Passive maintenance of high angle of attack and its lift generation during flapping translation in crane fly wing.

We have studied the passive maintenance of high angle of attack and its lift generation during the crane fly's flapping translation using a dynamically scaled model. Since the wing and the surrounding fluid interact with each other, the dynamic similarity between the model flight and actual insect flight was measured using not only the non-dimensional numbers for the fluid (the Reynolds and Strouhal numbers) but also those for the fluid-structure interaction (the mass and Cauchy numbers). A difference was observed between the mass number of the model and that of the actual insect because of the limitation of available solid materials. However, the dynamic similarity during the flapping translation was not much affected by the mass number since the inertial force during the flapping translation is not dominant because of the small acceleration. In our model flight, a high angle of attack of the wing was maintained passively during the flapping translation and the wing generated sufficient lift force to support the insect weight. The mechanism of the maintenance is the equilibrium between the elastic reaction force resulting from the wing torsion and the fluid dynamic pressure. Our model wing rotated quickly at the stroke reversal in spite of the reduced inertial effect of the wing mass compared with that of the actual insect. This result could be explained by the added mass from the surrounding fluid. Our results suggest that the pitching motion can be passive in the crane fly's flapping flight.

5-Hydroxydecanoate inhibits ATP-sensitive K+ channel currents in guinea-pig single ventricular myocytes.

We investigated the effect of 5-hydroxydecanoate, a novel antiarrhythmic agent, on the electrical activity of guinea-pig ventricular myocytes. The outward K+ current increased by lowering the intracellular ATP concentration (0.5 mM) was efficiently blocked by 5-hydroxydecanoate when recording in the whole cell configuration with the application of voltage ramps. The increase in the time-independent outward K+ current induced by reducing intracellular ATP to 0 mM was also blocked by 5-hydroxydecanoate (10 or 100 microM) and by tolbutamide (1 mM). Using the single channel recording technique, we found that 5-hydroxydecanoate blocked ATP-sensitive K+ channels when its channel open probability was increased by 1 mM ATP together with 1 mM ADP or by an intracellular pH of 6.6. These conditions are well documented to reflect metabolic changes in the early stages of myocardial ischemic attack. These results suggest that 5-hydroxydecanoate could inhibit ATP-sensitive K+ channels, resulting in an antiarrhythmic effect specifically on ischemic hearts.

An experimental and three-dimensional computational study on the aerodynamic contribution to the passive pitching motion of flapping wings in hovering flies.

The relative importance of the wing's inertial and aerodynamic forces is the key to revealing how the kinematical characteristics of the passive pitching motion of insect flapping wings are generated, which is still unclear irrespective of its importance in the design of insect-like micro air vehicles. Therefore, we investigate three species of flies in order to reveal this, using a novel fluid-structure interaction analysis that consists of a dynamically scaled experiment and a three-dimensional finite element analysis. In the experiment, the dynamic similarity between the lumped torsional flexibility model as a first approximation of the dipteran wing and the actual insect is measured by the Reynolds number Re, the Strouhal number St, the mass ratio M, and the Cauchy number Ch. In the computation, the three-dimension is important in order to simulate the stable leading edge vortex and lift force in the present Re regime over 254. The drawback of the present experiment is the difficulty in satisfying the condition of M due to the limitation of available solid materials. The novelty of the present analysis is to complement this drawback using the computation. We analyze the following two cases: (a) The equilibrium between the wing's elastic and fluid forces is dynamically similar to that of the actual insect, while the wing's inertial force can be ignored. (b) All forces are dynamically similar to those of the actual insect. From the comparison between the results of cases (a) and (b), we evaluate the contributions of the equilibrium between the aerodynamic and the wing's elastic forces and the wing's inertial force to the passive pitching motion as 80-90% and 10-20%, respectively. It follows from these results that the dipteran passive pitching motion will be based on the equilibrium between the wing's elastic and aerodynamic forces, while it will be enhanced by the wing's inertial force.

Effects of 2-[(5-chloro-2-methoxyphenyl) azo]-1H-imidazole (M6434) on alpha adrenergic receptors.

