Biomedical subjects
Publications and source records attributed to K Kogi.
A synthesis of a novel and chemically stable homoisocarbacyclin analog, TY-11223 (3), has been accomplished. The analog (3), given intravenously or orally, showed potent and long-lasting activities in inhibiting platelet aggregation and, in addition, a good selectivity in biological activities.
We examined the affinity for adenosine receptors and the antihypertensive effects of 2-alkynyladenosines, especially 2-hexynyladenosine (2-H-Ado) and 2-octynyladenosine (2-O-Ado). The order of decreasing affinity of 2-H-Ado, 2-O-Ado, and other agonists tested for A1 receptors was N6-cyclopentyladenosine (CPA) greater than N6-cyclohexyladenosine (CHA) greater than N6-R-phenylisopropyladenosine (R-PIA) greater than 2-chloroadenosine (CADO) = 5'-N-ethylcarboxamideadenosine (NECA) greater than N6-S-phenylisopropyladenosine (S-PIA) greater than 2-H-Ado greater than 2-O-Ado greater than 2-phenylaminoadenosine (CV-1808), and that for A2 receptors was 2-H-Ado greater than 2-O-Ado = NECA greater than CADO greater than CV-1808 greater than R-PIA greater than CPA greater than CHA greater than S-PIA. The Ki values of 2-H-Ado and 2-O-Ado for [3H] NECA binding to A2 receptors were 4.1 and 12.1 nM, respectively, and those for [3H]CHA binding to A1 receptors were 146 and 211 nM, respectively: the affinity of 2-H-Ado and 2-O-Ado for A2 receptors was about 36- and 17-fold higher than their affinity for A1 receptors. Injection of 2-H-Ado and 2-O-Ado (0.03-100 micrograms/kg) decreased the blood pressure of anaesthetized spontaneously hypertensive rats (SHR). A slight decrease in heart rate was observed after i.v. injection of 100 micrograms/kg 2-H-Ado and 2-O-Ado. A potent and long-lasting antihypertensive effect was also observed after oral administration of 2-H-Ado and 2-O-Ado to conscious SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
We investigated the cardiovascular effects of 2-octynyladenosine (YT-146), an adenosine A2 agonist, in various mammalian preparations in comparison with adenosine and 2-chloroadenosine. YT-146, when intravenously administered, caused a dose-dependent decrease of blood pressure in anesthetized normotensive rats (with ED30 values of 0.4 micrograms/kg), and YT-146 was 250 times more potent than adenosine. Whereas adenosine and 2-chloroadenosine decreased heart rate at approximately equihypotensive doses, YT-146 had no negative chronotropic effects at h hypotensive doses. Orally given YT-146 (0.1 - 1 mg/kg) produced a potent and long-lasting antihypertensive effect in spontaneously hypertensive rats. YT-146 was 15.9 and 12.5 times more potent than adenosine in producing relaxation of isolated porcine coronary arteries and in increasing dog coronary blood flow, respectively. Although YT-146 was equipotent to adenosine in causing a negative inotropic effect in isolated guinea pig atria, it was less potent than adenosine in producing atrioventricular conduction block in guinea pigs. On the other hand, 2-chloroadenosine was 9.1, 1.8 and 2.4 times more potent than adenosine in lowering blood pressure, relaxing isolated porcine coronary arteries and increasing dog coronary blood flow, respectively. 2-Chloroadenosine was the most potent in producing cardiodepression, i.e., negative inotropy and atrioventricular conduction block in guinea pigs. From these results, we concluded that YT-146 is a potent coronary vasodilator and also a potent, orally active and long-acting hypotensive agent having less cardiac depressant activity.
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Recent ILO experiences show that concrete ergonomics improvements can result from learning-by-doing training in real settings. Particularly important is to build on local practice focusing on good examples already available. Checklist exercise, demonstrating low-cost solutions and group work are effective training tools. Opportunities can be widely created by such enabling training.
