hardly affected that in nucleus basalis magnocellularis-lesioned or aged rats. In radial arm maze tasks, behavioral indices of spatial memory, such as first correct choices and number of errors, were impaired by an injection of scopolamine (0.5 mg/kg) or by lesions of the medial septum or fimbria-fornix. FR121196 ameliorated the scopolamine-induced memory deficit with a bell-shaped dose-response curve, whereas methamphetamine had the opposite effect. These two drugs had little effect on memory deficits brought about by medial septum or fimbria-fornix lesioning, whereas physostigmine ameliorated these deficits in scopolamine-treated and medial septum-lesioned rats, but not in fimbria-fornix-lesioned rats. Behavioral studies using Animex demonstrated that FR121196, in contrast with methamphetamine, does not increase locomotor activities in rats up to a dose of 10 mg/kg. These results are discussed in relation to the cholinergic and dopaminergic mechanisms of memory.
Aging↗
Possible involvement of hyperinsulinemia and adrenergic activation in the pathogenesis of indomethacin-induced antral ulcers in nonfasted hamsters and refed rats.
Subcutaneous doses of indomethacin (IND) produced mainly antral ulcers in refed rats, almost exclusively corpus erosions in fasted rats, but no antral or corpus mucosal insult in nonfasted rats. In contrast, IND-treatment in nonfasted hamsters caused antral ulcers but minimal corpus erosions. Mild and severe hyperinsulinemia were observed in refed rats and nonfasted hamsters, respectively. The hyperinsulinemia and antral ulcers in the animals were significantly attenuated by a pretreatment (80 mg/kg, i.v., in rats, 60 mg/kg, i.p., in hamsters) of streptozotocin. Furthermore, the antral ulcers were dose-dependently attenuated by prazosin, an adrenergic alpha-1 antagonist, and yohimbine, an adrenergic alpha-2 antagonist, but not by propranolol, an adrenergic beta antagonist. The large doses of atropine (3.2-10 mg/kg, p.o.) also attenuated the ulcers. The histamine H2 receptor antagonist, famotidine (1-10 mg/kg, p.o.), significantly attenuated the antral ulcers in nonfasted hamsters, but not in refed rats. The latter two drugs exhibited greater inhibition of the corpus erosions in fasted rats compared with the antral ulcers in refed rats and nonfasted hamsters. The corpus erosions were more extensive after streptozotocin treatment (80 mg/kg, i.v.) and were aggravated significantly by yohimbine, whereas they were hardly affected by prazosin or propranolol. It is thus concluded that hyperinsulinemia and adrenergic activation are commonly involved in the etiology of the IND-induced antral ulcers in refed rats and nonfasted hamsters. Vagal activity, which plays a crucial role in the etiology of the corpus erosions in fasted rats, may play a part in the antral ulcer formation in nonfasted hamsters, but not in refed rats.
Animals↗
Involvement of dopamine in the mechanism of action of FR64822, a novel non-opioid antinociceptive compound.
A novel compound, FR64822(N-(4-pyridylcarbamoyl)amino 1,2,3,6,-tetrahydropyridine), displays antinociceptive activities in a variety of assays with mice and rats. It has a strong antinociceptive activity in the acetic acid writhing test (ED50 = 1.8 mg/kg p.o.), whereas it has little antinociceptive activity in the tail flick test. The antinociceptive profile is similar to that of nefopam but different from that of anti-inflammatory agents. The involvement of monoamines in the mechanism of action of FR64822 was investigated. Pretreatment with reserpine (2 mg/kg) significantly reduced the antinociceptive activity of FR64822, when tested against acetic acid writhing. A similar reduction of activity was found in mice pretreated with sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, but not with Sch23390 (0.25 mg/kg), a dopamine D1 receptor antagonist. Pretreatment with p-chlorophenylalanine, yohimbine and naloxone hardly affected the antinociceptive activity of FR64822. These results were compared with those for nefopam and clonidine. It is suggested that FR64822 induces antinociceptive activity through a novel mechanism of action, indirect stimulation of dopamine D2 receptors, which differs from that of nefopam in that no specific neurotransmission could be determined in nefopam analgesia.
Acetates↗
Differential effects of physostigmine and pilocarpine on the spatial memory deficits produced by two septo-hippocampal deafferentations in rats.
