Biomedical subjects

I Takayanagi

Publications and source records attributed to I Takayanagi.

At least 127 records · Page 7Linked to original sources

PubMed1990

Characterization of tachykinin receptors in urinary bladder from guinea pig.

The contractile responses to substance P (SP), neurokinin A (NKA), Tyro-neurokinin B (Tyr-NKB), senktide (NK3 receptor selective agonist) and SP methyl ester (SPOMe, NK1 receptor selective agonist) were investigated in detrusor strips from guinea pigs. Except for senktide, all drugs induced a concentration-related contraction with the following rank order of potency: SPOMe greater than SP greater than NKA greater than or equal to Tyr-NKB. After desensitization of NK1 receptors with SPOMe, the rank order of potency was NKA greater than or equal to Tyr-NKB greater than SP greater than SPOMe. Both NK1 and NK2 receptors exist in the detrusor strip from guinea pigs.

Animals↗

PubMed1990

Evidence for release of prostaglandin F2 alpha in contractile response of guinea pig trachea to norepinephrine.

The concentration (10(-8)-10(-5) M)-dependent contractile response of norepinephrine was completely inhibited by cyclooxygenase inhibitors but not by a thromboxane synthetase inhibitor. The amount of prostaglandin F2 alpha was significantly increased in the presence of norepinephrine (10(-5) M). Norepinephrine increased the amount of prostaglandin D2, although not significantly. The norepinephrine-evoked prostaglandin release was inhibited by tolazoline (3 x 10(-5) M). These results suggest that norepinephrine evoked the release of prostaglandins, mainly prostaglandin F2 alpha to induce the contraction of the guinea pig trachea.

Animals↗

PubMed1989

Potentiating effect of 3-isobutyryl-2-isopropylpyrazolo-[1,5a]-pyridine (KC-404), a new cerebral vasodilator with anti-platelet activity, on prostacyclin-induced increase of cyclic AMP content in platelets of rat.

1. The effect of KC-404, a new antiplatelet and cerebrovasodilating drug, on prostacyclin (PGI2)-induced accumulation of cyclic AMP was investigated using washed platelets of rat. 2. PGI2 enhanced the cyclic AMP content in a concentration-dependent manner. 3. KC-404 at a relatively high concentrations (above 4.34 microM) significantly increased the maximum cyclic AMP accumulation induced by PGI2, without change in its sensitivity. 4. It is concluded that KC-404 potentiates a mechanism of action of PGI2, and a possible relevance of KC-404 for the treatment of cerebrovascular disorders with a tendency of accompanying thromboembolism is suggested.

Animals↗

PubMed1989

Effect of histamine on two different affinity sites in beta-adrenoceptors.

1. To study the effect of histamine on two different affinity sites in beta-adrenoceptors, we tested specific binding of [3H]befunolol to microsomal fractions from the guinea pig taenia caecum in the presence and absence of histamine (10(-5) M). 2. The Scatchard plot of data in the absence of histamine was recognized as two straight lines suggesting the existence of two different affinity sites: high and low. However, a curvilinear plot with upward concavity was observed in the presence of histamine (10(-5) M). 3. These results suggest the possibility that histamine alters the binding sites of beta-adrenoceptors into several classes of sites with lower affinity. 4. Further, an antagonism between isoprenaline and BFE-55, which interacts only with the high affinity site, was tested on the atria (beta 1-adrenoceptor predominant) and tracheae (beta 2-adrenoceptor predominant) of the guinea pig. The pA2-values in the atria were almost equal to those in the trachea, suggesting that both beta 1- and beta 2-adrenoceptors contained two different affinity sites.

Adrenergic beta-Agonists↗

PubMed1989

Kappa-receptor mechanisms in synaptosomal Ca uptake.

