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PubMed1996

[The effect of salmeterol on the activity of neutrophil chemotactic factor in patients with asthma].

OBJECTIVE: The activity of neutrophil chemotactic factor (NCF) in serum of 40 patients with asthma on their acute attacks was measured with membrane filter method. METHODS: Of the 26 patients, 13 were administed salmeterol 50 micrograms bid by inhaler and another 13 took procaterol 50 micrograms bid orally for four weeks. RESULTS: It was found that in patients with asthma NCF was 82 +/- 17 cell/10 HP, which was significantly higher than that in normal subjects (33 +/- 5 cell/10 HP, P < 0.01). After treatment with salmeterol the decrease in NCF activity was 26 cell/10 HP (P < 0.01), while the decrease in another group treated with procaterol was 8 cell/10 HP (P > 0.05). The difference between the two treated groups was significant (P < 0.01). In salmeterol treated group the decrease in NCF activity was more remarkable than the improvement in lung function. CONCLUSIONS: It was considered that the result may be related to the anti-inflammatory effect of salmeterol.

Adrenergic beta-Agonists↗
PubMed1996

[The changes of glucocorticoid receptor and beta-adrenoreceptor of lung tissues in SD rat asthma models and the effects of antiasthmatics on them].

OBJECTIVE: To observe the changes of glucocorticoid receptor (GR) and beta-adrenoreceptor (beta-AR) of lung tissue and the effects of oral procaterol, salbutamol and intraperitoneal (i.p.) or inhaled (i.h.) dexamethasone (Dex). METHOD: The GR or beta-AR were determined by using 3H-dexamethasone and 3H-Dihydroalprenolol as ligand respectively, in groups of rat asthma models at 1, 3, 7, 14th day and groups received antiasthmatics on the 7th day after daily consecutive challenges. RESULTS: The GR Bmax of asthma groups increased significantly after the first challenge, but decreased since the third day to a lower level than that of healthy control. The KD also decreased significantly since the third day. The beta-AR Bmax of asthma group gradually decreased to a significant low level on the 14th day. The Dex i.p. group had the lowest GR Bmax and the Dex i.h. group had the highest beta-AR Bmax among the treated. In the procaterol and salbutamol group, there had no decrease of GR Bmax compared with that of controls. CONCLUSIONS: The GR and beta-AR levels of lung tissues changed after daily challenges. The GC played a down-regulation role on GR and an up-regulation role on beta-AR in lung tissues. The Dex i.h. had more advantages than Dex i.p. in terms of GR and beta-AR regulations.

Adrenergic beta-Agonists↗
PubMed1994

Regulation of beta-adrenoceptors in the guinea-pig sinoatrial node.

This study examined the changes of beta-adrenoceptors in the guinea-pig sinoatrial nodal region following 7 day (-)-isoprenaline (400 micrograms/kg/h s.c.) infusion and the relationship between beta-adrenoceptor desensitization and receptor down-regulation. Changes in beta 1- and beta 2-adrenoceptor density were measured using quantitative autoradiography and function in organ bath studies. (-)-Isoprenaline treatment produced a marked decrease in total (from 57.5 to 33.9 fmol/mg protein), beta 1- (from 49.4 to 32.8 fmol/mg protein), and beta 2-adrenoceptor density (from 8.1 to 1.05 fmol/mg protein) in the sinoatrial node. In adjacent right atrium, treatment produced no change in total (39.5 and 36.7 fmol/mg protein) or beta 1-adrenoceptors (35.9 and 36.4 fmol/mg protein) but did decrease beta 2-adrenoceptors (from 3.7 to 0.3 fmol/mg protein). Chronotropic effects were measured in spontaneously beating right atrium. Procaterol, a selective beta 2-adrenoceptor agonist, caused a biphasic chronotropic response in control right atria, the first part of which was abolished in the tissue from treated animals. The maximum increase in right atrial rate to RO363, a beta 1-adrenoceptor selective partial agonist, was reduced from 114 bpm in control to 43 bpm in treated animals. In electrically driven right atrium with the sinoatrial node removed procaterol failed to produce a positive inotropic response via beta 2-adrenoceptors, but the maximum response to RO363 was reduced from 0.75 g in the control tissue to 0.12 g in the treated tissue. This study showed that changes in beta 2-adrenoceptor density following 7 day (-)-isoprenaline infusion are compatible with reduced functional responsiveness in the SA node. The reduction of beta 1-adrenoceptor number in the SA node was also compatible with the reduced chronotropic response in this tissue. However the lack of effect on beta 1-adrenoceptor density in the right atrium was not consistent with the decrease in beta 1-adrenoceptor mediated inotropic response in this tissue. This suggests that beta-adrenoceptor desensitization is not always associated with receptor down-regulation but depends also on the changes in the cell signalling system beyond the level of the receptor which differ according to the cardiac location.

