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Biomedical subjects

Y Shiraki

Publications and source records attributed to Y Shiraki.

At least 37 records · Page 2Linked to original sources

Extracellular production of mouse interferon beta by the Bacillus subtilis alpha-amylase secretion vectors: antiviral activity and deduced NH2-terminal amino acid sequences of the secreted proteins.

Using two Bacillus subtilis alpha-amylase secretion vectors, mouse interferon-beta (IFN-beta) cDNA was expressed. Ten kinds of mature and hybrid forms of biologically active mouse IFN-beta proteins were synthesized in B. subtilis and were secreted into the culture medium. Similar amounts of proteins, which were determined by immunoblot analysis, were secreted from the B. subtilis transformants, while the antiviral activity in the medium was markedly different in each one of them. The highest antiviral activity was observed in a hybrid protein, in which eleven amino acids consisting of the prosequence of alpha-amylase (eight amino acids) and three amino acids encoding in the HindIII linker DNA were assumed to be extended in front of the Leu residue at position 6 of the mature form of mouse IFN-beta. Its activity was higher than that of the mature form of the mouse IFN-beta secreted from a B. subtilis transformant. These results indicate that the amino acid sequence around the NH2-terminal region of the mouse IFN-beta is closely related to the antiviral activity, but the NH2-terminal amino acid is not. The hybrid proteins of mouse IFN-beta show no interferon activity against a human cell line, HEL.

Amino Acid Sequence↗

The roles of alpha- and beta-adrenoceptors in the chronotropic responses to norepinephrine in carp heart (Cyprinus carpio).

1. The chronotropic effect of norepinephrine was studied in isolated spontaneously beating atrial preparations of carp (Cyprinus carpio) heart. 2. Norepinephrine, 0.1 microM, caused a positive chronotropic effect, while at 1 microM it caused either a positive or a negative chronotropic effect. The positive chronotropic effect, observed in 13 preparations, was potentiated by phentolamine and almost completely blocked by propranolol. 3. The negative chronotropic effect observed in the other 5 preparations was greater in the presence of propranolol, reduced by phentolamine and not affected by atropine. 4. These results indicate that alpha- and beta-adrenoceptors may coexist, mediating the negative and positive chronotropic effects, respectively, in isolated atrial preparations of carp heart.

Animals↗

Demonstration in Tupaia papillary muscle preparations of alpha-adrenoceptors mediating positive inotropic effects: comparison with guinea-pigs.

1. Positive inotropic responses to alpha- and beta-adrenoceptor agonists of isolated papillary muscles from the tree shrew (Tupaia), were compared with those from guinea-pigs. 2. In Tupaia, the concentration-response curve for phenylephrine, unlike that for isoprenaline, was not affected by pindolol in a concentration (10(-8) M) sufficient to block beta-adrenoceptor-mediated responses, but it was significantly shifted to the right by phentolamine (10(-6) M). In guinea-pig papillary muscles, however, the concentration-response curve for phenylephrine, like that for isoprenaline, was shifted to the right by pindolol (10(-8) M) but was unaltered by phentolamine (10(-6) M). Furthermore, when the mean concentrations of agonists inducing maximal positive inotropic responses were compared (relative to that of isoprenaline = 1.0), phenylephrine was found to be only slightly less potent (0.84 +/- 0.04; n = 5) in Tupaia and much less potent (0.33 +/- 0.06; n = 5) in the guinea-pig. 3. Although in Tupaia papillary muscles the increase in developed tension induced by a combination of phenylephrine and isoprenaline did not significantly differ from that by phenylephrine alone, it was approximately 3 times larger than that produced by phenylephrine alone in guinea-pigs. 4. These results indicate that in papillary muscles from Tupaia, unlike the guinea-pig, the positive inotropic effects of phenylephrine can be mediated by alpha-adrenoceptors.

Adrenergic alpha-Agonists↗

Comparative effects of ouabain on isolated papillary muscle from tree shrews, guinea-pigs and rats.

Inotropic effects of ouabain were investigated in the isolated papillary muscle preparations of the tree shrew (Tupaia glis), guinea-pigs and rats. In the guinea-pig and shrew papillary muscles, ouabain at concentrations of 10(-8) to 3 x 10(-7) M caused a concentration-dependent positive inotropic response in a similar magnitude, while in the rat, ouabain at concentrations of 10(-7) to 3 x 10(-6) M elicited negative inotropic one. Either phentolamine or pindolol in a concentration sufficient to block the alpha- and beta-adrenoceptors did not antagonize the positive inotropic effect of ouabain in the papillary muscle preparation of the shrews.

