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Biomedical subjects

I Takayanagi

Publications and source records attributed to I Takayanagi.

At least 55 records · Page 3Linked to original sources
PubMed1994

Comparison of interactions of R(+)- and S(-)-isomers of beta-adrenergic partial agonists, befunolol and carteolol, with high affinity site of beta-adrenoceptors in the microsomal fractions from guinea-pig ciliary body, right atria and trachea.

1. The stereoselectivities of beta-adrenergic partial agonists for the high affinity binding site of beta-adrenoceptors in the guinea-pig ciliary body, right atria and trachea were studied. 2. The inhibition curves by the S(-)-isomers of befunolol and carteolol were not significantly different from that by the R(+)-isomers in the guinea-pig ciliary body. 3. The inhibition curves by the S(-)-isomers of befunolol and carteolol were about 10 times as potent as the R(+)-isomers in the guinea-pig atria and trachea. 4. The pKi values of the S(-)-isomers of befunolol and carteolol were significantly larger than those of R(+)-isomers in the guinea-pig atria and trachea but not larger than those of the R(+)-isomers in the guinea-pig ciliary body. 5. These results suggest that the high affinity binding site of beta-adrenoceptors in ciliary body cannot discriminate stereoselectively between the R(+)- and S(-)-isomers, while in other tissues there is stereoselectivity between the two enantiomers.

Adrenergic beta-Agonists↗
PubMed1994

Effects of ageing on regional differences in the contractile responses to acetylcholine and neurokinin A in rabbit airway.

1. Experiments were designed to study the effects of ageing on muscarine and NK2 receptor mechanisms in the three different regions of rabbit airway. 2. The pD2 value of acetylcholine changed with age in three different regions while that of carbamylcholine, which is resistant to acetylcholinesterase, did not. 3. The pD2 values of neurokinin A and the activity of protease, a degradative enzyme, changed with age. However, by the pretreatment with phosphoramidon, a protease inhibitor, the regional difference and age related change of the pD2 value of neurokinin A disappeared. 4. In conclusion, the observations about age related changes and regional differences of pD2 value of acetylcholine and neurokinin A were due to the difference of their degradative enzyme activities.

Acetylcholine↗
PubMed1994

[Effects of aging on drug receptor mechanisms in smooth muscles].

The effects of aging on some drug receptor mechanisms were studied in isolated smooth muscles. Potencies of alpha- and beta-adrenoceptor agonists increased from the young stage to the adult stage and decreased slowly thereafter to the old stage. The affinities of the adrenergic drugs on their receptors did not alter with aging. Excellent relationships between the potencies or efficacies of the agonists and the amounts of receptors or receptor reserve were found, suggesting that changes in the adrenoceptor mechanisms with aging were due to changes in the amount of receptors. However, it was also found that the decrease in the potency of beta-adrenoceptor agonists in preparations from the older animals was due to the change in post beta-adrenoceptor processes in responsiveness. However, the serotonin, acetylcholine (ACh) and tachykinin (NK2) receptor mechanisms did not alter with aging. Enzyme activities altered with aging. For example, activities of acetylcholinesterase and choline acetyltransferase decreased with aging. The potencies of nicotine, which accelerates ACh release, and exogenously applied ACh were modified by the change in enzyme activities with aging. Similar observations were obtained in the tachykinin (NK2) receptor mechanism. Effects of aging on physiological functions seem to be complementary. In iris dilator muscles, the potency of norepinephrine (NE), which altered with aging, was proportional in the receptor reserve. No age-related change was observed in the activity of sympathetic nerves, which innervate the iris dilator muscles. On the other hand, in iris sphincter muscles innervated by parasympathetic nerves, the ACh (muscarine) receptor mechanisms did not alter, but the activity in cholinergic nerves changed with aging.