The effects of a newly synthesized compound, 2-[(5-chloro-2-methoxyphenyl)azo]-1H-imidazole (M6434) on alpha-adrenergic receptors were investigated by using the atria of normal and hypothyroid rats, rat vasa deferentia and canine arteries. M6434 showed a positive inotropic effect on rat left atria, which was suppressed by phentolamine but not by propranolol and reserpine. M6434 also showed a positive chronotropic effect on rat right atria. These positive inotropic and chronotropic effects of M6434 were enhanced in propylthiouracil-induced hypothyroid rats. M6434 caused contraction of rat vas deferens and increased its spontaneous movement. These effects on vas deferens were suppressed by phentolamine. M6434 induced contraction of canine arteries. The pD2 values for vasoconstrictive effects of M6434 on the aorta, pulmonary artery, renal artery and femoral artery were about equal to those of phenylephrine, and the intrinsic activity of M6434 was somewhat lower than that of phenylephrine. These results suggest that M6434 is an adrenergic alpha-agonist which is about as potent as phenylephrine and that M6434 has neither a beta-stimulating activity nor a catecholamine-releasing one.

[Effects of urinastatin on an energy metabolism disorder during shock].

We investigated the effect of urinastatin on energy metabolism disorder during shock. Intravenous administration of urinastatin at the dose of 50,000 U/kg ameliorated the decrease in total adenine nucleotide (TA) levels and in energy charge (EC) of liver and pancreas during traumatic-shock induced by the Noble-Collip drum method in rats. Urinastatin, at a concentration of 3,000 U/ml, suppressed the decrease in EC of rat liver slices exposed to the medium including 10% serum obtained from traumatic-shock rats. Aprotinin showed a similar effect. Depression in respiratory activity of liver mitochondria exposed to the shock rat serum was also ameliorated by 1,000 U/ml of urinastatin, but aprotinin failed to reverse this depression. In the isolated rat livers perfused with normal rat serum, urinastatin at the concentration of 3,000 U/ml did not affect ATP and TA levels and EC. These results suggest that, unlike aprotinin, urinastatin ameliorates the depression of energy metabolism in liver during shock without affecting normal energy metabolism, probably by antagonizing the actions of depressant factors released into blood during the shock state and by protecting against the decrease in the adenine nucleotide pool.

Effects of protizinic acid on leukokinin generation and its physiological action.

The effect of protizinic acid (PRT), a non-steroidal antiinflammatory drug, on the in vivo leukokinin (LK) generation system using feline acute ischemia model, in vitro LK generation system and the LK-induced contraction of the isolated smooth muscle was investigated. When 3 mg/kg PRT was injected twice intravenously to cats with acute cardiac ischemia, increased blood acid protease activity was inhibited and significant inhibitory action on the decrease of leukokininogen, the precursor of LK, was observed. Simultaneously, ST-segment elevation on the electrocardiogram tended to be suppressed and the lowered mean aortic blood pressure was significantly restored. On the LK generation induced by rabbit kininogen and acid protease derived from mouse L-1210 leukemic cells or rabbit polymorphonuclear leukocytes, PRT showed a dose-dependent inhibition while indomethacin (IM) and ibuprofen (IB) at a concentration of 3 X 10(-4) M showed no effect. However, potencies of the inhibitory actions of PRT, IM and IB on the LK generation induced by bovine spleen cathepsin D were almost the same at a concentration of 3 X 10(-4) M. Furthermore, PRT as well as IM showed antagonistic action on the isolated rat uterine contraction induced by LK. These results suggest that PRT not only inhibits the in vitro and in vivo generation of LK but also antagonizes to it on the receptor site of LK.

[General pharmacological studies on human natural tumor necrosis factor (MHR-24)].

The general pharmacological properties of MHR-24 were studied in various experimental animals. Intravenously (i.v.)-administered MHR-24 at 8.6 x 10(2) JRU/kg or more produced fever in rabbits. MHR-24 at 3 x 10(4) JRU/kg or more caused tachycardia; and at 1 x 10(5) JRU/kg or more, it lowered arterial blood pressure in anesthetized monkeys. In rats, MHR-24 at 2.9 x 10(4) JRU/kg or more showed a diuretic action and inhibitory effects on gastric juice secretion and carrageenin-induced paw edema. Furthermore, MHR-24 at a large dose (8.6 x 10(4) or 2.9 x 10(5) JRU/kg, i.v.) decreased spontaneous locomotor activity, had an inhibitory effect on acetic acid-induced writhing and potentiated intestinal propulsion in mice; and it caused the appearance of rest wave on acute spontaneous electroencephalograms in rabbits. Pretreatment of the animals with the cyclooxygenase inhibitor indomethacin abolished the fever and potentiation of intestinal propulsion caused by MHR-24. Therefore, these data seem to indicate that some of the effects of MHR-24 are mediated via cyclooxygenase pathways. The results suggested that, except for the above results, MHR-24 has no noticeable effects on the central nervous, autonomic nervous, respiratory and cardiovascular systems and others in general pharmacological studies.

