Effect of ageing on alpha 2-adrenoceptor and prostaglandin F2 alpha release in single cells of guinea-pig tracheal smooth muscles.
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Aging↗
Biomedical subjects
I Takayanagi
Publications and source records attributed to I Takayanagi.
Interactions of R(+)- and S(-)-isomers of beta-adrenergic partial agonists with the high affinity site of beta-adrenoceptors.
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Adrenergic beta-Agonists↗
Effects of tachykinins and guanethidine on the acetylcholine output stimulated by nicotine from guinea-pig bladder.
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Acetylcholine↗
Alpha 1A-adrenoceptors in rabbit bronchus.
In the presence of propranolol, bronchial preparations from rabbits were markedly contracted by norepinephrine and phenylephrine but only slightly by clonidine. The contractile responses to norepinephrine were inhibited by prazosin and by high concentrations of yohimbine. The concentration-response curve of norepinephrine was shifted in parallel by WB4101 and 5-methylurapidil but not by 60-min treatment with chloroethylclonidine. These results suggest strongly that norepinephrine-induced contraction of rabbit bronchus is mediated through alpha 1A-adrenoceptors. Furthermore, cyclooxygenase inhibitors did not influence the response to norepinephrine, so norepinephrine-induced contraction is considered not to be mediated through the release of prostaglandins.
Adrenergic alpha-Antagonists↗
Effects of aging on alpha 2-adrenoceptor mechanisms in isolated guinea-pig tracheal preparations.
The effects of aging on alpha 2-adrenoceptor mechanisms in tracheal preparations isolated from 3-, 6-, 10-, 40- and 100-week-old guinea-pigs were studied. The potency of noradrenaline decreased with age. The specific binding of [3H]p-aminoclonidine to microsomal fractions prepared from tracheal smooth muscles from 6- and 40-week-old guinea-pigs was analysed by Scatchard analysis. The capacity of maximum binding sites of [3H]p-aminoclonidine was greater in the preparations from 40-week-old guinea-pigs than in 6-week-old animals, whereas the dissociation constant did not change with age. The amount of prostaglandin F2 alpha released by noradrenaline and the contractile response to prostaglandin F2 alpha decreased with age. These results suggest that an age-related decrease in the potency of noradrenaline is due to the decrease in the amount of excitable prostaglandin F2 alpha released by noradrenaline and in the contractile response to prostaglandin F2 alpha, but not to a change in the total number of alpha 2-adrenoceptors or in the dissociation constant of a drug from alpha 2-adrenoceptors. Extraneuronal uptake also plays a role in the response to noradrenaline in the tracheal preparations from older guinea-pigs.
Adrenergic alpha-Agonists↗
Propylbenzilylcholine mustard-sensitive and -resistant muscarinic receptors in cardiac muscle.
1. A left atrium of guinea pig driven electrically was used as a test organ containing M2-cholinoceptors. 2. Concentration-response curves of carbachol and butyltrimethylammonium, muscarinic full agonists, were progressively inhibited by 10 and 30 min treatments of the atrium with propylbenzilylcholine mustard (PrBCM; 10(-6) M). The 50 min treatment with PrBCM had no further significant inhibitory effect on their curves. 3. The 30 min treatment of the atrium with PrBCM completely inhibited the concentration-response curve of pilocarpine, a partial agonist. In the atrium after the 30 min treatment with PrBCM, pilocarpine shifted the concentration-response curves of the full agonists, suggesting a competitive antagonism. 4. These results suggest an existence of two subtypes of M2-receptors; PrBCM-sensitive and -resistant ones, and that the full agonists inhibit the twitch through an interaction of both the receptors, while the partial agonist produce inhibition through an activation of PrBCM-sensitive ones.
Animals↗
Effects of ageing on nicotine-induced contraction and substance P-like materials release in guinea-pig bronchus.
1. Effects of ageing on nicotine-induced contraction and release of substance P-like materials in the bronchial preparations from guinea-pigs of different ages were studied. 2. The pD2 value (potency) of nicotine decreased with age from 10 to 100 weeks. The pD2 value of substance P did not change with age suggesting that substance P receptor mechanisms do not alter with age. 3. The amount of substance P-like materials released by nicotine (10(-4) M) decreased with age from 10 to 100 weeks, supporting our previous findings that nicotine contracts the guinea-pig bronchus through the release of substance P-like materials. 4. These results suggest that the age-related decrease in the pD2 value (potency) of nicotine is due to the reduction in the amount of substance P-like materials released by nicotine.