Acetylcholine↗
PubMed1994

Involvement of beta 3-adrenoceptor in the relaxation response in guinea pig taenia caecum.

beta-Adrenoceptors in the guinea pig taenia caecum were investigated by measuring relaxation responses to agonists and by a radioligand binding assay using [3H]CGP 12177. The rightward shift of the isoprenaline concentration-response curve was observed by butoxamine, a beta 2-selective antagonist, and the pA2 value for butoxamine was 6.46. In control preparations, catecholamines caused relaxation with the following rank order of potency: isoprenaline > adrenaline > noradrenaline. However, in the presence of 10(-6) M phentolamine, 3 x 10(-4) M atenolol and 10(-4) M butoxamine, the rank order of potency of the agonists was: isoprenaline > noradrenaline > adrenaline. CGP 12177 caused graded relaxation of the guinea pig taenia caecum, and this response was not influenced by 10(-6) M phentolamine, 3 x 10(-4) M atenolol, 10(-4) M butoxamine or 10(-6) M propranolol. The Scatchard plot of the specific [3H]CGP 12177 binding to microsomal fractions from the guinea pig taenia caecum showed two affinity sites of the receptor: high affinity (KD = 0.64 nM) and low affinity (KD = 142.21 nM) sites. The pKD value of the high affinity site of [3H]CGP 12177 was in agreement with its pA2 value, and that of the low affinity site was in agreement with its pD2 value. These results suggest that isoprenaline-, noradrenaline- and adrenaline-induced relaxations of the guinea pig taenia caecum predominantly involve beta 2- and beta 3-adrenoceptors, whereas CGP 12177-induced relaxation is mediated solely through beta 3-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1993

Effect of tachykinins on the acetylcholine output stimulated by nicotine from guinea-pig bladder.

Effects of tachykinins on contractile responses and acetylcholine release evoked by nicotine were determined by isotonic transducer and radioimmunoassay. A sympathetic nerve blocker guanethidine and tachykinin antagonist, [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-substance P (rpwwL-SP) partially inhibited the acetylcholine release evoked by nicotine to much the same degree. In preparations treated with rpwwL-SP to block the tachykinin receptors, guanethidine had no effect on the response to nicotine and vice versa, suggesting an exclusive contribution of the sympathetic nerve communications to the action of tachykinins. A concentration response curve to neurokinin A but not SP methyl ester or Tyr0-neurokinin B was shifted to the left after cholinesterase inhibition with methanesulphonyl fluoride (MSF) and was partially inhibited by atropine. In the presence of guanethidine, an acetylcholine output by nicotine was facilitated in the presence of neurokinin A (10 nM) but not SP methyl ester (10 nM) or senktide (10 nM). These results indicate that acetylcholine release evoked by nicotine is increased by the coordinated action of sympathetic nerves and tachykinins. Tachykinin receptor subtype involved in acetylcholine release is NK2.

Acetylcholine↗
PubMed1993

Vascular relaxing mechanism of denopamine in isolated canine coronary, femoral, mesenteric, and renal arteries.

We investigated the mechanism of vascular relaxation produced by denopamine (deno), an oral positive inotropic agent that has selective beta 1-adrenergic action. Deno concentration-dependently (0.1 microM-30 microM) relaxed ring segments of canine femoral, mesenteric, and renal arteries which were partially precontracted with 1 micron phenylephrine or norepinephrine, but did not relax those precontracted with 5 microM prostaglandin F2 alpha or 40 mM K+. The relaxation was not significantly inhibited by pretreatment with 10 microM propranolol or metoprolol. Deno produced a parallel rightward shift in concentration-response curves to phenylephrine in femoral and renal arteries. The Schild plot yielded linear regressions of slopes of 1.301 +/- 0.106 and 0.823 +/- 0.122, respectively, which were not significantly different from unity. The pA2 values of Deno against phenylephrine in femoral and renal arteries were 5.41 +/- 0.03 and 5.76 +/- 0.06, respectively. On the other hand, Deno concentration-dependently (10 nM-10 microM) relaxed ring segments of canine coronary arteries which were partially precontracted with 5 microM prostaglandin F2 alpha. The relaxation was significantly inhibited by pretreatment with 10 microM metoprolol. In conclusion, vascular smooth muscle relaxation by Deno was mediated through beta 1-adrenergic action in canine coronary arteries and through the blocking effect of alpha-adrenoceptors in canine femoral, mesenteric, and renal arteries.

Adrenergic beta-Agonists↗
PubMed1993

Subtype of muscarinic receptors mediating relaxation and contraction in the rat iris dilator smooth muscle.

