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Biomedical subjects

M Otsuka

Publications and source records attributed to M Otsuka.

At least 433 records · Page 24Linked to original sources
PubMed1985

Studies on the affinity and selectivity of denopamine (TA-064), a new cardiotonic agent, for beta-adrenergic receptors.

Denopamine is a new orally active cardiotonic agent. The present experiment was carried out to characterize the binding affinity and selectivity of this drug for beta-adrenergic receptor subtypes. Binding studies were performed using 3H-dihydroalprenolol as the radioligand. Binding affinities of denopamine and some beta-agonists for rat heart membranes (KiH), which contain predominantly the beta 1-subtype, were in the order of isoproterenol (Iso, 14.1 nM) greater than prenalterol (158) greater than norepinephrine (Nor, 227) greater than or equal to epinephrine (Epi, 248) greater than denopamine (545) greater than or equal to dobutamine (645) greater than procaterol (1440) greater than terbutaline (6420). In rat lung membranes (predominantly beta 2-subtype), the order of potency (KiL) was Iso (20.6 nM) greater than procaterol (70.2) greater than Epi (136) greater than prenalterol (412) greater than dobutamine (735) greater than or equal to Nor (744) greater than denopamine (2205) greater than terbutaline (2500). The beta 1/beta 2-selectivity as judged from the KiL/KiH values was in the order of denopamine (4.1) greater than Nor (3.3) greater than prenalterol (2.6) greater than Iso (1.5) greater than dobutamine (1.1) greater than Epi (0.55) greater than terbutaline (0.39) greater than procaterol (0.05). Practolol, a beta 1-antagonist, showed a high beta 1-selectivity (KiL/KiH = 15.3). In the presence of guanine nucleotide (GTP), the denopamine radioligand competition curve showed a rightward shift, and its Hill coefficient increased like other agonists, although the degree of the shift was less than that observed with full agonists such as Iso. These results essentially correspond with the pharmacological and biochemical properties of denopamine and confirm the beta 1-selectivity and the agonist property of this compound.

Animals↗
PubMed1985

Effect of GTP on the affinity of denopamine, a new cardiotonic agent, for beta-adrenergic receptors of turkey erythrocytes and rat reticulocyte membranes.

Affinities of denopamine, a new cardiotonic agent, and several beta-adrenergic drugs for turkey erythrocyte membranes (TEM) and rat reticulocyte membranes (RRM) which contain homogeneous beta 1- and beta 2-receptors, respectively, were studied by receptor binding. The order of potencies of denopamine and several beta-adrenergic agonists in displacing 3H-dihydroalprenolol binding (Ki, nM) in TEM was isoproterenol (Iso, 27) greater than norepinephrine (Nor, 360) greater than epinephrine (Epi, 860) greater than dobutamine (DB, 1380) greater than denopamine (1540) greater than dopamine (DA, 49500). The order in RRM was Iso (7.3) greater than Epi (58) greater than DB (750) greater than Nor (1090) greater than denopamine (2300) greater than DA (26800). In the presence of GTP, competition curves for full agonists like Iso, Epi and Nor shifted to the low affinity side (Ki values increased by 300-500% in TEM and 200-460% in RRM), and the slopes were steepened in both membrane preparations. The Ki value for denopamine increased only in TEM (70%) and that in RRM was not influenced by GTP. This suggests that denopamine has an agonist property at the beta 1-receptor but not at the beta 2-receptor and that the intrinsic activity at the beta 1-receptor of the drug is lower than full agonists. Affinities of DB and DA for TEM were influenced by GTP as well as those for RRM, although the extent of the rightward shift was less than full agonists.

Animals↗
PubMed1985

Relationship between positive inotropic action and blood levels of denopamine in cats.