Aging↗
Effect of ageing on response to nicotine in rabbit bronchial preparation.
1. Effect of ageing on the response to nicotine was tested in the bronchial muscle preparations from 5, 13, 100 and 125 week-old rabbits. The pD2 value (potency) of nicotine significantly increased in the preparation from the 125 week-old rabbits. No age-related change was found in the pD2 value of carbamylcholine or pA2 value of atropine. 2. No age-related change in characteristics of nicotine receptors. Choline acetyltransferase activity, the amount of acetylcholine released by nicotine and acetylcholineesterase activity decreased in the preparations from the 125 week-old rabbits. 3. Decrease in the pD2 value of nicotine in the preparation from the older rabbit is due to a decline in choline acetyltransferase activity followed by a reduction in the acetylcholine released, and not to a change in characteristics of nicotine receptors. 4. These results also suggest that enzymes may be influenced more easily with age than drug receptors.
Acetylcholine↗
Characterization of muscarine receptors in rabbit ciliary body smooth muscle using propylbenzilylcholine mustard.
1. A piece of rabbit ciliary body was mounted in organ bath and used as a test organ containing muscarine receptors. 2. A concentration response curve of carbachol was completely inhibited by a 50 min treatment of the smooth muscle preparation with propylbenzilylcholine mustard(PrBCM; 10(-6) M). This treatment was reported to block PrBCM-sensitive muscarine receptors in intestinal smooth muscle completely. 3. It is suggested that an existance of only PrBCM-sensitive muscarinic receptors, though there are two subtypes of muscarine receptors; PrBCM-sensitive and -resistant ones in intestinal smooth muscles.
Animals↗
Interactions of N-cyclopropylmethyl(-)-6 beta-acetylthionormorphine with mu-, kappa-, delta- and sigma-opioid receptors.
1. Affinities of N-cyclopropylmethyl(-)-6 beta-acetylthionormorphine (KT-90) to mu-, kappa-, delta- and sigma-receptors were tested in rat brain membrane fractions using radioligand-receptor assays. 2. Though KT-90 had nonselectively high affinities to mu-, kappa- and delta-receptors, affinity of KT-90 to sigma-receptors was lower than those to the other three receptors. 3. Affinity of KT-90 to sigma-receptors was 1000 times lower than that of buprenorphine.
Animals↗
Contractile responses of rat aorta to phenylephrine and serotonin, and aging.
1. The potency (pD2 value) of phenylephrine increased with age from 3 to 10 weeks, but decreased thereafter from 10 to 80 weeks, while the affinity (pKA value) of phenylephrine to alpha 1-adrenoceptors did not alter with aging. 2. The potency (pD2 value) of serotonin did not alter with aging. 3. There is no significant difference between slopes of regression lines between a cytosolic free Ca2+ level ([Ca2+]i) and tension in the presence of phenylephrine in aorta strips from 10- and 60-week-old rats, suggesting that the sensitivity of contractile system to Ca2+ did not alter with aging. 4. Effect of ryanodine on the transient increase of [Ca2+]i and the followed sustained contraction induced by phenylephrine or serotonin in Ca2+ free solution did not alter with aging.
Aging↗
Effects of aging on postsynaptic alpha 1-adrenoceptor mechanisms in rat aorta.