Adrenergic beta-Agonists↗
PubMed2002

The efficiency of beta 2-agonist delivery through tracheal tubes with the metered-dose inhaler: an in vitro study.

PURPOSE: To study the delivery efficiency of procaterol aerosols administered through the tracheal tube (ETT) with a metered-dose inhaler (MDI) during apnea. METHODS: First, in a normal room air environment (at ambient temperatures of 24 degrees to 26 degrees C), we measured the amount of aerosol delivered through the ETT by comparing the weight of a 2-l bottle before and after firing the MDI directly into the 15-mm adapter of the ETT. The distal half of the ETT was inserted in the bottle. This procedure was repeated using five different ETTs with an internal diameter of 4-8.5 mm. The delivery efficiency was obtained by dividing the amount of aerosol delivered through the ETT by the total aerosol output per MDI puff. Next, we investigated whether the connector attached to the 15-mm ETT adapter could reduce the delivery, by repeating the same procedure with 4-mm and 5-mm ETTs. Finally, we compared the efficiencies of aerosol delivery through the 5-mm ETT and the 7.5-mm ETT in a normal room air environment with results obtained under a humidified condition (100% humid air at 37 degrees C). RESULTS: The percentages of aerosol delivered through the ETTs in a normal room air environment were 40%-60%, except for the 4-mm ETT, for which the percentage was 32.7% +/- 6.6% ( P < 0.05 vs that with the 5-mm ETT or the 6-mm ETT). A connector attached to the 15-mm ETT adapter significantly decreased the delivery efficiencies (19.0% +/- 5.8% vs 32.7% +/- 6.6% with the 4-mm ETT, 24.6% +/- 11.8% vs 51.7% +/- 10.8% in the 5-mm ETT) when compared with those without a connector. The delivery efficiencies under the humidified condition in the 5-mm ETT and the 7.5-mm ETT were 65.5% ( P < 0.05) and 89.8% of those in the normal room air environment, respectively. CONCLUSION: The efficiency of delivery of procaterol aerosol through the ETTs was unexpectedly high (approximately half of the total aerosol output per MDI puff in the 5-mm to 8.5-mm ETTs, and one third of the total aerosol output per MDI puff in the 4-mm ETT). A connector attached to the 15-mm ETT adapter noticeably decreased the delivery efficiency. In the smaller-sized ETT, delivery efficiency was significantly lower under the humidified condition than in the normal room air environment.

Journal Article↗
PubMed1986

Classification of beta-adrenergic subtypes in immature rabbit bone marrow erythroblasts.

The beta-adrenergic receptors of immature rabbit bone marrow erythroid cells (proerythroblasts and basophilic erythroblasts) were identified. [125I]iodocyanopindolol bound to membrane preparations derived from these erythroblasts in a rapid, reversible and saturable manner. Scatchard analysis of binding data revealed a single class of binding sites (Hill coefficient of 0.954) with an apparent equilibrium dissociation constant (Kd) of 8 pM, and a density of binding sites (Bmax) of 1.53 pM/10(6) cells, corresponding to 920 receptors per cell. The binding of [125I]iodocyanopindolol was inhibited stereospecifically by concentrations of (-)-propranolol 2 orders of magnitude lower than by the (+)-isomer. Only L-isoprenaline and L-adrenaline activated the adenylate cyclase of immature rabbit erythroblasts, while L-noradrenaline, a beta 1-adrenergic agonist, was inactive. The order of potency of different agonists for displacement of bound [125I]iodocyanopindolol was: isoprenaline greater than adrenaline greater than noradrenaline with respective EC50 (concentration required for half maximal inhibition of binding) of 7.9 X 10(-7) M, 1.5 X 10(-5) M and 7.9 X 10(-5) M. This agonist potency series did not change with differentiation of rabbit bone marrow erythroblasts. The inhibition of specific [125I]iodocyanopindolol binding to immature cells by beta 1- and beta 2-selective drugs (noradrenaline, practolol, procaterol and butoxamine) resulted in linear Hofstee plots. The inhibition curves obtained with procaterol and butoxamine, with apparent Kd values of 3.1 X 10(-9) M and 4.9 X 10(-9) M, further evidence that the high-affinity binding sites correspond to a homogeneous beta 2-receptor subtype.