The relationship between the positive inotropic action and blood levels of (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol (denopamine, TA-064) was studied after intraduodenal administration of 3H-denopamine (100 micrograms/kg) in cats. The increase in cardiac contractile force attained the peak (about 100% increase) 15 min after the administration and the effect persisted for over 90 min. The blood levels of denopamine also reached the peak at 15 min with a concentration of 20 ng/ml and decreased gradually thereafter. Thus, it was indicated that the time courses of the increase in cardiac contractile force were closely related to those of blood levels of the drug. Furthermore, denopamine was distributed to the liver, kidney, parotid gland and heart, followed by being excreted into the urine and bile mostly as metabolites.

Animals↗
PubMed1984

Tail-pinch method in vitro and the effects of some antinociceptive compounds.

An in vitro preparation for testing antinociceptive drugs is described. The preparation consists of isolated spinal cord, spinal nerve roots and functionally connected tail of the newborn rat. Noxious pressure stimulation given to the tail induced in a lumbar ventral root a depolarizing response of 1-2 mV lasting about 15-30 s, which is referred to as tail-pinch potential. Single shock stimulation of a lumbar dorsal root induced in the ipsilateral ventral root of the same segment monosynaptic and polysynaptic reflexes, which were followed by a depolarizing response lasting ca. 20 s. The latter slow response is referred to as ipsilateral slow ventral root potential (VRP). Morphine, [Met5]enkephalin, [Leu5]enkephalin and [D-Ala2,Met5]enkephalinamide depressed both the tail-pinch potential and the ipsilateral slow VRP, but did not exert any noticeable effect on the monosynaptic and polysynaptic reflexes. The effects of morphine and enkephalins were completely abolished by naloxone. Naloxone potentiated the tail-pinch potential and the ipsilateral slow VRP in the fresh preparations which had not been exposed to opiate compounds or enkephalins, suggesting that the endogenous enkephalinergic mechanism occurs in the spinal cord and modulates the incoming nociceptive signals. The present isolated spinal cord-tail preparation will be useful for studying actions of analgesic drugs and for screening compounds for analgesic effects.

Analgesics↗
PubMed1984

The excitatory action of the newly-discovered mammalian tachykinins, neurokinin alpha and neurokinin beta, on neurons of the isolated spinal cord of the newborn rat.

The actions of two new mammalian tachykinins, neurokinin alpha and neurokinin beta, were examined using the isolated spinal cords of newborn rats. Depolarizing responses of spinal motoneurons were recorded extracellularly from the lumbar ventral root during application of neurokinin alpha or neurokinin beta at concentrations ranging from 3 X 10(-8) M to 10(-6) M. The potencies of various tachykinins in depolarizing the motoneurons showed the following order: physalaemin greater than neurokinin beta divided by kassinin divided by substance P greater than neurokinin alpha. When the synaptic transmission in the spinal cord was blocked by tetrodotoxin, the depolarizing action of neurokinin alpha and neurokinin beta was markedly reduced but not completely abolished. The depolarizing action of neurokinin alpha and neurokinin beta was depressed by a substance P antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]SP. The possibility that neurokinin alpha and neurokinin beta act as neurotransmitters in the mammalian spinal cord is discussed.

Animals↗
PubMed1984

Changes in natural killer activities in experimental secondary amyloidosis.

Natural killer (NK) cell activity in experimental murine amyloidosis was studied. In CBA/J mice, which show a high incidence of amyloidosis, NK activity was significantly decreased after 1 week of casein treatment. In C3H mice, which show a low incidence of amyloidosis, NK activity was not changed by casein treatment. Pretreatment with lipopolysaccharide in vivo enhanced the NK activities in CBA/J and C3H mice. These increases were not observed after casein treatment. The lowered NK activity of cells from CBA/J mice after casein treatment was restored to the normal range by indomethacine in vitro. Depletion of adherent cells from the spleen cells treated with casein had no effect on NK activity. Single-cell assay showed that casein treatment impaired the killing but not the binding of NK cells to target cells. After casein treatment, the splenic serum amyloid A (SAA) level gradually increased in CBA/J mice but remained low in C3H mice. NK activity was suppressed by the addition of serum obtained from CBA/J mice treated with casein but not by normal control serum. And partially purified AA protein obtained from the spleen of CBA/J mice treated with casein also suppressed NK activity in vitro.

Amyloid↗