β1-Adrenoceptors mediating relaxation of the guinea-pig trachea: experiments with prenalterol,a β1-selective adrenoceptor agonist

In the presence of 17 β-oestradiol, prenalterol, a β₁-selective adrenoceptor agonist, caused a dose-dependent relaxation of the isolated, pilocarpine-contracted guinea-pig trachea. This effect was blocked by the antagonists propranolol (non-selective) and practolol (β₁-selective) but not by IPS 339 [(t-butylamino-3-ol-2-propyl)oximino-9-fluorene HCl] (β₂-selective). The relaxing effect of terbutaline, a β₂-selective adrenoceptor agonist, was more efficiently blocked by IPS 339 than by practolol. These data support the hypothesis that the guinea-pig trachea contains both β₁- and β₂-adrenoceptors mediating relaxation and that the β₁-adrenoceptors are selectively stimulated by prenalterol. The efficacy of prenalterol was less than that of terbutaline, thus confirming its partial agonistic activity. In the absence of 17 β-oestradiol, the ability of prenalterol to relax the pilocarpine-contracted trachea was lost. It is suggested that 17 β-oestradiol may act as a functional antagonist to pilocarpine as it caused a partial relaxation itself.     

Further Studies on the Cardiomegaly Induced by β-Adrenoceptor Agonists

Abstract: Rats received continuous infusions of β-adrenoceptor agonists by means of Alzet osmotic mini-pumps implanted subcutaneously. After 7 days of isoprenaline infusion (2 mg/kg per day) the heart/body weight ratio increased about 40 per cent compared with placebo treatment. The difference persisted after freeze-drying indicating a true hypertrophy and not merely an oedema. When terbutaline (20 mg/kg per day) was substituted for isoprenaline, the increase in wet weight ratio reached only about 5 per cent. Procaterol (2 mg/kg per day) and pirbuterol (20 mg/kg per day) had no effect on the heart weight. It is concluded that in doses expected to cause comparable stimulation of β₂-adrenoceptors the unselective agonist isoprenaline is able, more than the β₂-selective agonists terbutaline, procaterol and pirbuterol to cause cardiac hypertrophy thus indicating the involvement of β₁-adrenoceptors.     

β1- and β3-adrenoceptors mediate relaxation in ovine trachealis smooth muscle

1 Isoprenaline (non-selective) and noradrenaline (β₁-selective) concentration-dependently relaxed ovine tracheal strips precontracted with carbachol. The pD₂ values were 7.07 ± 0.08 and 6.13 ± 0.10 for isoprenaline and noradrenaline, respectively. In the same preparation, salbutamol either produced weak relaxation or in some cases, contractile responses indicating the presence of very little or no β₂-adrenoceptors in this preparation. 2 Isoprenaline-and noradrenaline-induced relaxations were antagonized by propranolol and atenolol with pA₂ values in the range reported in the literature for an action on β₁-adrenoceptors. ICI 118551 also antagonized isoprenaline- and noradrenaline-induced relaxation but at concentrations much higher than are required to block β₂-adrenoceptors, confirming that β₂-adrenoceptors do not contribute significantly to these responses. 3 The selective β₃-adrenoceptor agonist, BRL 37344A produced concentration-dependent relaxation of tracheal strips. BRL 37344A was a full agonist producing 100% relaxation of carbachol-induced tone. BRL 37344A-induced relaxation was weakly antagonized by propranolol confirming an action, mainly, on β₃-adrenoceptors. Cyanopindolol antagonized isoprenaline-induced relaxation (in the presence of propranolol, 10^??7 m ) with a pA₂ value of 8.06 ± 0.24. 4 It was therefore concluded that β₁- and β₃-adrenoceptors mediated agonist-induced relaxation in sheep tracheal strips.     

Potentiation of the relaxing action of isoproterenol by forskolin in rabbit aortic rings: The involvement of β2-adrenoceptors

• 1.1. Forskolin, an activator of adenylate cyclase, potentiated the relaxing response to isoproterenol in rabbit aortic rings precontracted by phenylephrine (PE).
• 2.2. The potentiating effect of forskolin was inhibited by propranolol, a β-adrenoceptor inhibitor, but not by methylene blue, a guanylate cyclase inhibitor.
• 3.3. The relaxing response to terbutaline, a β₂-adrenoceptor agonist, but not lower concentrations of dobutamine, a β₁-adrenoceptor agonist, also was potentiated by forskolin. Forskolin, however, potentiated the relaxing response to high concentrations of dobutamine, which activates both β₁- and β₂-adrenoceptors.
• 4.4. Yohimbine, an α₂-adrenoceptor inhibitor, glyburide, an ATP-sensitive K⁺ channel inhibitor, iberiotoxin, a Ca²⁺-activated K⁺ channel inhibitor, or endothelium-removal failed to affect the potentiating effect of forskolin.
• 5.5. Dibutyryl cyclic AMP (cAmp) also potentiated the relaxing response to terbutaline.
• 6.6. These results suggest that in rabbit aortic rings forskolin causes the apparent potentiation of isoproterenol-induced relaxation by mainly affecting the relaxing response due to the activation of β₂-adrenoceptors by the forskolin-induced increase in the level of cAMP.