Animals↗

Contribution of the tissue angiotensin converting enzyme to the antihypertensive effect of altiopril calcium (MC-838) in spontaneously hypertensive rats.

The effect of a new orally active angiotensin converting enzyme (ACE) inhibitor, calcium (-)-N-[(S)-3-[(N-cyclohexylcarbonyl-D-alanyl)thio]-2-methylpropionyl+ ++]-L- prolinate (MC-838, altiopril calcium), on systemic blood pressure (SBP) and tissue ACE activity has been examined in conscious spontaneously hypertensive rats (SHRs). MC-838 (3 mg kg-1) given orally to SHRs elicited a long-lasting hypotension lasting over 24 h. With the development of the hypotension, MC-838 significantly reduced ACE activity in the lung, kidney and aorta, but not in the brain and heart. Suppression of plasma ACE and rise of plasma renin activity occurred only transiently at an earlier stage.

Animals↗

Characterization of a novel alpha 1-adrenoceptor antagonist, SGB-1534, in contractile response of isolated canine arterial and venous smooth muscle to exogenous noradrenaline: comparison with prazosin, phentolamine and yohimbine.

The pharmacological properties of SGB-1534, 3-[2-[4-[(o-methoxyphenyl)-1-piperazinyl]ethyl]-2,4(1H,3H)- quinazolinedione monohydrochloride, a selective alpha 1-adrenoceptor antagonist, compared with prazosin, phentolamine and yohimbine, were examined in contractile responses of isolated canine mesenteric arteries and veins and femoral arteries and veins to exogenous noradrenaline. The arteries and veins concentration-dependently contracted when exposed to noradrenaline. The sensitivity to noradrenaline, when compared in terms of pD2 values, was significantly higher in the veins than in the arteries. Phentolamine and yohimbine were competitive antagonists against noradrenaline in the arteries and the veins. SGB-1534 and prazosin caused a parallel shift to the right of the concentration-response curves for noradrenaline only in the arteries: the two antagonists were less effective in the veins than in the arteries when low concentrations of noradrenaline were applied. The pharmacological characteristics of SGB-1534 resemble those of prazosin. The pA2 values for SGB-1534 against noradrenaline in the arteries were much higher than those for prazosin, phentolamine and yohimbine. The result indicates that SGB-1534 may predominantly act upon arterial resistance vessels rather than the venous side, resulting in potent hypotension.

Adrenergic alpha-Antagonists↗

Enhancement of adenosine-induced relaxant responses of the guinea-pig isolated taenia coli and aortae by a novel nootropic agent BY-1949: comparison with dipyridamole.

In muscle strips of guinea-pig taenia coli and aortae, the effects of 3-methoxy-11-methyldibenz[b,f][1,4]oxazepine-8-carboxylate (BY-1949) on the relaxant response to adenosine have been compared with those of dipyridamole. BY-1949 (3 x 10(-5)-10(-4) M) as well as dipyridamole (3 x 10(-7)-10(-5) M) resulted in a significant potentiation of relaxant responses to a cumulative administration of adenosine (10(-6)-10(-3) M), but the drugs did not affect the response to noradrenaline and acetylcholine. The results indicate that BY-1949 exerts a selective potentiating effect on reactivity to exogenous adenosine.

Adenosine↗

Comparative vasorelaxing profiles of nicorandil, isosorbide dinitrate and nitroglycerin in isolated coronary arteries of the dog.

The vasorelaxing effects of nicorandil (NCR), isosorbide dinitrate (ISDN) and nitroglycerin (NTG) were studied in isolated canine coronary arteries. In rings of coronary arteries precontracted with prostaglandin F2 alpha (3 x 10(-6) M) or KCl (30 mM), removal of the endothelium significantly augmented the relaxing effects of NCR, while it did not affect those of ISDN and NTG. In unrubbed rings precontracted with KCl (30 mM), methylene blue (5 x 10(-6) M) significantly inhibited vasorelaxing responses to the three drugs. The order of the inhibition was as follows: NTG greater than ISDN greater than NCR. When the unrubbed tissue was incubated with NTG (10(-5) M) or ISDN (10(-4) M) for 10 min, it developed acute tolerance in relaxing response to NTG or ISDN. Unlike NTG and ISDN, NCR did not develop any tolerance. The treatment with N-acetylcysteine (5 x 10(-5) M) tended to potentiate relaxant effects of NTG and to reduce the degree of acute tolerance to NTG. The results suggest that cGMP plays a role in the relaxation of the coronary artery induced by the drugs and furthermore that the mode of the vasorelaxing action of NCR may be somewhat different from that of NTG or ISDN.