Adenylyl Cyclases↗
PubMed1992

Both beta 1- and beta 2-adrenoceptors are involved in mediating phosphatidylcholine secretion in rat type II pneumocyte cultures.

A primary culture of rat type II pneumocytes was used for the pharmacological and functional characterization of beta-adrenoceptor subtypes. The beta-adrenoceptor agonists, isoprenaline, dobutamine and procaterol concentration dependently increased the secretion of phosphatidylcholine. These effects were attenuated by propranolol. The effect of dobutamine was attenuated by atenolol, and that of procaterol by ICI 118,551. Isoprenaline-induced secretion was attenuated by the combination of the two blockers but not by each one alone. In conclusion, both beta 1- and beta 2-adrenoceptor subtypes mediate phosphatidylcholine secretion in rat type II pneumocytes.

Adrenergic beta-Agonists↗
PubMed1990

Demonstration of both beta 1- and beta 2-adrenoceptors mediating negative chronotropic effects on spontaneous activity in isolated bovine mesenteric lymphatics.

The pharmacological classification of beta-adrenoceptor subtypes in isolated bovine mesenteric lymphatics was studied by using various beta-adrenoceptor agonists and antagonists. Isoproterenol (ISP) (10(-10)-10(-8) M) produced dose-dependent negative chronotropic effects on the rhythm of spontaneous contractions in the lymphatic preparation. The ISP-induced effects were dose-dependently blocked by pretreatment with 10(-8)-10(-7) M metoprolol (a selective beta 1 antagonist) as well as 10(-8)-10(-7) M propranolol (a beta 1 and beta 2 antagonist). Dobutamine (a selective beta 1 agonist) caused a dose-dependent negative chronotropic effect, which was significantly blocked by pretreatment with 10(-8) M metoprolol. Salbutamol and procaterol (selective beta 2 agonists) also produced dose-dependent negative chronotropic effects, which were dose-dependently inhibited by pretreatment with 10(-8)-10(-7) M propranolol, but not by 10(-7) M metoprolol. The decreasing order of the relative potency was as follows: ISP greater than procaterol greater than salbutamol greater than dobutamine. These results suggest that bovine mesenteric lymphatics contain both beta 1- and beta 2-adrenoceptors and that both subtypes can produce a negative chronotropic effect on the rhythm of spontaneous contractions, when stimulated.

Adrenergic beta-Agonists↗
PubMed1998

Beta-adrenoceptor subtypes in the ureteral smooth muscle of rats, rabbits and dogs.

We investigated the beta-adrenoceptor subtypes mediating ureteral relaxation in rats, rabbits and dogs. The relaxing effects of beta-adrenoceptor agonists were evaluated on KCl-induced ureteral contractions. The rank order of potency of the catecholamines tested was isoprenaline > noradrenaline > adrenaline in rat ureter; isoprenaline > adrenaline > noradrenaline in rabbit ureter; only isoprenaline was effective in canine tissues. The beta1-adrenoceptor agonist, dobutamine, produced relaxation of rat ureter. The beta2-adrenoceptor agonist, procaterol, produced more significant relaxation of rabbit ureter than did dobutamine. CL-316243 [(R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1,3-b enzodioxole-2,2-dicarboxylate] and CGP-12177A [(+/-)[4-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-+ ++benzimidazol-2-one hydrochloride], beta3-adrenoceptor agonists, were more effective in relaxing canine ureter than were dobutamine and procaterol. Isoprenaline-induced relaxation was antagonized by a beta1-adrenoceptor antagonist, CGP-20712A [2-hydroxy-5(2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1H-imidazol e-2-yl)phenoxy)propyl)amino)ethoxy)-benzamide monomethane sulphonate], in rats and by a beta2-adrenoceptor antagonist, ICI-118,551 [(+/-)-1-[(2,3-dihydro-7-methyl- 1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride], in rabbits. The non-selective beta-adrenoceptor antagonist, bupranolol, antagonized isoprenaline-induced relaxation in all species tested. In conclusion, beta-adrenoceptor agonists may relax ureter by stimulating mainly beta1-adrenoceptors in rats, beta2-adrenoceptors in rabbits and mainly beta3-adrenoceptors in dogs.