1. Effects of aging on alpha 1-adrenoceptor and S2-serotonin receptor mechanisms in rat aorta were studied. 2. In rat aorta, the potency (pD2 value) of norepinephrine or phenylephrine increased with age from 3 to 10 weeks, but decreased thereafter with age from 10 to 80 weeks. The affinity (pKA value) of norepinephrine or phenylephrine and of prazosin (pA2 value) did not alter with aging. 3. In rat vas deferens, the efficacy of norepinephrine and the maximum binding sites of [3H]prazosin increased with age from 3 to 18 weeks, but decreased thereafter with age from 18 to 60 weeks. The affinity (pKA value) of norepinephrine and the dissociation constant (KD value) of prazosin did not alter with aging. 4. In rat aorta, the potency (pD2 value) and affinity (pKA value) of serotonin, and affinity (pA2 value) of ketanserin did not alter with aging. 5. There is no significant difference between slopes of regression lines between a cytosolic free Ca2+ level [( Ca2+]i) and tension in the presence of phenylephrine in aorta strips from 10- and 60-week-old rats. 6. These results suggest that changes in alpha 1-adrenoceptor mechanisms with aging are due to changes in receptor density or receptor reserve, but not to changes in affinity of drugs to alpha 1-adrenoceptor or sensitivity of contractile system to Ca2+ mediated through alpha 1-adrenoceptor, and that S2-serotonin receptor mechanisms in rat aorta do not alter with aging.
Aging↗
Ca2(+)-dependence of endothelin-1 induced contraction of rat tail artery.
1. In rat tail artery, endothelin-1(ET-1) caused an increase in the cytosolic free Ca2+ level ([Ca2+]i) followed by a relatively sustained but not steady-state contraction in Ca2+ containing solution. 2. In the early phase of the contraction, the rate of increase in [Ca2+]i, was much faster than that in muscle tension. However, after the increases in [Ca2+]i and muscle tension reached at their peaks, there was a good correlation between the changes of the two parameters. 3. ET-1 could not induce an apparent contractile response in Ca2(+)-free medium, notwithstanding it evoked a [Ca2+]i transient in this medium. 4. The results indicate that ET-1 induce a contraction of rat tail artery which is almost fully dependent on the [Ca2+]i changes, and may inhibit the Ca2(+)-sensitivity of the contractile filaments in the early phase of the contraction.
Animals↗
Vascular smooth muscle relaxation by alpha 1-adrenoceptor blocking action of denopamine in isolated rabbit aorta.
We investigated the mechanism of vascular relaxation by denopamine (Deno), an oral positive inotropic agent that has selective beta 1-adrenergic action. Deno relaxed, dose-dependently (0.1-30 microM), ring segments of rabbit aorta, which were partially precontracted with 1 microM phenylephrine (Phe) or norepinephrine (NE), 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 parallel shifts in concentration-response curves to Phe, but this was not true for clonidine. The Schild plot analysis resulted in a linear regression of a slope of 1.075 +/- 0.063, which was not significantly different from unity, and the pA2 value of Deno against Phe was 5.57 +/- 0.02. The specific binding of [3H]prazosin to a rabbit aorta membrane preparation was displaced in a concentration-dependent manner by the simultaneous addition of Deno. The slope of a Hill plot was not significantly different from unity (1.102 +/- 0.147). The pK1 value for Deno calculated from the displacement curve was 5.29 +/- 0.17, which was not significantly different from the pA2 value of Deno. In conclusion, vascular smooth muscle relaxation by Deno was mediated by the blocking effect of alpha 1-adrenoceptors. Thus, these findings suggest that Deno may be effective in the treatment of congestive heart failure because it elicits a positive inotropic effect by beta 1-adrenergic action and vasodilation by alpha 1-adrenergic blocking action.
Adrenergic alpha-Antagonists↗
Contrasting effects of tachykinins and guanethidine on the acetylcholine output stimulated by nicotine from guinea-pig bladder [corrected].