[Pharmacological properties of MO-8282, a novel antidepressant].

The pharmacological properties of MO-8282 (1,2,3,4-tetrahydro-2-methyl-9H-dibenzo [3,4: 6,7]cyclohepta [1,2-c]pyridine maleate) as an antidepressant were investigated. At doses 10 times less than those of amitriptyline, MO-8282 showed similar potencies in reducing the duration of immobility during forced swimming in rats and in potentiating stereotype induced by L-DOPA. Intermediate doses of MO-8282 reduced the duration of immobility during forced swimming, in mice as well, suppressed muricide behavior of olfactory-bulbectomized rats and antagonized clonidine-induced suppression of exploratory activity in mice. MO-8282 moderately antagonized the ptosis but not the hypothermia induced by reserpine in mice. MO-8282 exhibited weak antagonism against the tremor, lacrimation and diarrhea induced by tremorine, but its activity was milder than that of amitriptyline. The uptake of noradrenaline into rat hypothalamic synaptosomes was inhibited by MO-8282 at concentrations 20 times less than equally effective doses of amitriptyline, but the uptake of dopamine or serotonin was unaffected by MO-8282. A single oral administration of MO-8282 at a dose of 30 mg/kg accelerated noradrenaline turnover, but did not affect dopamine and serotonin turnover in the rat brain. MO-8282 strongly inhibited noradrenaline-, histamine- or adenosine-sensitive adenylate cyclase activity of guinea pig brain. Its mode of action differed from that of imipramine, rather resembling that of mianserin. MO-8282 did not affect monoamine oxidase activity of rat liver. These results suggest that the pharmacological characteristics of MO-8282 are different from those of tricyclic antidepressants and rather similar to those of mianserin, but more potent. The results, therefore, indicate that MO-8282 is possibly a novel antidepressant.

Possible antiarrhythmic activities of trapidil.

Possible antiarrhythmic activities of 5-methyl-7-diethylamino-s-triazolo(1,5-a)pyrimidine (trapidil, Rocornal) were investigated in vitro and in vivo. Trapidil significantly increased the amount of aconitine or ouabain needed for production of ventricular arrhythmias in rats and guinea pigs. Trapidil also produced a significant increase in threshold current of electrical stimuli which induced ventricular tachycardia in dogs under acute myocardial ischemia. Electrophysiological examinations on effects of trapidil on isolated rabbit ventricular muscle cells showed shortening of the action potential duration (APD) and prolongation of the effective refractory period (ERP), resulting in an increase in the ratio of ERP/APD. The results indicate that trapidil will have a possible effectiveness in inhibiting ventricular arrhythmias.

[Experimental study of the effects of bromelain on the sputum consistency in rabbits].

Effects of bromelain (BR) on rabbit sputum consistency were investigated in vitro and in vivo. On the sputum showing relatively low viscosity, BR and other enzymes such as serratiopeptidase (SP), the mixed preparation of pronase and pancreatin, and lysozyme exerted lowering effects; and the effect of BR was the most potent. However, bromhexine had virtually no effect. On the sputum showing relatively high viscosity, BR exerted more potent lowering effects on the viscosity and yield value of sputum than those of SP. Furthermore, 320,000 U/head BR and 120,000 U/head SP lowered the viscosity significantly and yield value of sputum in rabbits with oral administration for 3 days. The lowering effect on the yield value of BR was more potent than that of SP. BR also increased the sputum volume in rabbits. BR and SP showed tendencies to decrease the contents of acid glycoprotein and sialic acid in sputum. It can be considered that these results support the effectiveness of BR as an expectorant in clinical use.

Protective effects of urinary trypsin inhibitor in experimental shock.