Adrenergic beta-Agonists↗
PubMed1989

Classification of beta-adrenoceptors in ferret tracheal smooth muscle by pharmacological responses.

Beta-adrenoceptors in ferret tracheal smooth muscle were classified into beta 1 or beta 2 by determination of (i) the potency rank order for isoprenaline, noradrenaline and adrenaline, and (ii) apparent pA2-values for a specific beta 1-antagonist (practolol) and a specific beta 2-antagonist (ICI 118.551) and (iii) concentration-inhibition curves for procaterol, a beta-agonist showing a biphasic concentration-response curve in organs with a mixed beta 1 and beta 2 adrenoceptor population. We used in vitro tracheal rings and assessed the responses to beta-adrenoceptor agonists as inhibition of phasic contractions elicited by electrical field stimulation (2 Hz for 20 s) or relaxation of tonic contractions elicited by acetylcholine (0.5 microM). The potency rank order for the agonists was isoprenaline greater than noradrenaline approximately adrenaline indicating action through beta 1-receptors. Apparent pA2-values for the antagonists were for 1, 3 and 10 microM practolol 6.0 (SE 0.27), 6.1 (SE 0.21) and 6.3 (SE 0.03), respectively. Apparent pA2 for 0.1, 1 and 10 microM ICI 118.551 were 6.8 (SE 0.25), 6.7 (SE 0.12) and 6.1 (SE 0.14), respectively. These values agree well with published pA2-values for the action of these drugs on beta 1-adrenoceptors. However, the Schild plot for ICI 118.551 was alinear indicating a possible heterogeneity of the beta-adrenoceptors in ferret trachea. The concentration-response curve for procaterol showed the biphasic form typical for organs with a mixed beta 1 and beta 2 population. However, the lower part of the curve, reflecting stimulation of beta 2-adrenoceptors reached only 17.5% (SE 1.4) of the maximally achieved inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Plasma concentrations of disodium cromoglycate after various inhalation methods in healthy subjects.

AIMS: To compare the plasma concentrations of disodium cromoglycate (DSCG) following various inhalation procedures in healthy volunteers. METHODS: Nine healthy subjects inhaled 2 mg of aerosol, 20 mg of nebuliser solution only, 20 mg of nebuliser solution mixed with isotonic saline, or 20 mg of nebuliser solution mixed with saline and procaterol, a beta2-adenoceptor agonist, on separate occasions 2-3 weeks apart. Plasma concentrations of DSCG were determined by high-performance liquid chromatography (h.p.l.c.). RESULTS: The peak plasma concentrations of DSCG were 1.5+/-0.7 (range 0.4-2.4) ng ml-1 in the aerosol group, 8.8+/-6.2 (range 5.3-19.9) ng ml-1 in the nebuliser solution only group, 17.2+/-16.3 (range 5.0-38.6) ng ml-1 in the nebuliser solution plus isotonic saline group, and 24.5+/-11. 9 (range 10.2-44.9) ng ml-1 in the nebuliser solution plus saline and procaterol group. Thus subjects who used the nebuliser had markedly higher plasma concentrations of DSCG than subjects who used the aerosol inhaler. CONCLUSIONS: These findings may have important implications for the evaluation of inhalation treatment with DSCG for bronchial asthma.

Administration, Inhalation↗
PubMed2001

Characterization of increased cough sensitivity after antigen challenge in guinea pigs.