     

Inhibitory effect of sodium nitroprusside on the relaxing action of isoproterenol in isolated rat urinary bladder

1. Isoproterenol caused relaxation of rat detrusor muscles contracted by electrical stimulations. Sodium nitroprusside (SNP) and methylene blue inhibited the relaxation induced by isoproterenol without affecting forskolin-induced relaxation.2. In the presence of theophylline, zaprinast still potentiated isoproterenol-relaxation. In the presence of butoxamine, a selective β₂-adrenoceptor inhibitor, but not metoprolol, a selective β₁-adrenoceptor inhibitor, SNP still inhibited isoproterenol-relaxation.3. SNP inhibited the relaxation to dobutamine, a β₁-adrenoceptor agonist, but not that to terbutaline, a β₂-adrenoceptor agonist. The relaxation to dobutamine was also inhibited by methylene blue. Further, in the presence of theophylline, zaprinast still potentiated dobutamine-relaxation.4. Isoproterenol increased tissue level of cGMP, which was inhibited by propranolol.5. These results suggest a possibility that, in rat detrusor muscles, isoproterenol causes relaxation due to increases in the level of both cAMP and cGMP.     

β-Adrenergic regulation of renin expression in differentiated U-937 monocytic cells

Previous studies from our laboratories demonstrated that human decidual macrophages and peripheral mononuclear cells express renin. In the present study, we found that U-937 monocytes, induced to differentiate into macrophage-like cells by treatment with phorbol dibutyrate (PDBU), express renin mRNA and release renin (95% of which is in the form of prorenin). Treatment of these PDBU-exposed cells with dibutyryl-cAMP (1 mM) caused a 20-fold increase in renin mRNA and a 10-fold increase in prorenin release. Forskolin (10 μM), an activator of adenylyl cyclase, and terbutaline (100 μM), a β₂-adrenergic agonist known to increase cAMP levels, also increased renin mRNA and prorenin release. The secretory response to terbutaline was potentiated by the type IV cyclic AMP-phosphodiesterase (PDE) inhibitor Ro 20–1724 (50 μM). Angiotensin II agonist inhibited the stimulatory effect of terbutaline on renin secretion as did the cytokines tumor necrosis factor-α and lipopolysaccharide plus interferon-γ. Since other studies have shown that U-937 cells possess β₂-adrenergic receptors and express mainly the type IV PDE, the present findings strongly suggest that β-adrenergic receptors in mononuclear cells are coupled to renin expression via the cAMP transduction pathway. The results support a possible role for the renin-angiotensin system in macrophage function and suggest potential autocrine regulatory mechanisms in prorenin expression.     

Modulation of adenosine 3',5'-monophosphate contents of rat peritoneal macrophages mediated by beta2-adrenergic receptors.

The modulation of cAMP contents of rat peritoneal macrophages by β-adrenergic stimulants and blocking agents were studied. The maximum increase of cAMP contents induced by isoproterenol, epinephrine, norepinephrine and hexoprenaline (a selective β₂-adrenergic stimulant) was about 170 ~ 200 per cent and about 100 per cent by salbutamol (a selective β₂-adrenergic stimulant) above the basal level. The activity of phenylepherine, a α-adrenergic stimulant, was very weak. The concentration giving a half maximum stimulation was as follows: isoproterenol; 6.3 × 10^?8 M, hexoprenaline; 8.9 × 10^?8 M, salbutamol; 3 × 10^?7 M, epinephrine; 5.6 × 10^?7 M, and norepinephrine; 5.6 × 10^?6 M. Taking propranolol as a standard for comparison, antagonists of the isoproterenol induced increase in cAMP in macrophages ranged in their minimum effective concentrations as follows: bufetolol; 1. metoprolol (a selective β₁-adrenergie blocking agent); 1000, practolol (a selective β₁-adrenergic blocking agent); > 1000, while in rat hearts bufetolol; 1, metoprolol and practolol; 100. The increase of cAMP by 10^?5 M epinephrine or 10^?5 M hexoprenaline in rat peritoneal macrophages was blocked by bufetolol at a concentration of 10^?7 M or 10^?6 M, but not by practolol at a concentration of 10^?4 M. Phentolamine, a α-adrenergic blocking agent, showed no antagonistic activity against isoproterenol in rat peritoneal macrophages.These observations suggest that the increases in cAMP in rat peritoneal macrophages by catecholamines are mediated by β₂-adrenergic receptors.     