Rats that had received two kinds of septo-hippocampal deafferentations, medial septum (MS) lesion and fimbria-fornix (FF) transection, were assayed for brain cholineacetyltransferase (ChAT) activity and spatial memory in an 8-arm radial maze task. Both lesions produced profound and long-lasting spatial memory impairments, which were characterized by a reduction in the numbers of correct arm choices and first correct choices, a reduction in the percent of correct choices and an increase in the number of errors. The degree of memory impairment was severer in FF- than in MS-lesioned rats, and paralleled that of decreases in ChAT activity in the hippocampus. MS lesion reduced ChAT activity in the hippocampus by approximately 45%, while FF lesion almost completely depleted the activity. An intraperitoneal injection of physostigmine (0.0032-0.32 mg/kg), an acetylcholinesterase (AChE) inhibitor, significantly ameliorated the spatial memory deficit induced by MS lesion, but hardly affected that by FF lesion. In contrast, intraperitoneal doses (0.032-3.2 mg/kg) of pilocarpine, a muscarinic agonist, showed a significant improvement of both types of memory deficit with bell shaped dose-response curves. The drug was more potent in the FF- than in the MS-lesioned rats. These results suggest that the septo-hippocampal cholinergic system plays a crucial role in the maintenance of spatial memory, and that the degree of septo-hippocampal deafferentation affects the efficacy of cholinergic drugs.
Animals↗
Endothelin-1 and endothelin-3 play different roles in acute and chronic alterations of blood pressure in patients with chronic hemodialysis.
We measured plasma concentrations of endothelin-1 (ET-1), ET-3 and big ET-1 by sandwich-enzyme immunoassays in patients (Pt) with chronic hemodialysis (HD) (Pt-HD, n = 23) and age-matched normal subjects (NS, n = 17). In Pt-HD, plasma levels (before HD) of ET-1, ET-3 and big ET-1 were significantly higher than those in NS. Reverse-phase HPLC analysis indicated that plasma concentrations of ET-1, ET-3 and big ET-1 in both Pt-HD and NS can be precisely measured by these sandwich-enzyme immunoassays. In Pt-HD, although the plasma ET-3 or big ET-1 levels did not significantly correlate with blood pressure (BP), plasma ET-1 levels significantly (p less than 0.01) correlated with both the levels of systolic (r = 0.63) and diastolic (r = 0.54) BP. After 4-hour HD, the plasma level of ET-3, but not ET-1 or big ET-1, was significantly elevated and BP was significantly lowered. The present findings indicate that ET-1 and ET-3 play different roles in acute and chronic alterations of BP in Pt-HD.
Antibodies, Monoclonal↗
[Physiopathology and diagnosis of bradycardia].
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Aged↗
Functional recovery of hibernating myocardium after coronary bypass surgery: does it coincide with improvement in perfusion?
To determine the relationship between functional recovery and improvement in perfusion after coronary artery bypass graft surgery (CABG), 49 patients were studied. Radionuclide angiography was performed before, 1 month after, and 6 to 12 months after CABG to evaluate regional wall motion. Exercise thallium-201 myocardial perfusion imaging was done before and 1 month after CABG to assess regional perfusion. Preoperative asynergy was observed in 108 segments, and 74 of them showed an improvement in wall motion 1 month after CABG (segment A). Sixty-six of these segments (89%) were associated with an improvement in perfusion. Eight segments that had not improved 1 month after CABG demonstrated a delayed recovery of wall motion 6 to 12 months after CABG (segment B). However, seven of eight segments (88%) already showed an improvement in perfusion 1 month after CABG. A total of 82 segments exhibited functional recovery after CABG and were considered hibernating segments. In the preoperative study segment B more frequently had areas of akinesis or dyskinesis than segment A (75% vs 34%, p less than 0.05). The mean percent thallium-201 uptake in segment B was lower than that in segment A (74% +/- 9% vs 83% +/- 8%, p less than 0.05). Functional recovery of hibernating myocardium usually coincided with an improvement in perfusion. However, delayed functional recovery after reperfusion was observed in some instances. Severe asynergy and severe thallium-201 defects were more frequently observed in these segments with delayed recovery. Hibernating myocardium might remain stunned during those recovery periods.
Coronary Artery Bypass↗
Blasticidin S-resistance gene (bsr): a novel selectable marker for mammalian cells.
Blasticidin S is a microbial antibiotic that inhibits protein synthesis in both prokaryotes and eukaryotes. The blasticidin S-resistance gene (bsr), isolated from Bacillus cereus K55-S1 strain, was inserted into pSV2 plasmid vector and introduced into cultured mammalian cells by transfection. The bsr gene was integrated into the genome and conferred blasticidin S resistance on HeLa cells. The transfection frequency of the bsr gene was as high as that of the aminoglycoside phosphotransferase gene, the so-called neo gene, which is a representative selectable marker for mammalian cells. Transfectants in which several copies of bsr had been integrated into the genome were highly resistant to blasticidin S. Furthermore, blasticidin S killed the cells more rapidly than G418, which is conventionally used as a selective drug for the neo gene. Thus bsr is concluded to be useful as a drug-resistance marker for mammalian cells.