Increased sensitivity of cough reflex is a fundamental feature of bronchodilator resistant non-productive cough associated with eosinophilic tracheobronchitis. Our hypothesis is that cough sensitivity is increased by airway allergic reaction characterized by airway eosinophilic inflammation. The aim of this study was to elucidate the hypothesis and clarify the characteristics of the increased cough sensitivity. Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an aerosolized antigen or saline in actively sensitized or non-sensitized (naive) conscious guinea pigs and then bronchoalveolar lavage was performed. The cough response was also measured 1 day before and 1, 2, 3, 5 and 7 days after an aerosolized antigen challenge in sensitized or naive animals. In addition, effect of procaterol (0.1 mg/kg), atropine (1 or 10 mg/kg), phosphoramidon (2.5 mg/kg) given intraperitoneally 30 min before the capsaicin challenge or capsaicin desensitization on the cough response was examined. Furthermore, the thromboxane A2 (TXA2) receptor antagonist S-1452 in a dose of 0.01 or 0.1 mg/kg or vehicle (saline) was given intraperitoneally at 24 and 1 h before the measurement of cough response. Number of coughs caused by capsaicin was extremely increased 24 h after an antigen challenge in sensitized guinea pigs compared with a saline or an antigen challenge in naive animals or a saline challenge in sensitized animals. The increased cough response disappeared at 3-7 days after the antigen challenge. Eosinophils in bronchoalveolar lavage fluid obtained after the measurement of capsaicin-induced coughs, which was performed 24 h after the antigen challenge, were significantly increased in sensitized guinea pigs. The eosinophil count was significantly correlated to the number of capsaicin-induced coughs. Procaterol or atropine did not alter the antigen-induced increase of cough sensitivity, whereas atropine did reduce the cough response in naive animals. Phosphoramidon increased the number of capsaicin-induced coughs in naive guinea pigs but not in sensitized and antigen-challenged animals. Capsaicin desensitization decreased the cough response in both antigen-challenged sensitized guinea pigs and naive animals. S-1452 reduced the antigen-induced increase of cough response in sensitized guinea pigs, but not in naive animals. Airway allergy accompanied with airway eosinophilia induces transient increase in cough sensitivity, which is not mediated by bronchoconstriction. The increased cough sensitivity may result in part from inactivation of neutral endopeptidase and TXA2, one of the inflammatory mediators.

Allergens↗
PubMed1998

Molecular identification and coexpression of galanin and GalR-1 galanin receptor in the human ocular ciliary epithelium: differential modulation of their expression by the activation of alpha2- and beta2-adrenergic receptors in cultured ciliary epithelial cells.

Here we report the coexpression of the neuropeptide galanin and GalR-1 galanin receptors in the human ciliary epithelium, a bilayer of neuroepithelial cells [nonpigmented (NPE) and pigmented (PE)] with neuroendocrine functions, and in a cell line (ODM-2) derived from the NPE cells. Stimulation of ODM-2 cells with phorbol ester [phorbol 12-myristate 13-acetate (PMA)] or forskolin resulted in an up-regulation (two- to threefold) of galanin mRNA expression. Procaterol, a selective beta2-adrenergic agonist, and the catecholamine isoproterenol exerted a long-term down-regulation on galanin mRNA expression when added alone or in combination with PMA or forskolin. These actions exerted by procaterol or isoproterenol were abolished in the presence of ICI 118,551, a selective beta2-adrenergic antagonist. A radioimmunoassay for galanin peptide indicated that galanin or a galanin-like product is present in the human aqueous humor fluid and is accumulated with time in the culture medium of ODM-2 cells. It is interesting that norepinephrine, which exhibited no effect on galanin mRNA expression, induced a down-regulation in the level of galanin or galanin-like product accumulated in the medium of cultured ODM-2 cells to levels even lower than those induced by beta2-adrenergic agonists. This effect is best explained by the concomitant up-regulation (four- to fivefold) of GalR-1 galanin receptor transcripts induced through the activation of alpha2-adrenergic receptors. These findings support the view that pathways elicited by the activation of alpha2- and beta2-adrenergic receptors influence the expression of galanin and GalR-1 galanin receptors in ciliary epithelial cells.