The effects of human urinary trypsin inhibitor (UTI) were studied in experimental shock models. Administration of 50,000 U/kg, i.v., of UTI protected against mortality from shock induced by burn, endotoxin or trauma. Aprotinin at a dose of 50,000 U/kg improved only endotoxin shock and showed a moderate but not significant effect on burn and traumatic shock. Administration of 50,000 U/kg, i.v., of UTI protected against the aggravation in systemic hemodynamics in canine hemorrhagic shock. Furthermore, in rat traumatic shock, 50,000 U/kg, i.v., administration of UTI significantly reversed the increased serum beta-glucuronidase and trypsin activities and the decreased hepatic ATP level, and it moderately suppressed the increased serum uric acid level. Aprotinin failed to affect all these biochemical changes induced by drum trauma. These results suggest that the protective effect of UTI against experimental shock is possibly exerted through lowering the elevated enzyme activities in the serum during shock.

Reduction of myocardial infarct size by trapidil in anesthetized dogs.

We studied the effect of trapidil on acute experimental myocardial infarction in anesthetized, openchest dogs. The size of myocardial infarction 8 h after ligation of the left anterior descending coronary artery was determined by planimetry of myocardial slices stained by the nitroblue tetrazolium method. Systemic hemodynamic variables, epicardial ST-segment elevation, activity of serum creatine phosphokinase (CPK), and changes of myocardial blood flow in the ischemic area were measured. Infusion of 3 mg/kg trapidil reduced the size of infarction and ameliorated the infarction-induced deterioration of systemic hemodynamic variables, such as the decrease in left ventricular dP/dt, aortic blood flow, and regional endomyocardial blood flow in the ischemic area. This dose of trapidil also suppressed ST elevation and significantly inhibited the increase in activity of serum CPK. Hyaluronidase also reduced the size of infarction significantly. These results suggest that trapidil alters the course of acute myocardial infarction favorably, presumably by increasing regional endomyocardial blood flow.

Tofisopam, a new 2,3-benzodiazepine. Inhibition of changes induced by stress loading and hypothalamic stimulation.

Effects of tofisopam, a new 2,3-benzodiazepine compound, were investigated on the following: gastric ulceration, induced by water-immersion stress in normal rats and by immobilization stress in olfactory-bulbectomized (OB) rats; and propulsion of the small intestine caused by water-immersion stress in rats and autonomic responses to electrical stimulation of the hypothalamus in rabbits. In the latter, the results were compared with those of diazepam and gamma-oryzanol. Tofisopam (30 and 100 mg/kg, po) significantly inhibited the gastric ulceration induced by water-immersion stress in normal rats in a dose-dependent manner. Immobilization-stress loading increased the incidence and average index of gastric ulceration in OB rats, compared with nonstressed rats. Tofisopam (100 mg/kg, po) significantly inhibited the gastric ulceration induced by stress loading in OB rats. Water-immersion stress loading induced a significant increase in intestinal propulsion in rats. This increase was reversed to control levels by tofisopam (100 mg/kg, po). Tofisopam (1.0 mg/kg, iv, or 0.1 mg/kg by intracerebrospinal injection) inhibited the constriction of ear microvessels, the decrease in earlobe temperature, and mydriasis induced by electrical stimulation of the medial hypothalamic area in rabbits. However, diazepam and gamma-oryzanol failed to inhibit the autonomic responses to medial hypothalamic stimulation. From these results, it can be concluded that tofisopam restores the autonomic abnormality induced by stress loading possibly via intervention in the central autonomic area, i.e., the hypothalamus, by an action different from that of diazepam.

[Effects of tofisopam on the physiological changes induced by stress loading and hypothalamic stimulation (author's transl)].

Effects of tofisopam on the gastric ulceration induced by immobilization stress in olfactory-bulbectomized rats, propulsion of the small intestine caused by water immersion-stress in rats and autonomic responses to electrical stimulation of the hypothalamus in rabbits were investigated. Immobilization stress loading of 16.5 hours each for 10 days caused the augmentation of incidence and average index of gastric ulceration in olfactory-bulbectomized rats, compared with non-treated rats. Tofisopam 100 mg/kg, p.o. significantly inhibited the gastric ulceration in olfactory-bulbectomized rats. Water immersion-stress loading for 2 hours caused a significant increase in propulsion of the small intestine in rats. This increase was reversed to control levels after the oral administration of tofisopam in a dose of 100 mg/kg. Tofisopam at dose of 1 mg/kg i.v. inhibited the contraction of ear microvessels, the decrease in earlobe temperature and the mydriasis induced by electrical stimulation of the medial hypothalamic area in rabbits, Moreover, these inhibitions were also shown by the intra-cerebrospinal injection of tofisopam at a dose of 0.1 mg/kg. From these results, it is concluded that tofisopam could restore the autonomic abnormality induced by stress-loading and exerts such effects by acting on the hypothalamus, an area of the brain, which regulates autonomic nervous functions.