1. Carbachol produced a relaxation of dilator muscle at a concentration lower than 1 microM and a contraction at a concentration higher than 1 microM. 2. We studied the effects of the M1-selective antagonist, pirenzepine, the M2-selective antagonist, himbacine, the M3-selective antagonist, 4-diphenyl-acetoxy-N-methylpiperidine methiodide (4-DAMP) and the non-selective antagonist, atropine, on carbachol-induced relaxation and contraction of the rat iris dilator smooth muscle. All the antagonists competitively inhibited both the responses to carbachol. 3. In relaxation and contraction, the low affinity of pirenzepine and himbacine suggest that the rat iris dilator smooth muscle receptors are not of the M1 and M2 subtypes. In contrast, 4-DAMP potently inhibited the carbachol-induced relaxation and contraction with affinities similar to those reported for the M3 subtype. 4. Carbachol-induced relaxation and contraction of the rat iris dilator appears to be mediated through a homogeneous population of M3 subtype.

Alkaloids↗
PubMed1993

Pharmacological action of (-)-(2S,3aR,7aS)-1-[(S)-N-[(S)-1-carbonyl-3- phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic acid (trandolaprilat) in isolated smooth muscle preparations.

1. Trandolaprilat was found to inhibit angiotensin I (Ang I)-induced contraction of the rat thoracic aorta, and to augment bradykinin(BK)-induced contraction of the guinea pig ileum. In inhibitory activity (IC50) on the Ang I induced contraction of the rat thoracic aorta, trandolaprilat was about 2.4 times as potent as enalaprilat. Concerning the augmenting activity (AC50) on bradykinin-induced contraction of the guinea pig ileum, the activity of trandolaprilat was similar to that of enalaprilat. 2. Trandolaprilat had no effect on contractions induced by norepinephrine, PGF2 alpha, 5-HT or CaCl2 in the thoracic aorta of rats. 3. Trandolaprilat produced endothelium-dependent relaxation. This relaxation was inhibited by NG-methyl-L-arginine treatment, suggesting that endothelium-dependent relaxation of trandolaprilat is related to endothelium-derived-relaxation-factor(EDRF/NO). Like trandolaprilat, captopril also produced endothelium-dependent relaxation, whereas enalaprilat had no effect.

Angiotensin I↗
PubMed1993

Contractile responses and calcium movements induced by alpha 1-adrenoceptor stimulant, norepinephrine, in rabbit iris dilator muscle.

1. The mechanisms involved in contraction of rabbit iris dilator muscle induced by norepinephrine (NE) were studied. 2. The concentration-response curve of NE was not influenced by Ca2+ blockers in the normal physiological saline solution (PSS) and removal of Ca2+ from PSS. 3. In 0.01 mM EGTA containing Ca(2+)-free PSS, the NE-induced contraction was phasic, which was suppressed by TMB-8, cyclopiazonic acid, ionomycin and A23187 but still partly remained. 4. In 2 mM EGTA containing Ca(2+)-free PSS, NE increased the intracellular Ca2+ ([Ca2+]i) and muscle tension. Ryanodine abolished the increase in [Ca2+]i induced by NE but slightly inhibited the tension. 5. These results suggest that the NE-induced contraction of rabbit iris dilator in normal PSS is mainly due to the increase in the release of intracellularly sequestered Ca2+ and partly due to the Ca(2+)-independent processes.

Adrenergic alpha-Agonists↗
PubMed1993

Tachykinin receptors of the NK2 type involved in the acetylcholine release by nicotine in guinea-pig bladder.

1. The effects of guanethidine and tachykinins on nicotine- and electrical stimulation-induced cholinoceptor responses were studied in isolated urinary bladder from the guinea-pig. 2. Acetylcholine release and the contractile response stimulated by nicotine were partially reduced by a sympathetic nerve blocker, guanethidine. Neurokinin A (but not substance P methyl ester or senktide) enhanced both acetylcholine release and contraction by nicotine in the presence of guanethidine. 3. Frequency-contraction curves (1 to 50 Hz) for electrical field stimulation (EFS) were partially reduced by atropine (1 microM), and after desensitization to alpha,beta-methylene adenosine 5'-triphosphate, the atropine-resistant contraction to EFS was completely abolished. Guanethidine, the tachykinin antagonist [D-Arg1, D-Pro2, Trp7,9, Leu11]-substance P and application of neurokinin A or substance P did not change the contractile response to EFS. Preganglionic nerve stimulation (5 Hz and 20 Hz) also evoked a similar response to EFS and was not influenced at all by guanethidine or neurokinin A. 4. We conclude that the ability of nicotine to release acetylcholine is enhanced both by endogenous tachykinins (probably released from sympathetic nerves) and by exogenously applied tachykinins as a result of interaction with NK2 receptors in the urinary bladder.