Adrenergic alpha-Agonists↗
PubMed1989

Coexistence and localization of beta 1- and beta 2-adrenoceptors in the human heart.

Quantitative autoradiography was used to determine the location and density of beta 1- and beta 2-adrenoceptors in the right atrium (RA), left ventricular free wall (LVFW), right ventricular free wall (RVFW), interventricular septum (IVS), right atrium from an area near the atrioventricular node (RAAV) and cardiac nerves (N) taken from a patient with end-stage cardiac failure. The densities of beta-adrenoceptors detected by the non-selective beta-adrenoceptor antagonist radioligand (-)-[125I] cyanopindolol (50pM) were 4.93 (N), 10.6 (RVFW), 12.2 (RA), 12.4 (IVS), 15.8 (LVFW) and 18.7 fmol (mg protein)-1 (RAAV). The proportion of beta 2-adrenoceptors ranged from 19.5% (RAAV) to 95% (N). RA taken from patients with ischaemic heart disease had a higher density of beta-adrenoceptors (29.3 fmol (mg protein)-1). The results suggest that both beta 1- and beta 2-adrenoceptors are down-regulated in patients with end-stage cardiac failure. Positive inotropic responses were established to (-)-isoprenaline, RO363 (beta 1-selective), procaterol (beta 2-selective) and dopexamine in the absence or presence of the antagonist CGP 20712A (beta 1-selective) or ICI 118,551 (beta 2-selective) in electrically driven human right atrial appendage strips. RO363 and procaterol were nearly full agonists in this preparation and produced their responses through activation of beta 1- or beta 2-adrenoceptors, while dopexamine was a partial agonist which produced its inotropic responses through activation of both receptor subtypes. These studies demonstrate the presence and location of beta 1- and beta 2-adrenoceptors in the human heart.

Animals↗
PubMed1984

Pre- and postjunctional adreno- and muscarinic receptor functions in the isolated human corpus spongiosum urethrae.

In isolated tissue from the human corpus spongiosum urethrae (CS) the effects of adrenoreceptor and muscarinic receptor active drugs on release of 3H-noradrenaline (NA) from noradrenergic nerves and on isometric tension were investigated. The electrically induced release of 3H was reduced by clonidine (alpha 2-adrenoreceptor agonist), increased by rauwolscine (alpha 2-adrenoreceptor antagonist), and little affected by phenylephrine (alpha 1-adrenoreceptor agonist) and prazosin (alpha 1-adrenoreceptor antagonist). Isoprenaline (beta 1- and beta 2-adrenoreceptor agonist) and procaterol (beta 2-adrenoreceptor agonist) increased the release, propranolol (beta 1- and beta 2-adrenoreceptor antagonist) reduced it, and prenalterol (beta 1-adrenoreceptor agonist) and atenolol (beta 1-adrenoreceptor antagonist) had no effect. Carbachol (muscarinic receptor agonist) decreased and scopolamine (muscarinic receptor antagonist) increased stimulation-induced efflux of 3H. NA, phenylephrine and clonidine contracted isolated CS preparations, clonidine being less potent and having less intrinsic activity than phenylephrine. Prazosin was more effective than rauwolscine for inhibition of NA-induced contractions, and prazosin, but not rauwolscine, abolished electrically induced contractions. Isoprenaline and procaterol, but not prenalterol, relaxed NA-contracted preparations. These relaxations could be blocked by propranolol but not by atenolol. Acetylcholine and carbachol relaxed NA-contracted preparations but had no contractant effect on any of the preparations tested. The results suggest that prejunctionally in the human CS, the alpha-adrenoreceptors are of alpha 2-type and the beta-adrenoreceptors of beta 2-type. Postjunctionally, the main alpha-adrenoreceptor function seems to be of alpha 1-type and the beta-adrenoreceptor function of beta 2-type. Stimulation of muscarinic receptors may inhibit the effects of NA both by decreasing its release from noradrenergic nerves and by counteracting its postjunctional effects.

Adrenergic alpha-Agonists↗
PubMed1986

Thyroxine treatment of aged or young rats demonstrates that vascular responses mediated by beta-adrenoceptor subtypes can be differentially regulated.