This study was designed to determine the extent, to which isosorbide-5-mononitrate (5-ISMN) contributes to the hemodynamic effect of isosorbide dinitrate (ISDN) in conscious dogs. Test drugs (ISDN or 5-ISMN) were given orally. Either ISDN or 5-ISMN produced a decrease in blood pressure dose-dependently, the decrease in pulse pressure being specific; the pattern of blood pressure change induced by ISDN or 5-ISMN was different from that induced by nifedipine or prazosin. The effect of ISDN (2 mg/kg) was almost equivalent to that of 5-ISMN (4 mg/kg) and the effect of ISDN (4 mg/kg) to that of 5-ISMN (8 mg/kg). After administration of ISDN, both ISDN and 5-ISMN appeared in the plasma, and the effect of ISDN well-correlated with the increase in the plasma concentration of 5-ISMN. Contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% from the value of the plasma concentration of 5-ISMN at 3 to 4 hr after administration, when the maximal response to ISDN occurred. Based on the data of the area under the plasma concentration curve of 5-ISMN (from 0 to 10 hr after administration), the fraction of biotransformation to 5-ISMN from ISDN was calculated to be 73.6 to 76.6% (based on moles). Because the ability of 5-ISMN to decrease pulse pressure was about 1/2 (or 41% based on moles) of that of ISDN, the contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% in total, the value being similar with that estimated at 3 to 4 hr after administration.
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The mechanisms of the marked inhibitory effects of 10 ppm formaldehyde (HCHO) inhalation on heart rate and respiratory movement were investigated in unanesthetized rabbits. Inhibition of the heart rate and respiratory movement induced by HCHO inhalation was caused by a reflex reaction during sensory irritation of the upper respiratory tract, mainly the nasal mucosa, but not of the lower respiratory tract, mainly the lung. These reflex reactions, particularly decreases in the heart rate, were not blocked by vagotomy, atropine or prazosin, but were blocked by propranolol, phenoxybenzamine, phentolamine, yohimbine and guanethidine. These results suggest that these reflex reactions are derived from sympathetic nervous activity rather than parasympathetic nervous activity, and the reflex bradycardia is caused by inhibiting the transmitter release at the adrenergic nerve endings.
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Effects of isosorbide 5-mononitrate (5-ISMN) on cardiovascular function were compared with those of isosorbide dinitrate (ISDN), verapamil and propranolol. In anesthetized open-chest dogs, intravenous injection of 5-ISMN (1 mg/kg, 3 mg/kg) scarcely decreased cardiac contractile force (CCF) and heart rate (HR). The systolic blood pressure (SBP) fell in a dose-dependent manner, and the degree of the change was greater than that in diastolic blood pressure (DBP). Especially, left ventricular pressure (LVP) and left ventricular dp/dt (LVdp/dt) were significantly decreased, and a considerable reduction in left ventricular end-diastolic pressure (LVEDP) was also observed. Intravenous injection of verapamil (0.3 mg/kg) considerably lowered DBP. While HR, CCF, LVP and LVdp/dt were markedly decreased, LVEDP showed a moderate increase. Propranolol (0.5 mg/kg, i.v.) greatly decreased LVdp/dt together with HR and CCF. Conversely, LVEDP showed a slight increase. There was no change in SBP, DBP and LVP. The vasodilating potency of 5-ISMN was 150 times smaller than that of ISDN on the contractile response in isolated rabbit thoracic aorta. On the other hand, in terms of decrease in pulse pressure, the potency exhibited by 5-ISMN was about 4 times (intravenous administration in anesthetized dogs) or 1.5 times (oral administration in conscious dogs) smaller than that of ISDN. The present results suggest that 5-ISMN shows a high bioavailability and a potency comparable to ISDN, especially in the case of peroral administration. Taking these results together with the fact that transient left ventricular failure occurs during myocardial ischemia into consideration, it is thought that peroral 5-ISMN preparation may be useful in the therapy of angina pectoris.