Acetylcholine↗
PubMed1993

Eicosanoid-induced Ca2+ release and sustained contraction in Ca(2+)-free media are mediated by different signal transduction pathways in rat aorta.

1. The effects of 12-O-tetradecanoyl 4 beta-phorbol 13-acetate (beta-TPA) on the inositol 1,4,5-trisphosphate (IP3) production, Ca2+ release from the intracellular Ca2+ stores and sensitization of contractile apparatus, induced by prostaglandin F2 alpha (PGF2 alpha) and U46619, a thromboxane A2-mimetic, were studied, using fura-2-loaded and -unloaded rat thoracic aortic strips. 2. Both eicosanoids had characteristic patterns of responses in Ca(2+)-free, 2 mM EGTA-containing solution (Ca(2+)-free solution). They induced transient increases in intracellular Ca2+ concentration ([Ca2+]i) without corresponding transient contraction, but produced delayed, sustained contraction, where [Ca2+]i was returned to the basal level. 3. Treatment with beta-TPA for 60 min reduced the eicosanoids-induced IP3 production, suggesting that the treatment inhibits PIP2 breakdown. 4. The treatment also attenuated [Ca2+]i transient induced by the eicosanoids, but not by caffeine (an IP3-independent releaser of stored Ca2+), in fura-2-loaded preparations incubated in Ca(2+)-free solution. 5. In contrast in the presence of beta-TPA, the sustained contractions evoked by the eicosanoids in Ca(2+)-free solution were potentiated, suggesting that the sites of actions of beta-TPA and the eicosanoids may differ from each other. 6. PGF2 alpha and U46619 utilize different and parallel signal transduction pathways to release Ca2+ by IP3 produced by PIP2 breakdown (beta-TPA-sensitive), and to increase the sensitivity of contractile apparatus, in which protein kinase C may not be involved (beta-TPA-insensitive).

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

[Drug-receptor interactions in single smooth muscle cells].

Smooth muscle tissues were contracted by excitation of each muscle cell. Single cells prepared from guinea pig taenia caecum and trachea were contracted by extracellular application of acetylcholine and/or carbachol, whose concentrations were the same as those in the tissues. The concentration-response curve was shifted in a parallel fashion by competitive antagonists. The pA2-values of the antagonists were in good agreement with those estimated using the intact tissue. The apparent dissociation constants of cholinergic drugs estimated from inhibition of the specific binding of [3H]QNB (quinuclidinyl benzilate) to the single cells by the cholinergic drugs were also in agreement with the values in other membrane preparations. Similar findings were obtained in the single cells, microsomal fractions and isolated tissues from the guinea pig tracheal smooth muscles. In rabbit aortic single cells, the existence of two pharmacologically distinct alpha 1-adrenoceptor subtypes, alpha 1A and alpha 1B, in vascular smooth muscle cells was supported. Furthermore, the amount of prostaglandin F2 alpha released from guinea pig tracheal single cells was increased through activation by alpha 2-adrenoceptor agonists. The amount of prostaglandin F2 alpha released by norepinephrine decreased with age, while the total amount of alpha 2-adrenoceptors and the dissociation constants of the alpha 2-adrenergic drugs from the receptor did not change. The relaxation induced by beta-adrenoceptors did not alter with age. The total amount of beta-adrenoceptor and the dissociation constants of beta-adrenergic drugs from their receptor did not alter with age. An excellent relationship between the potency of isoprenaline and the maximum binding of [3H]dihydroalprenolol estimated in the single cells from 6- to 40-week-old guinea pigs was found, suggesting that the increase in the potency of isoprenaline is due to the increase in the maximum binding. The value in the single cells from 100-week-old guinea pigs deviated significantly from the regression line. This result suggests that the decrease in potency in the single cells from 100-week-old animals is due to a change in post beta-receptor processes in responsiveness. The smooth muscle single cells are useful for the study of drug-receptor interactions. Furthermore, post-receptor processes in responsiveness were discussed.

Acetylcholine↗
PubMed1993

Chloroethylclonidine discriminates between alpha 1A- and alpha 1B-adrenoceptors in the presence of guanosine 5'-triphosphate in rabbit thoracic aorta.