Responses to vascular relaxant drugs were obtained on KCl (15 mM)-contracted isolated ring preparations of pulmonary artery and aorta from young (1-2 months old) and aged (greater than 16 months old) rats. These vessels contain both beta 1- and beta 2-adrenoceptors. Relaxant responses (i.e. relaxation expressed as a % of the KCl-induced contraction) to isoprenaline, procaterol (beta 2-selective partial agonist), fenoterol (beta 2-selective) and noradrenaline (beta 1-selective) but not those of forskolin, 3-isobutyl-1-methylxanthine, enprofylline or sodium nitrite, were smaller on preparations from aged rats than on those from young rats. Thyroxine (T4)-treatment (1 mg kg-1 s.c. thrice weekly for 3-5 weeks) of aged or young rats enhanced responses to isoprenaline and noradrenaline but reduced those to procaterol, when compared with preparations from age-matched saline-treated control rats. The agonist order of potency, determined in young rats, was isoprenaline greater than noradrenaline greater than adrenaline in preparations from T4-treated rats compared with isoprenaline greater than adrenaline greater than noradrenaline in saline-treated control rats. It is concluded (a) that the age-related decline in vascular responses to beta-adrenoceptor agonists involves beta-adrenoceptor mechanisms specifically and possibly beta 2-adrenoceptors more than beta 1-adrenoceptors; and (b) that T4-treatment of rats enhances beta 1-adrenoceptor-mediated and reduces, or does not change, beta 2-adrenoceptor-mediated responses of preparations of rat pulmonary artery and aorta. In preparations from control rats beta 2-adrenoceptors were functionally predominant but in preparations from T4-treated rats beta 1-adrenoceptors appeared to become functionally predominant.

Adrenergic beta-Agonists↗
PubMed1987

Influence of thyroid status on responses of rat isolated pulmonary artery, vas deferens and trachea to smooth muscle relaxant drugs.

1 Responses to relaxant drugs have been examined on isolated KCl-contracted smooth muscle preparations from rats in which thyroid status was changed by prior treatment with either thyroxine (T4) for 1 week (preparations of pulmonary artery, trachea and vas deferens) or methimazole for 10-12 weeks (pulmonary artery preparations). 2 On pulmonary artery preparations, T4 treatment caused a significant increase in the magnitude of the relaxant responses to noradrenaline and isoprenaline but not those to adrenaline. The potency of noradrenaline was increased 5.6 fold but that of isoprenaline and adrenaline was unchanged. This resulted in a change in the relative potencies from adrenaline greater than noradrenaline (controls) to noradrenaline = adrenaline (T4-treated). Methimazole treatment caused a significant reduction in the magnitude of the responses to noradrenaline and in its potency (2.8 fold). Isoprenaline and procaterol were unaffected. 3 On pulmonary artery preparations, T4 treatment did not affect the magnitude of the responses to forskolin, sodium nitrite or isobutylmethylxanthine (IBMX) or their potency. In vitro treatment with the monoamine oxidase (MAO) inhibitors, iproniazid or pargyline, did not potentiate responses to either noradrenaline or isoprenaline. Therefore, it was concluded that the T4-induced changes in the magnitude of the responses to noradrenaline and isoprenaline and in the potency of noradrenaline were unlikely to be due to reduced activity of cyclic nucleotide phosphodiesterase(s) or MAO. 4 On preparations of vas deferens and trachea, T4 treatment had no effect on the magnitude of the responses to noradrenaline, isoprenaline, adrenaline or procaterol. 5 We concluded that, on pulmonary artery T4 treatment of rats increased, while methimazole treatment reduced, the magnitude of the responses to, and/or the potency of, the beta-adrenoceptor agonists, noradrenaline and isoprenaline, by a mechanism which is specifically associated with the beta-adrenoceptors, and which is probably selective for the beta-subtype. T4 treatment caused no change in responses of vas deferens to beta-adrenoceptor agonists. On trachea the only change was a small increase in the potency of noradrenaline. The differences in the effects of T4 treatment on beta-adrenoceptormediated responses of rat pulmonary artery, vas deferens and trachea may be due to the differences in the beta-adrenoceptor populations of these three tissue types and/or differences in the effects of thyroid hormones on vascular compared with non-vascular smooth muscle.