Acetylcysteine↗

MC-838 (altiopril calcium): a novel orally active angiotensin converting enzyme inhibitor.

MC-838, calcium (-)-N-[(S)-3-(N-cyclohexylcarbonyl-D-alanyl) thio]-2-methylpropionyl]-L- prolinate, is a new orally active angiotensin converting enzyme (ACE) inhibitor in which the mercapto-group is taken up in a stable thiolester linkage. The linkage was relatively resistant against enzymatic hydrolysis by rat liver homogenates. The ACE prepared from rabbit lung was inhibited by MC-838 in a concentration-dependent manner. In isolated rat aortic ring and guinea-pig ileum preparations, MC-838 was highly specific in suppressing the contractile response to angiotensin-I (A-I) an in augmenting the contractile one to bradykinin. However, the ACE inhibitory activity of MC-838 was 30-100 times less potent than that of captopril. In conscious two-kidney (2 KG), renal hypertensive rats and spontaneously hypertensive rats (SHRs), MC-838 (3 and 10 mg/kg) given orally caused a long-lasting hypotensive effect with a slow onset. When compared on a weight basis (3 mg/kg), the antihypertensive effect of MC-838 was comparable to that of captopril in magnitude, but the duration of action of MC-838 was approximately 2 times longer than that of captopril.

Administration, Oral↗

Effects of an indazole derivative, FKK, a novel bronchodilator, on the cardiovascular system in dogs.

The cardiovascular effects of FKK (2,3-dihydro-7-methyl-9-phenyl-1H-pyrazolo [1,2-a]indazolium bromide) were compared with those of aminophylline and isoproterenol in anesthetized dogs. The doses of the three drugs used were sufficient to cause significant tracheal dilation in the anesthetized dogs. FKK (0.1-3.0 mg/kg, i.v.) slightly increased respiratory frequency, left ventricular (LV) dp/dt max and myocardial contractile force. A slight increase followed by a decrease was observed in systemic blood pressure and LV systolic pressure. The drug caused direct vasodilation in the coronary, mesenteric and femoral vasculatures, but had no effect on the renal vasculature. Similar results were obtained with aminophylline (0.3-30.0 mg/kg, i.v.) and isoproterenol (0.003-0.3 microgram/kg, i.v.), but their effects on the measured cardiac parameters were much more potent and long-lasting than those of FKK, when compared in doses producing a bronchodilation in similar magnitude. It is particularly pertinent that FKK (30 mg/kg, i.d., enough to cause marked bronchodilation), unlike aminophylline (30 mg/kg, i.d.), did not significantly influence the cardiovascular system.

Aminophylline↗

Comparative effects of nicorandil and nitroglycerin on tracheal and vascular smooth muscle in the dog, in vivo and in vitro.

The effects of nicorandil (NCR) on tracheal and vascular smooth muscle in the dog were compared with those of nitroglycerin (NTG) in in vitro and in vivo preparations. In the isolated tracheal strip and coronary artery preparations contracted with KCl (30 mM), the ability of NCR to relax these muscles and arteries by 50% was 1/10-1/15 as potent as NTG. In blood-perfused tracheal preparations, single doses of NCR and NTG injected into the tracheal artery produced dose-related decreases in the intraluminal pressure (ILP) of the trachea (relaxation) and increases in the tracheal blood flow (TBF). When the potency of NCR relative to that of NTG was compared on the basis of doses decreasing the ILP and increasing the TBF by 50%, NCR was 822 times less potent than NTG in producing tracheal relaxation and 572 times less potent in producing tracheal vasodilation. The effects of NCR on the ILP and TBF were not antagonized by propranolol. In non-perfused tracheal preparations, the two drugs administered i.v. elicited the effects in a similar dose-dependent manner; decreases in systemic blood pressure (SBP), left ventricular systolic pressure (LVP), pressure-rate product (PRP), femoral vascular resistance (FVR), and ILP and increases in heart rate (HR) and LVdP/dt max. The results show that NCR has a potent bronchodilating action and that its pharmacological profile is somewhat similar to NTG.