Effect of antianginal agents on arteriolar diameter in normal and cholesterol-fed rabbits.

The effect of antianginal agents on the cutaneous arteriolar diameter in normal and cholesterol-fed rabbits was investigated. The change in the potency of trapidil to dilate arterioles in cholesterol-fed rabbits was relatively minor when compared with normal rabbits. On the other hand, the potencies of other agents decreased markedly in cholesterol-fed rabbits as compared with normal rabbits. For example, in arterioles of 45-50 micron in diameter, the effective doses of tapidil and dilazep at which the agents dilated the vessel by 20% (ED20) were 1.0 and 0.07 mg/kg i.v., respectively, in normal rabbits, and 2.3 and 2.0 mg/kg i.v., respectively, in cholesterol-fed rabbits. The other agents, such as dipyridamole, diltiazem and nifedipine, virtually did not show any dilating effects on arterioles of cholesterol-fed rabbits at the doses which were effective in normal rabbits. The maximum changes in systemic blood pressure and carotid blood flow induced by the administration of trapidil, dilazep or dipyridamole did not decrease in cholesterol-fed rabbits as compared with normal rabbits. These results suggest that it is more desirable to evaluate the therapeutic potency of antianginal agents in cholesterol-fed rabbits than in normal rabbits, and that the action of antianginal agents on arterioles is not dependent on its action on systemic hemodynamics.

[Effects of 5-methyl-7-diethylamino-s-triazolo-(1, 5-a) pyrimidine (trapidil) on various experimental hyperlipemias (author's transl)].

Effects of 5-methyl-7-diethylamino-s-triazolo-1, 5-a) pyrimidine (trapidil, Rocornal), a therapeutic agent for ischemic heart disease, on various types of experimental hyperlipemias were studied. With administration of trapidil, elevation of serum high density lipoprotein cholesterol (HDL-C) levels and reduction in serum total cholesterol (TC), low density lipoprotein and very low density lipoprotein cholesterol (LDL-C) and the ratio of HDL-C to LDL-C (LDL-C/HDL-c) were observed in most disease models. Changes in HDL-C levels and LDL-C/HDL-C in the hyperlipemia induced by lipid-enriched diet in mice and in the hyperlipemia induced by high cholesterol diet in Japanese quails were of statistical significance. Also, amelioration of reduction in HDL-C induced by high fat emulsion plus 6-n-propyl-2-thiouracil in rats was observed to be significant. Moreover, trapidil significantly reduced TC, LDL-C levels and LDL-C/HDL-C in the hyperlipemia in hamsters. To investigate possible mechanisms of therapeutic effects of trapidil, blood enzyme activities in Japanese quails with hyperlipemia were assayed. Trapidil showed increases in plasma lipoprotein lipase and serum lecithin-cholesterol acyltransferase activities. These results suggest that trapidil may be an effective chemotherapeutic agent for treating ischemic heart disease.

[Study of mechanism and effect of sodium 5-hydroxydecanoate on experimental ischemic ventricular arrhythmia].

We investigated the effects of sodium 5-hydroxydecanoate (5-HD) on experimentally induced ischemic arrhythmia and its mechanisms of action by biochemical and electrophysiological techniques. 5-HD, at the single dose of 200 mg/kg (p.o.) or at the one week multiple doses of 3 to 100 mg/kg (p.o.), suppressed the incidence of ventricular fibrillation induced by coronary ligation in rats. 5-HD at the dose of 3 or 10 mg/kg (i.v.) elevated the ischemically decreased ventricular fibrillation threshold in the coronary ligated dogs. In isolated rat heart, 5-HD suppressed the K+ release from ischemic myocardium at the doses of 10(-5) to 10(-3) M. 5-HD at the dose of 10(-4) M decreased the open state probability of ATP regulated K+ channel in isolated myocardial cell of guinea pig. Contents of high-energy-phosphate compounds were markedly decreased in ischemic myocardium of rats, and they were not affected by 5-HD. These results demonstrate the efficacy of 5-HD against experimental ischemic ventricular arrhythmia. Its antiarrhythmic action may be attributed, at least in part, to the suppression of K+ release from ischemic myocardium by possibly inhibiting the ATP regulated K+ channel.