1. Contractile responses and acetylcholine release evoked by nicotine in guinea-pig detrusor strips were determined by isotonic transducer and radioimmunoassay, respectively. Nicotine stimulated acetylcholine release and a contractile response in guinea-pig detrusor strips treated with the cholinesterase inhibitor, methanesulphonyl fluoride (MSF). Both actions evoked by nicotine were antagonized by the nicotinic receptor antagonist, hexamethonium but were insensitive to tetrodotoxin. 2. A sympathetic nerve blocker, guanethidine and a 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. The inhibitory effects of guanethidine and rpwwL-SP on acetylcholine release were significantly greater than corresponding effects on the contraction evoked by nicotine. 3. In preparations treated with rpwwL-SP to block the tachykinin receptors, guanethidine had no effect on the response to nicotine. Conversely, after treatment with guanethidine to block release of a mediator from sympathetic nerve endings, nicotine-induced responses were not affected by rpwwL-SP. 4. Nicotine-induced contraction was reduced to 30% by the muscarinic cholinoceptor antagonist, atropine and completely abolished after desensitization of P2-purinoceptors with alpha,beta-methylene ATP in the presence of atropine. 5. A concentration-contractile response curve to neurokinin A (NKA) was shifted to the left after cholinesterase inhibition with MSF. Atropine abolished the facilitatory effect of MSF and partially inhibited contractions induced by NKA at 100 nM to 1 microM. The contractile responses to substance P methyl ester (SPOMe) and Tyr0-neurokinin B (Tyr0-NKB) were not influenced by MSF or atropine. 6. After desensitization of NK, tachykinin receptors with SPOMe or preincubation with senktide, the cholinergic component of the nicotine-induced contraction was the same as the control value (100%). 7. Our findings give further support to our previous results: nicotine stimulates acetylcholine release in a tetrodotoxin-resistant manner in guinea-pig bladder and acetylcholine release evoked by nicotine is increased by the coordinated action of sympathetic nerves and tachykinin(s). It is suggested that the tachykinin receptor subtype involved in acetylcholine release is NK,.
Acetylcholine↗
Comparison of interactions of R-(+)- and S-(-)-isomers of beta-adrenergic partial agonists, befunolol and carteolol, with high affinity site of beta-adrenoceptors in isolated rabbit ciliary body and guinea-pig taenia caeci.
The stereoselectivities of beta-adrenergic partial agonists for the high affinity binding site of beta-adrenoceptors in the rabbit ciliary body and the guinea-pig taenia caeci were studied. The pA2 values of the S-(-)-isomers of befunolol and carteolol against S-(-)-isoprenaline, which were calculated from the shift of each concentration - response curve in increasing cyclic AMP levels, were significantly larger than those of the R-(+)-isomers in the guinea-pig taenia caeci, while the pA2 values of the S-(-)-isomers were not significantly larger than those of the R-(+)-isomers in the rabbit ciliary body. The pK1 values determined from the binding experiments were in good agreement with the pA2 values from the increases in cyclic AMP levels. These results suggest that the high affinity binding site of beta-adrenoceptors in the guinea-pig taenia caeci may be able to discriminate stereoselectively between the R-(+)- and S-(-)-isomers, while in the rabbit ciliary body there is no stereo-selectivity between the two enantiomers.
Adrenergic beta-Antagonists↗
Effects of the R(+)- and S(-)-isomers of beta-adrenoceptor blockers with intrinsic sympathomimetic activity, befunolol and carteolol, on rabbit intraocular pressure.
Effects of the R(+)- and S(-)-isomers of befunolol and carteolol, beta-adrenoceptors with intrinsic sympathomimetic activity, on the rabbit intraocular pressure were tested. The intraocular pressure was decreased by instillation of the R(+)- and S(-)-isomers of befunolol (0.1 and 0.3%) and of carteolol (1.0%) to the eye and attained the minimum level at 60 min. However, 0.3% of the R(+)- and S(-)-isomers of carteolol did not influence the pressure. The corresponding time courses for the intraocular pressure for the R(+)- and S(-)-isomers did not differ, suggesting that in the treatment of glaucoma, the therapeutic advantage of the R(+)-isomers of befunolol and carteolol may be similar to the S(-)-isomers.
Adrenergic beta-Antagonists↗
Differences in alpha 1-adrenoceptor mechanisms for phenylephrine and tizanidine in rabbit thoracic aorta and common iliac artery.
Based on affinity for WB4101 and susceptibility to chloroethylclonidine, we evaluated the subtype of alpha 1-adrenoceptors activated by phenylephrine (a full agonist) and tizanidine (a partial agonist). The rabbit thoracic aorta and common iliac artery contain both alpha 1A- and alpha 1B-adrenoceptors, but the alpha 1B-subtype may be more predominantly in the common iliac artery than in the thoracic aorta. In rabbit thoracic aorta and common iliac artery, phenylephrine induced contraction through both alpha 1A- and alpha 1B-subtypes and tizanidine through only the alpha 1A-subtype. The subtype activated by phenylephrine may be partly different from that activated by tizanidine in the preparations used herein.
Animals↗