Anti-Bacterial Agents↗
Role of inflammatory responses in initiation of atherosclerosis: effects of anti-inflammatory drugs on cuff-induced leukocyte accumulation and intimal thickening of rabbit carotid artery.
Immediately after a cuff-sheathing of rabbit carotid artery, a large number of leukocytes adhered to injured endothelium then infiltrated into the media. These inflammatory responses were followed by an atherosclerotic change, intimal thickening, of the artery. A simultaneous injection of dexamethasone (10 mg/kg i.m.) inhibited the leukocyte accumulation by 74% when evaluated 18 h thereafter. Similarly, 39% inhibition was obtained with the same dose of FR110302, a potent 5-lipoxygenase inhibitor. On the other hand, the same dose of indomethacin, a cyclooxygenase inhibitor, had little effect on the leukocyte accumulation. The intimal thickening which was evaluated 3 weeks after the cuff-treatment was attenuated by a daily dose (10 mg/kg i.m.) of dexamethasone or FR110302 but not by one of indomethacin. The inhibition by the two former drugs were 91 and 58%, respectively. In vitro, the three drugs in concentrations up to 10 microM hardly affected endothelial adhesion of PMN which was induced by LPS or IL-1. Though 10 microM of FR110302 and indomethacin significantly decreased PMN chemotaxis induced by LTB4, the decreases were less than that at 10 microM dexamethasone. These results confirm a possible linkage between inflammation and atherosclerosis, and suggest that 5-lipoxygenase products contribute to the initiation and development of atherosclerosis.
Animals↗
Characterization of a novel aldose reductase inhibitor, FR74366, and its effects on diabetic cataract and neuropathy in the rat.
FR74366 (FK366) ([3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-1-yl] acetic acid) is a chemically novel aldose reductase (AR) inhibitor. It exhibited a highly potent, reversible, and mixed type inhibition of partially purified AR from the rat sciatic nerve (IC50 = 3.6 nmol/L) and rat lens (IC50 = 4.4 nmol/L). FR74366 inhibited sorbitol accumulation in the isolated human erythrocyte (IC50 = 1.6 mumol/L), rat lens (IC50 = 39 mumol/L), and rat sciatic nerve (IC50 = 17 mumol/L) incubated with high glucose concentrations. The oral administration of FR74366 to streptozotocin (STZ)-induced diabetic rats for 2 weeks decreased sorbitol levels (ED50 = 3.7 mg/kg for sciatic nerve, 23 mg/kg for lens, 52 mg/kg for retina, and 62 mg/kg for renal cortex). Administration of FR74366 to diabetic rats for 17 weeks delayed cataract formation and admixture of 0.028% FR74366 in the diet completely inhibited the cataract formation. Moreover, the recovery of reduced motor nerve conduction velocity by FR74366 in diabetic rats was demonstrated in prevention and reversal experiments. This recovery effect correlated well with reduction of accumulated sorbitol and fructose levels and normalization of decreased myoinositol levels. The duration and tissue specificity of inhibitory effects of FR74366 on sorbitol accumulation also correlated well with the levels of FR74366 in various tissues of diabetic rats. These data indicate that both decreases in tissue sorbitol levels and improvement of functional defects reflect FR74366 levels in tissue rather than plasma in diabetic rats. These results, taken together, suggest that FR74366, which is currently undergoing clinical trials in Japan and the United States, will be a useful therapeutic agent for diabetic complications.
Aldehyde Reductase↗
Plasma concentrations of endothelin-1 and endothelin-3 are altered differently in various pathophysiological conditions in humans.
Several studies have indicated that endothelin-1 (ET-1) and endothelin-3 (ET-3) are produced by different cells. Although ET-1 is produced by vascular endothelial cells, these cells do not produce ET-3. In the present study, we measured plasma concentrations of both ET-1 and ET-3 by sandwich-enzyme immunoassays which we developed recently in patients on chronic hemodialysis, age-matched normal subjects, patients with acute myocardial infarction, patients undergoing surgery, and healthy subjects before and after strenuous endurance exercise. Plasma levels of ET-1 and ET-3 were demonstrated to be altered differently in the above conditions in humans. Although the exact origin of circulating endothelins has yet to be elucidated, the different alterations of plasma levels suggest that both ET-1 and ET-3 may play different roles in physiological and/or pathophysiological responses to various conditions in humans.
Adult↗
A novel orally active dopamine (DA) prodrug TA-870. IV. Renal vasodilatory and negative chronotropic effects in anesthetized dogs: influence of DA1 and DA2 dopamine receptor selective antagonists.