Effects of isosorbide 5-mononitrate (5-ISMN) on cardiovascular function were compared with those of verapamil hydrochloride and propranolol hydrochloride in anesthetized open-chest dogs. Intravenous injection of 5-ISMN (3 mg/kg) considerably lowered systolic blood pressure (SBP). Especially, stroke volume (SV), cardiac output (CO), cardiac work (CW) and systolic right ventricular pressure (SRVP) were significantly decreased. 5-ISMN also produced a continuous reduction in mean pulmonary artery pressure (MPAP), mean pulmonary capillary wedge pressure (MPCWP) and mean right atrium pressure (MRAP), while heart rate (HR) and total peripheral resistance (TPR) were not altered significantly. Intravenous injection of verapamil (0.3 mg/kg) considerably lowered diastolic blood pressure (DBP). Verapamil also caused a significant decrease in HR, CW and TPR and a slight decrease in SRVP and MPCWP. However, SV was significantly increased, and slight increases in MPAP and MRAP were also observed. Propranolol (0.5 mg/kg, i.v.) greatly decreased HR together with CO, CW, SRVP and MPAP and slightly decreased MPCWP, while it caused a considerable increase in 3V and a slight increase in TPR. The finding that administration of 5-ISMN resulted in reduction of pre-load and after-load suggests the possibility that this drug might decrease venous return and thereby reduce myocardial oxygen requirements.
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Recent increase in industrialization has resulted in attention being drawn to diversity of working schedules and their interrelation with content of work. The results of joint research revealed that adaptation to industrial jobs is made difficult because of urban conditions and modern work-control systems, such as workers in flexible-working-time systems who apparently favored regular daily working cycles. Long overtime work in smaller undertakings and the spread of shift systems are two important features of industrial work schedules, each being dominant among skilled and non-skilled jobs. Another important facet is the problem of intra-shift work-rest schedules significant for machine operations and vigilance tasks. It is suggested that phases of work that become intolerable are correlated with unnatural work rhythms. More emphasis should thus be laid on both phase-shifted work and non-self-governing work, the key factor being the relevance of attained data to real work in the whole course of schedules of work and rest.
One-arm cranking was done by ten healthy male adults at an oxygen intake level of about 1.0 liter/min. Each subject performed two kinds of cranking at a speed of 60 rpm: forced cranking using only one arm continuously for 15 min and free cranking for 30 min with the instructions to alternate from one arm to the other whenever fatigue set in. The results, excluding those of a subject who changed arms very frequently, were analyzed. In forced cranking, oxygen intake and heart rate steadily increased, the average time of appearance of local fatigue being 161 sec for the stronger arm and 122 sec for the weaker one. In free cranking, the working arm was changed 6 to 23 times during the 30-minute period, while oxygen intake and heart rate increased with fluctuations. The mean duration interval was 175 sec with the stronger arm and 123 sec with the weaker one. The mean interval of arm alternation was positively correlated with the individual time of onset of the sensation of local rigidness during forced cranking, but not with the individual time of initiation of respiratory distress. It is suggested that alternation of active muscles in moderately dynamic work may be linked with an early stage of local fatigue which is different from that of static work.
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The incidence of drowsings as a cause of near traffic accidents was studied on the basis of daily recordings or near accidental events by 288 locomotive drivers during a rotation period of 2-3 weeks. Of 198 near accidents reported during 2,290 trips, 34 cases, or 1,5 cases per 100 trips, were operation missess involving drowsing or strong drowsiness. Improper operation due to drowsing occurred at a certain rate for any group of drivers, irrespective of the type of train, running sections, weather, and other operative conditions such as train delays, whereas 117 cases of danger caused by unforeseen obstacles on the track were related to site characteristics, and 47 cases of other disorders were frequent in unusual operative conditions such as arrival-departure, poor signal display, wrong instructions, or equipment failure. Thus continued driving under ordinary track conditions at a more or less constant speed was likely to induce drowsiness under the dominant influences of fatigue and time of the day; 79% of such cases occurred between midnight and 6 a.m. Most drowsings on the second night appeared during the first 2-4 hr of duty. Effects of monotony and insufficient rest were discussed in relation to recurrent fluctuation in vigilance.