1. Inhibition of Ca uptake by certain opioids was tested in synaptosomes of rat brain. The potency order was dynorphin A 1-13, a kappa-selective agonist greater than nalorphine greater than nalorphine epoxide greater than morphine. 2. The pA2 values (negative logarithms of dissociation constant) of naloxone against four opioids were not significantly different from each other, suggesting that the site of action of the four opioids is identical. 3. Morphiceptin, a mu-selective agonist and DADLE, a delta-selective agonist had no effect on Ca uptake. 4. These results suggest that the site of action of the four opioids is kappa-receptors. 5. Potency order estimated from competition inhibition curves of specific binding of [3H]ethylketo-cyclazocine (kappa-selective ligand) by the test opioids was nalorphine greater than nalorphine epoxide greater than dynorphin A 1-13 greater than morphine. 6. The difference between the two potency orders suggests that affinities and intrinsic activities of the drugs are important factors in determining their agonistic activity in kappa-receptor mechanisms.

Animals↗

PubMed1989

Effect of tetrahydroisoquinoline (TIQ), one of endogenous substances inducing parkinsonism, on isolated rat vas deferens.

1. The effect of tetrahydroisoquinoline (TIQ) was examined on isolated rat vas deferens. 2. TIQ shifted the concentration-response curve for norepinephrine towards lower concentrations: the pD2-value of norepinephrine in the presence of TIQ was significantly greater than in its absence. 3. Tyramine-induced contraction in the presence of TIQ decreased by a significant 35% more than in the absence of TIQ. 4. These results indicate that the pharmacological effect of TIQ is due to the inhibition of the neuronal uptake of catecholamines.

Animals↗

PubMed1989

Involvement of threshold level in the contractile responses for some alpha 1-andrenoceptor agonists in the rabbit iris dilators.

1. The relationship between receptor occupancies and contractile responses for some alpha 1-adrenoceptor agonists were investigated in rabbit iris dilator smooth muscles. 2. Noradrenaline acted as a full agonists, while oxymetazoline and xylometazoline behaved as partial agonists with moderately higher intrinsic activity, and tizanidine and clonidine were partial agonists with lower intrinsic activity. 3. The pD2-values of oxymetazoline and xylometazoline were practically equal to the corresponding pKB-values, the negative log of dissociation constant, estimated by the partial irreversible blockade of alpha 1-adrenoceptors with phenoxybenzamine. However, the pD2-values of tizanidine and clonidine were significantly lower than the corresponding pKB-values. 4. The threshold phenomena lay between the receptor occupations and tissue responses, therefore, the pKB-values of partial agonists with lower intrinsic activity were different from their pD2-values. 5. These results suggest that the threshold phenomena in the tissue used may be an important factor in determining the agonist sensitivity.

Adrenergic alpha-Agonists↗

PubMed1989

Dose difference in beta-adrenergic blockers with intrinsic sympathomimetic action to block beta-adrenoceptors and induce sympathomimetic action.

1. Isoprenaline, a beta-adrenergic full agonist, and carteolol, befunolol and BFE-55, beta-adrenergic blockers with an intrinsic sympathomimetic action, induced dose-related increases in heart rate when administered intravenously (i.v.). 2. The beta-partial agonists administered i.v. shifted a dose-heart rate increased response curve of isoprenaline, suggesting a competitive antagonism. 3. In carteolol, doses to block beta-adrenoceptors were found to be 400-1000 times lower than that to induce agonistic action. In BFE-55, doses to block beta-adrenoceptors were equal to that to induce sympathomimetic action. The difference between doses of the befunolol to produce both actions was intermediate. 4. These results suggest that there may be a difference between doses blocking beta-adrenoceptors and inducing sympathomimetic action in some beta-adrenergic partial agonists and, therefore, that there may exist beta-partial agonists which do not induce sympathomimetic action in doses blocking beta-adrenoceptors.

Adrenergic beta-Agonists↗

PubMed1989

Pharmacological properties of tiropramide, an antispasmodic drug.