We investigated the involvement of the activations of dopamine (DA) receptors DA1 and DA2 in the effects of a novel DA prodrug TA-870 in anesthetized dogs and compared the effects with those of DA. Intravenous (i.v.) administration of TA-870 in anesthetized dogs produced a dose-dependent increase in free DA in blood and caused a decrease in renal vascular resistance (RVR) and an increase in renal blood flow (RBF). It also produced a bradycardia at high doses. In phenoxybenzamine-treated anesthetized dogs, the renal vasodilatory action of intrarenally administered TA-870 was less than or equal to that of i.v. TA-870, whereas that of intrarenally administered DA was greater than that of i.v. DA. The renal vasodilatory effects of TA-870 and DA were almost completely inhibited by the DA1 selective antagonist SCH-23390 but were not affected by the DA2 selective antagonist domperidone. In bilaterally vagotomized dogs, both TA-870 and DA at high doses partially reduced the positive chronotropic responses to the right postganglionic cardioaccelerator nerve stimulation; this effect was abolished after treatment with domperidone. In isolated guinea pig right atria, unchanged TA-870 and deethoxycarbonyl metabolite of TA-870, the intermediate from TA-870 to DA, did not affect the spontaneous atrial rate even at high concentrations, whereas DA produced a concentration-dependent increase in the rate. In addition, neither compound showed antagonistic action to the positive chronotropic effect of DA, which was competitively inhibited by propranolol. We conclude that the renal vasodilatory effect of TA-870 results simply from the activation of DA1 receptors by DA.(ABSTRACT TRUNCATED AT 250 WORDS)
Anesthesia↗
A novel, orally active dopamine prodrug TA-870. V. Natriuretic and positive inotropic effects in rats: an assessment after chronic administration.
We investigated the acute natriuretic and positive inotropic effects of the dopamine prodrug TA-870 in rats before and after repeated administration for 2 weeks. Single intraduodenal (i.d.) administration of TA-870 (10-250 mg/kg) to saline-loaded anesthetized rats produced a dose-dependent increase in urinary flow and sodium excretion. It also produced a decrease in renal vascular resistance and an increase in renal blood flow. In another series of normal anesthetized rats, TA-870 caused dose-dependent increases in cardiac contractility [left ventricular dP/dtmax (LV dP/dtmax)] at i.d. doses of 10-250 mg/kg. Although the heart rate was also increased, this effect was much smaller than the effect on LV dP/dtmax. SCH-23390 (0.3 mg/kg i.v.), a selective DA1 dopamine receptor antagonist, strongly inhibited the above diuretic, natriuretic, and renal vasodilatory effects of TA-870. The positive inotropic effect of TA-870 was not inhibited by SCH-23390, but the latter effect was inhibited by pretreatment with propranolol (0.5 mg/kg i.v.). After repeated oral administration of TA-870 to rats (250 mg/kg twice a day for greater than 2 weeks), there was no significant differences in the natriuretic and positive inotropic responses to TA-870 between the TA-870-pretreated and control groups indicating a lack of pharmacological tolerance. In conclusion, TA-870, when administered enterally to rats, produced the natriuretic effect via the DA1 dopamine receptor and positive inotropic effects via the beta 1 adrenergic receptor stimulation, and these effects were not attenuated by chronic treatment with TA-870.
Animals↗
Comparison of cardiorenal and emetic effects of dopamine prodrugs docarpamine (TA-870) and levodopa in dogs.
Positive inotropic and renal vasodilatory effects of a novel dopamine prodrug, docarpamine, [N-(N-acetyl-L-methionyl)-3,4-bis(ethoxycarbonyl)dopamine; TA-870] and those of levodopa were compared in anesthetized dogs, and emetic effects of the two drugs were compared in conscious dogs. Intraduodenal administrations of docarpamine and levodopa at 20 mg/kg produced similar increases in cardiac contractility. The maximal increases in the left ventricular dP/dtmax after docarpamine and levodopa were 36.6 +/- 14.2 and 39.2 +/- 12.1%, respectively. The two drugs also produced similar decreases in renal vascular resistance (21.2 +/- 2.2 and 13.6 +/- 3.4%, respectively) and increases in renal blood flow (27.9 +/- 3.2 and 17.9 +/- 5.2%, respectively), however, the duration of renal vasodilation after docarpamine was longer than that of levodopa. Oral administration of the two drugs in conscious dogs produced vomiting. The ED50 value of the emetic effect for docarpamine was greater than 160 mg/kg, and that for levodopa was 11.0 mg/kg. The emesis was inhibited by pretreatment with a DA2 antagonist, domperidone. In conclusion, docarpamine and levodopa produced similar cardiorenal effects, but the emetic effect of docarpamine was much weaker than that of levodopa. Docarpamine can be used as a selective dopamine prodrug for the peripheral circulation.
Animals↗