Animals↗
PubMed1987

Characterization and autoradiographic localization of beta-adrenoceptor subtypes in human cardiac tissues.

1 Receptor autoradiography using (-)-[125I]-cyanopindolol (CYP) was used to study the distribution of beta-adrenoceptor subtypes in human right atrial appendage, left atrial free wall, left ventricular papillary muscle and pericardium. 2 The binding of (-)-[125I]-CYP to slide-mounted tissue sections of human right atrial appendage was time-dependent (K1 = 4.11 +/- 1.01 X 10(8) M-1 min-1, K-1 = 1.47 +/- 0.25 X 10(-3) min-1, n = 3), saturable (42.02 +/- 2.96 pM, n = 4) and stereoselective with respect to the optical isomers of propranolol (pKD (-):8.97 +/- 0.02, (+):6.88 +/- 0.06, n = 3). 3 The proportions of beta-adrenoceptor subtypes were determined in slide-mounted tissue sections using the antagonists CGP 20712A (beta 1-selective) and ICI 118,551 (beta 2-selective). In right atrial appendage and left ventricular papillary muscle 40% (34-45%) of the beta-adrenoceptors were of the beta 2-subtype. 4 Images from X-ray film and nuclear emulsion coated coverslips exposed to (-)-[125I]-CYP-labelled sections showed an even distribution of beta-adrenoceptor subtypes over the myocardium of the right atrial appendage, left ventricular papillary muscle and left atrial free wall. Sections of pericardium exhibited predominantly beta 2-adrenoceptors. beta 2-Adrenoceptors were localized to the intimal surface of coronary arteries. 5 The selective beta 1-adrenoceptor agonist RO363 and beta 2-selective agonist procaterol produced concentration-dependent inotropic responses in right atrial appendage strips. Responses to RO363 were antagonized by CGP 20712A (pKB = 9.29) suggesting an interaction with beta 1-adrenoceptors. Responses to procaterol were antagonized by ICI 118,551 (pKB = 9.06) suggesting an interaction at beta 2-adrenoceptors. 6 The finding that a significant proportion of human myocardial adrenoceptors are of the beta 2-subtype has important clinical implications for the involvement of these receptors in the control of heart rate and force, and the autoradiographic evidence suggests other roles in the coronary vasculature and pericardium.

Adolescent↗
PubMed1990

Beta 1-adrenoceptors mediate smooth muscle relaxation in mouse isolated trachea.

1. The relaxant effects to the beta-adrenoceptor agonists isoprenaline, adrenaline, noradrenaline, RO363, procaterol and fenoterol were investigated in carbachol-contracted mouse isolated tracheal preparations. 2. The order of potencies for those beta-adrenoceptor agonists that induced full relaxation of carbachol-contracted mouse tracheal preparations was isoprenaline greater than RO363 greater than noradrenaline = adrenaline greater than fenoterol. The EC50 value of isoprenaline for relaxation was 46 nM. The beta 1-adrenoceptor-selective agonist, RO363 was ten times more potent than the beta 2-adrenoceptor-selective agonist, fenoterol. The highly beta 2-adrenoceptor-selective agonist procaterol was a partial relaxant and induced only 28 +/- 4% relaxation. 3. Relaxations induced by noradrenaline and isoprenaline were not significantly affected by the neuronal uptake inhibitor, cocaine (10 microM) or by the extraneuronal uptake inhibitor, deoxycorticosterone acetate (25 microM) respectively. The alpha-adrenoceptor agonist methoxamine induced no observable elevation of mouse tracheal smooth muscle tone. 4. Schild plots for the beta-adrenoceptor antagonists, atenolol and betaxolol (beta 1-adrenoceptor-selective) and ICI 118,551 (beta 2-adrenoceptor-selective) were linear, with slope values approaching unity. Mean pA2 values derived for atenolol, betaxolol and ICI 118,551 for antagonism of beta-adrenoceptor-mediated relaxation were 7.1, 8.4 and 7.2, respectively. These data were independent of the use of isoprenaline or noradrenaline as the agonist. 5. These findings indicate that beta-adrenoceptor-mediated relaxations of mouse isolated trachea occur predominantly through activation of beta 1-adrenoceptors.

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