1. The pharmacological properties of an antispasmodic drug, tiropramide, were studied in isolated smooth muscle preparations. 2. Tiropramide at concentrations of 10(-6) to 10(-4) M relaxed various smooth muscles contracted spontaneously and by smooth muscle stimulants or electrical stimulation. Tiropramide did not interact with all drug-receptors examined, suggesting a pure musculotropic smooth muscle relaxant activity. 3. Tiropramide was found to inhibit both Ca uptake and Ca release in the guinea pig urinary bladder. 4. Tiropramide is considered to be useful to inhibit the contractile response of the urinary bladder, as this organ is mainly innervated by noncholinergic excitatory neurons.

Animals↗

PubMed1989

Some pharmacological properties of a new antitumor drug, CPT-11, in isolated muscle preparations.

1. Pharmacological properties of a new antitumor drug, CPT-11, were studied in some muscle preparations. 2. CPT-11 induced contraction of guinea-pig ileal and tracheal preparations, which was blocked by atropine (10(-6) M). 3. CPT-11 potentiated the contractile responses of guinea-pig ileum to acetylcholine, nicotine, serotonin and BaCl2. 4. The chronic and inotropic effects induced by isoprenaline were depressed by CPT-11. 5. These results suggest that CPT-11 has an acetylcholine action.

Animals↗

PubMed1989

Effect of aging on presynaptic alpha 2-adrenoceptor mechanisms in guinea pig ileum.

1. Presynaptic alpha 2-adrenoceptor mechanisms in electrically stimulated longitudinal muscles of ilea isolated from 3, 10, 20 and 47 week-old guinea pigs were studied by analysis of the concentration-response curves of noradrenaline, a full agonist, and clonidine, a partial agonist, and the Scatchard plot of specific binding of [3H]-p-aminoclonidine to synaptosomal fractions from the longitudinal muscle of guinea pig ileum. 2. The pD2 value of noradrenaline and the maximum contraction induced by clonidine increased with age from 3 to 20 weeks and there after decreased to 47 weeks, while the pA2 value of yohimbine against noradrenaline did not alter with age. 3. The capacity of the maximum binding sites of [3H]-p-aminoclonidine increased with increasing age (3-20 weeks), while the dissociation constant (Kd) of [3H]-p-aminoclonidine did not change during the same period. 4. The changes in the presynaptic alpha 2-adrenoceptor mechanisms with age are considered to be due to the change in the total concentration of presynaptic of alpha 2-adrenoceptors.

Aging↗

PubMed1989

Effects of aging on alpha 1-adrenoceptor mechanisms and the inhibitory effect of diltiazem on noradrenaline maximum response in isolated rat aortic preparation.

The effects of aging on alpha 1-adrenoceptor mechanisms in aortic preparations isolated from 3-, 6-, 10-, 18-, and 40-week-old rats were studied and compared with serotonin receptor mechanisms in the same preparations. The potency (pD2 value) of noradrenaline increased with age from 3 to 10 weeks, but decreased thereafter with age from 10 to 40 weeks. The affinity (pKA value) of noradrenaline and of prazosin (pA2 value) did not alter with aging. The change in potency or the pD2 value of noradrenaline was proportional to receptor reserve (pD2-pKA value) for noradrenaline, suggesting that the change of potency of noradrenaline with age was due to a change of receptor reserve, but not to change of drug affinity to alpha 1-adrenoceptors. The potency (pD2 value) and affinity (pKA value) of serotonin, and the affinity (pA2 value) of ketanserin, did not alter with aging, suggesting that serotonin receptor mechanisms in rat aorta did not change with age. The inhibitory effect of diltiazem on noradrenaline maximum response decreased with age from 3 to 10 weeks, but increased with age from 10 to 40 weeks. An inverse relationship between changes of diltiazem inhibition and receptor reserve of noradrenaline was found. Diltiazem's inhibitory effect on serotonin maximum response did not alter with aging.

Aging↗

PubMed1989

Effects of a new positive inotropic agent with a vasodilatory action, 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), on agonists-induced contractions in the isolated rabbit thoracic aorta.