Animals↗

Effects of a new antianginal agent, nicorandil, on the cardiovascular system of the miniature pig: with special reference to coronary vasospasm.

The cardiovascular and vasospasmolytic effects of a newly developed nicotinamide derivative, N-(2-hydroxyethyl)nicotinamide nitrate(ester) (nicorandil), were examined in anesthetized, open-chest "miniature" pigs, and compared with those of nitroglycerin. Nicorandil, administered i.v. in doses of 10 micrograms/kg to 1 mg/kg, decreased systemic blood pressure, left ventricular (LV) systolic pressure, pressure rate product and coronary and femoral vascular resistance. It pronouncedly increased coronary blood flow and slightly increased heart rate. An increase, often preceded by a decrease, occurred in the LVdP/dt max. In doses of 10 to 100 micrograms/kg, nicorandil induced a slight increase followed by a decrease in femoral blood flow, but larger doses always decreased it. Similar results were obtained with nitroglycerin for all the cardiovascular parameters tested except LVdP/dt max and coronary blood flow. Unlike nicorandil, nitroglycerin induced a decrease often preceded by an increase in the LVdP/dt max. In doses of 1 to 30 micrograms/kg, nitroglycerin caused a decrease preceded by a slight and transient increase in the coronary blood flow. Nicorandil, administered i.v. in doses of 30 micrograms/kg to 1 mg/kg, inhibited coronary vasoconstriction caused by methacholine (3 or 10 micrograms) and norepinephrine (2-4 micrograms in the presence of propranolol) injected directly into the coronary artery. The magnitude and duration of this antagonism depended on the dose of nicorandil used. Although nitroglycerin in a dose of 10 or 30 micrograms/kg also effectively inhibited coronary vasoconstrictor responses to the two vasoactive agents, dipyridamole (60 micrograms/kg) failed to do so. Thus, nicorandil has prominent vasospasmolytic effects and is an efficacious coronary vasodilator which reduces afterload.

Animals↗

Pharmacologic potency and selectivity of a new bronchodilator agent, 2,3-dihydro-7-methyl-9-phenyl-1H-pyrazolo [1,2-a] indazolium bromide (FKK) on canine tracheal preparations "in vivo" and "in vitro".

In tracheal preparations of dogs anesthetized with pentobarbital, the bronchodilating activity and selectivity of FKK were compared with those of aminophylline and isoproterenol. When administered by either the i.a., i.v. or i.d. route in blood-perfused or nonperfused tracheal preparations, FKK produced a dose-dependent and long-lasting tracheal dilatation through all the administration routes, but unlike aminophylline and isoproterenol it hardly affected systemic blood pressure (SBP), heart rate (HR) and tracheal blood flow (TBF). The ability of i.a. and i.v. FKK to reduce the tracheal intraluminal pressure (ILP) (bronchodilation) by 50% (ED50), was approximately 5.4-6.2 times more potent than aminophylline and 1/3000-1/4500 as potent as isoproterenol. In the isolated canine tracheal preparations contracted with carbachol, the relaxing action produced by FKK was 1/60 and 10 times as potent as those caused by isoproternol and aminophylline, respectively. FKK has neither anti-cholinergic, ganglion blocking, alpha-adrenergic blocking nor beta-adrenergic stimulating properties. Acute lethal toxicity of FKK determined in rats by the oral route was considerably less than that of aminophylline.

Acetylcholine↗

Pseudoxanthoma elasticum associated with Hashimoto's thyroiditis.

A case of pseudoxanthoma elasticum (PXE) associated with Hashimoto's thyroiditis is reported. A 49-year-old woman had typical skin lesion of PXE and ocular lesions such as angioid streaks, peau d'orange pattern and subretinal bleedings. She also had a goiter for which histological examination revealed the findings of Hashimoto's thyroiditis. Antithyroidal autoantibodies were positive. Many members of her family for three generations back have had the ocular lesions of PXE, however, they did not have any findings supporting Hashimoto's thyroiditis. The present report was considered to be the first case of PXE associated with an immunological disorders.

Angioid Streaks↗