Studies on the displacement of [3H]prazosin binding by the alpha 1-agonist phenylephrine revealed the presence of at least high- and low-affinity binding sites in membrane preparations prepared from rabbit thoracic aorta. Although the low-affinity site was reduced by the pretreatment of tissues with chloroethylclonidine, this site was unaffected by the same pretreatment of membrane preparations that did not contain the GTP analog. However, in membrane preparations with the metabolically stable GTP analog GTP gamma-S (10(-5) M) and single cell preparations, the low-affinity site was completely eliminated by the chloroethylclonidine pretreatment. Displacement studies with the alpha 1-antagonist WB4101 also revealed high- and low-affinity binding sites labeled by [3H]prazosin. Displacement curves of WB4101 obtained from membrane preparations in the presence of GTP gamma-S (10(-5) M) did not differ from those in the absence of GTP gamma-S. These results suggest that the low affinity phenylephrine binding site labeled by [3H]prazosin was selectively bound by the chloroethylclonidine used to pretreat the tissues, membrane preparation containing GTP gamma-S and single cells, and that chloroethylclonidine is able to recognize these two distinct subtypes of alpha 1-adrenoceptors only when GTP gamma-S is present.

Adrenergic alpha-Antagonists↗
PubMed1993

Inhibitory effect of pilocarpine on norepinephrine release from electrically stimulated iris dilator muscles of rabbits as a most possible mechanism of pilocarpine-induced miosis.

Instillation of pilocarpine-induced a miosis in a rabbit. In an isolated iris sphincter muscle of rabbit, pilocarpine induced a small contraction and behaved as an antagonist of carbachol. The contractile response of an isolated rabbit dilator muscle to a field stimulation was inhibited by pilocarpine. This inhibitory action of pilocarpine was antagonized by atropine in a concentration-dependent manner. An amount of norepinephrine released from the electrically stimulated dilator muscle was inhibited by pilocarpine. The inhibitory effect of pilocarpine on norepinephrine release was decreased by atropine. A following explanation is proposed as a most possible mechanism for the pilocarpine-induced miosis in the rabbit. Pilocarpine activates the prejunctional cholinoceptors to inhibit norepinephrine release from the adrenergic nerve in the dilator muscle. Thus pilocarpine decreases tonus of the dilator muscle and induces the miosis.

Animals↗
PubMed1992

Characterization of alpha 1-adrenoceptor subtypes labeled by [3H]prazosin in single cells prepared from rabbit thoracic aorta.

alpha 1-Adrenoceptor agents with alpha 1-adrenoceptor subtypes sensitive and insensitive to inactivation by chloroethylclonidine were characterized in single cells prepared from rabbit thoracic aorta. WB 4101, 5-methylurapidil and spiperone interacted with high- and low-affinity sites labeled by [3H]prazosin. Chloroethylclonidine 10 microM pretreatment eliminated the low-affinity sites of displacement curves obtained with WB 4101 and 5-methylurapidil but had no effect on the high-affinity site for these agents. The treatment also reduced the site of the displacement curve obtained with spiperone but eliminated only the high-affinity site. Methoxamine and clonidine, alpha-adrenoceptor agonists, interacted with binding sites labeled by [3H]prazosin. The displacement curve for methoxamine was not affected by chloroethylclonidine 10 microM pretreatment, while that for clonidine was partially eliminated by the same type of pretreatment. These results suggest that, in single cells prepared from rabbit thoracic aorta: (1) WB 4101, 5-methylurapidil and spiperone interact with differing affinity at sites labeled by [3H]prazosin; (2) chloroethylclonidine-sensitive and -insensitive [3H]prazosin binding sites correspond to those with low- and high-affinity sites for WB 4101 and 5-methylurapidil, and a high- and low-affinity for spiperone, respectively; and (3) chloroethylclonidine treatment was shown to have no effect on the displacement curve of methoxamine but a partial effect on that of clonidine.

Animals↗
PubMed1992

Ca-blocking action of stereoisomers of CI-951, (+)-CI-951 (NC-1500) and (-)-CI-951 in the isolated muscle preparations.

1. Stereoselectivity of CI-951 in Ca-entry blocking activity was tested in guinea pig taenia caecum and urinary bladder and rabbit thoracic aorta and basilar artery. 2. NC-1500 ((+)-CI-951) and (-)-CI-951 had a selectivity to the basilar artery. 3. NC-1500 ((+)-CI-951) was about 6-16 times as potent as (-)-CI-951. 4. These results suggest that NC-1500 ((+)-CI-951) may be considered a cerebral vasodilator and have potential usefulness as a therapeutic drug.

Animals↗