The mechanism of the vasodilatory effect of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), a non-catecholamine and non-glycoside positive inotropic agent with a vasodilatory action, was investigated using helically-cut strips of the rabbit thoracic aorta. The contractile responses of the thoracic aorta to phenylephrine and prostaglandin F2 alpha were antagonized noncompetitively in a concentration-dependent manner by ZSY-27 (1 x 10(-4) - 1 x 10(-3) M). Furthermore, precontractions induced by high K (34.5 mM K) and by phenylephrine (1 x 10(-6) M) were relaxed in a concentration-dependent manner by ZSY-27 (1 x 10(-6) - 1 x 10(-3) M). These relaxant effects were not affected by a decrease in extracellular Ca or by pretreatment with methylene blue, an inhibitor of guanylate cyclase, but were significantly potentiated by pretreatment with forskolin, a direct stimulator of adenylate cyclase. Moreover, the amount of Ca stored in smooth muscle cells was estimated from the amplitude of the phasic contractions induced by phenylephrine in Ca-deprived medium. The first phasic contraction induced by phenylephrine was inhibited by pretreatment with ZSY-27. After ZSY-27 was washed out with a Ca-deprived solution, the second phasic contraction induced by phenylephrine occurred manifestly, but not in preparations untreated with ZSY-27. It is concluded that ZSY-27 caused a nonspecific relaxation of arterial smooth muscle contractility mainly by acting on some processes distal to adenosine 3',5'-monophosphate (cAMP) production by adenylate cyclase; probably inhibition of cAMP-phosphodiesterases.

Animals↗

PubMed1989

Relationship between cyclic nucleotide levels and 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), a new positive inotropic agent with a vasodilatory action, -induced relaxation of rabbit thoracic aorta.

The aim of this investigation was to substantiate the hypothesis that the vasorelaxant effects of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27) are mediated by accumulation of intracellular cyclic nucleotides as a consequence of inhibition of cyclic nucleotide phosphodiesterase activity. Both activities of adenosine 3',5'-monophosphate-phosphodiesterase (cAMP-PDE) in the presence of ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) and guanosine 3',5'-monophosphate-phosphodiesterase (cGMP-PDE) in the presence of calcium-calmodulin from rabbit thoracic aorta were inhibited in a concentration-dependent manner by ZSY-27 (10(-5) - 10(-3) M). The IC50 values for ZSY-27 on cAMP- and cGMP-PDE activity were 2.1 x 10(-4) and 8.8 x 10(-4) M, respectively. Furthermore, ZSY-27 antagonized competitively cAMP-PDE (Ki = 1.9 x 10(-4) M). On the other hand, ZSY-27 exhibited a mixed-type inhibitory pattern, with reduction of both maximum velocity and affinity for the substrate of the cGMP-PDE, with a Ki value of 1.0 x 10(-3) M. Spontaneous myogenic tone of rabbit thoracic aorta was significantly attenuated from 1 min after addition of ZSY-27 (3 x 10(-4) M). Contents of cAMP and cGMP were significantly increased from 1 and 3 min after addition of ZSY-27, respectively. Temporally, relaxant effects of ZSY-27 were associated with increases of cAMP content, but not with that of cGMP content.(ABSTRACT TRUNCATED AT 250 WORDS)

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed1989

Effects of a new positive inotropic agent with a vasodilatory action, 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), on calcium-movement and mechanical response in rabbit thoracic aorta.

The effects of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), a positive inotropic agent with a vasodilatory action, on a concentration-response curve of CaCl2 in the KCl-depolarized rabbit thoracic aorta and Ca-uptake by the microsomal fraction from the rabbit artery were tested. ZSY-27 (10(-5) - 10(-4) M) inhibited noncompetitively a concentration-response curve of CaCl2 in the KCl-depolarized preparation. Furthermore, ZSY-27 (10(-5) M) stimulated significantly Ca-uptake by the microsomal fraction in the presence of oxalate, as an indicator for Ca-uptake by the internal membrane, in every incubation time. However, it inhibited significantly that in the absence of oxalate, as an indicator for Ca-uptake by the plasma membrane-derived vesicle, after 6 min of incubation time. These results suggest that ZSY-27 stimulates Ca-uptake by the internal membranes and inhibits Ca-uptake by the plasma membrane-derived vesicles. Therefore, these effects of ZSY-27 are considered to be related to relaxation of vascular smooth muscle.

Animals↗

PubMed1989

Greater tension is developed at the same level of cytosolic Ca2+ concentration in the presence of clonidine, an adrenergic partial agonist, than in the presence of norepinephrine.

Fura 2-loaded thoracic aorta strips from rabbits were used. Norepinephrine and clonidine induced an increase in cytosolic Ca2+ concentration ([Ca2+]i) and in muscle tension in a concentration-dependent manner. A positive correlation between [Ca2+]i and tension development due to norepinephrine and clonidine was noted in muscle strips both untreated and treated with phenoxybenzamine (PBZ). As the total receptor population was reduced by the PBZ treatment, norepinephrine acted as a partial agonist in the treated strips. The slope of a regression line for norepinephrine in the untreated muscle strips was significantly smaller than the slopes for the same drug in PBZ-treated strips and for clonidine, suggesting that norepinephrine in the PBZ-treated strips and clonidine induced a greater tension at same [Ca2+]i than did norepinephrine in the untreated strips.

Animals↗

PubMed1989

Interaction of 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride, ryanodine and procaine with muscarinic cholinergic M2 receptor sites in smooth muscle.

We have characterized muscarinic cholinergic receptor sites and interaction of various modulators of intracellular Ca mobilization, such as 8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8), ryanodine, procaine and related drugs with the receptor sites, using a binding assay method with [3H]quinuclidinyl benzilate [( 3H]QNB) in guinea pig tenia cecum membrane fraction. [3H]QNB bound to a single population of sites, and the binding profile of pirenzepine suggest that the receptor sites are probably the M2 type. All the test drugs examined except for ryanodine displaced the [3H]QNB binding, and the slope factors were not different from unity. Affinities of these drugs were comparable to the concentrations usually used to modulate intracellular Ca mobilization. A Scatchard plot of [3H]QNB binding in the presence of TMB-8 or procaine showed that the apparent dissociation constant for [3H]QNB was increased without change in maximum binding. Neither TMB-8 nor procaine had any effect on the rate of dissociation of [3H]QNB from the steady-state complex. These results suggest that TMB-8 and procaine, and possibly other drugs, may interact directly with the muscarinic cholinergic M2 receptor sites in a competitive manner. In contrast, ryanodine had no effect on the [3H]QNB binding up to at least 100 microM. No interaction of ryanodine with M2 receptor sites lends a further support that the drug could be a useful probe for studying intracellular Ca mobilization.

Alkaloids↗

PubMed1988

Epithelium selectively controls hypersensitization of the response of smooth muscle to leukotriene D4 by endogenous prostanoid(s) in guinea-pig trachea.

The effect of epithelium removal on the sensitivity of smooth muscle to carbachol and leukotriene D4 (LTD4) was investigated in guinea-pig isolated tracheal preparations untreated and treated with a cyclooxygenase inhibitor, flurbiprofen (1 mumol/l). The pD2 value of carbachol was not changed by epithelium removal or by flurbiprofen-treatment, alone or in combination. On the other hand, the pD2 of LTD4 was higher in the tracheal strips without epithelium than in the intact preparations. In preparations devoid of epithelium, the pD2 value of LTD4 was decreased by treatment with flurbiprofen, suggesting that the sensitivity of the smooth muscle (namely, epithelium-free preparations) to LTD4 is enhanced by intramurally produced excitatory prostaglandin(s) [PG(s)]. However, in intact preparations with epithelium, no such sensitized response to LTD4 was observed. After flurbiprofen-treatment, in the continued presence of prostaglandin F2 alpha (PGF2 alpha, 200 nmol/l), the sensitivity to LTD4 was partially recovered in the epithelium-free preparations, but not in the intact ones. These results suggest that epithelium diminishes the sensitizing effect of intramural excitatory PG(s) on responsiveness of tracheal smooth muscle to LTD4, possible via a non-prostanoid substance(s).

Animals↗