Enhancement of the electrically induced release of norepinephrine from the rat portal vein: mediation by beta 2-adrenoceptors.

The effect of β-adrenoceptors agonist ont the electrically induced release of ³H-NE from the superfused rat portal vein was studied. It was observed that the β-adrenoceptor agonists isoproterenol and terbutaline produced a concentration dependent enhancement of the field-stimulation induced release of NE. In contrast to what was seen with drugs possesing β₂-activity, the β₁-agonist, dobutamine, was inactive. The enhancing effect of both isoproterenol and terbutaline was reduced or completely blocked by the β₁–β₂-antagonist, propranolol or the β₂-antagonist butoxamine but not by the β₁-antagonist, practolol. In the concentration used none of the three β-antagonists had any effect themselved in altering the stimulation induced release of NE. Epinephrine (EPI) at a concentration of 10^?8 M produced an enhancement of the electrically induced release of NE. The effects of EPI and terbutaline were additive with phenoxybenzamine. Higher concentrations (i.e., 10^?7 M) or norepinephrine (10^?8 or 10^?7 M) reduced the enhancement induced by the simultaneous administration of phenoxybenzamine. It is concluded that β-adrenoceptors of the β₂ type are present on adrenergic neurons innervating the rat portal vein. Activation of these receptors results in an enhancement of the electrically induced release of NE. Our data are consistent with the hypothesis of Stjärne and Brundin which suggests that the β-adrenoceptor mediated enhancement of NE release is an example of hormonal modulation of adrenergic transmission mediated by ciculating EPI of adrenal medullary origin.     

Effect of Different β-Adrenergic Agonists on the Intestinal Absorption of Galactose and Phenylalanine

Nutrient transport across the mammalian small intestine is regulated by several factors, including intrinsic and extrinsic neural pathways, paracrine modulators, circulating hormones and luminal agents. Because β-adrenoceptors seem to regulate gastrointestinal functions such as bicarbonate and acid secretion, intestinal motility and gastrointestinal mucosal blood flow, we have investigated the effects of different β-adrenergic agonists on nutrient absorption by the rat jejunum in-vitro. When intestinal everted sacs were used the β₂-agonist salbutamol had no effect either on galactose uptake by the tissue or mucosal-to-serosal flux whereas mixed β₁- and β₂-agonists (isoproterenol and orciprenaline) and β₃-agonists (BRL 35135, Trecadrine, ICI 198157 and ZD 7114) inhibited galactose uptake and transfer of D-galactose from the mucosal-to-serosal media across the intestinal wall (although the inhibiting effects of isoproterenol and Trecadrine were not statistically significant). In intestinal everted rings both Trecadrine and BRL 35135 clearly reduced galactose uptake, the effect being a result of inhibition of the phlorizin-sensitive component. Total uptake of phenylalanine by the intestinal rings was also reduced by those β₃-adrenergic agonists. These results suggest that β₁ and β₃-adrenergic receptors could be involved in the regulation of intestinal active transport of sugars and amino acids.     

Interaction Between Substance P and β-Adrenergic Agonists in the Modulation of the Secretion of Fluid and Protein by the Rat Submandibular Gland

The interactions between substance P and β-adrenergic agonists such as isoprenaline, dobutamine and terbutaline in the control of the secretion of fluid and protein from the rat submandibular gland have been examined. Substance P elicited large volumes of saliva whereas isoprenaline, dobutamine and terbutaline elicited small volumes only. The secretion of fluid in response to substance P was markedly enhanced when substance P was administered in combination with isoprenaline or dobutamine but not when it was administered in combination with terbutaline. Isoprenaline elicited large amounts of protein, whereas substance P elicited small amounts. The secretion of protein in response to isoprenaline did not change when isoprenaline was administered in combination with substance P. The secretion of fluid and protein induced by substance P in combination with isoprenaline was antagonized by metoprolol and by spantide, but it was unaffected by pretreatment with ICI118551. These results suggest that in the rat submandibular gland stimulation of β₁-adrenoceptors but not of β₂-adrenoceptors potentiates the secretion of fluid that is induced by stimulation of tachykinin receptors, whereas stimulation of tachykinin receptors does not enhance the secretion of protein that is induced by stimulation of β₁-adrenoceptors.     

Stimulatory effect of octopamine on β3-adrenoceptors to lower the uptake of [14C]-deoxy-D-glucose into rat adipocytes in vitro

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In vitro and in vivo pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in rats

To investigate the pharmacological properties of mirabegron in in vitro and in vivo, the effects on cAMP accumulation in Chinese hamster ovary (CHO) cells expressing rat β-adrenoceptors, the relaxant activity in isolated rat bladder smooth muscle, and the voiding effects in cerebral infarcted rats were evaluated. Mirabegron increased cAMP accumulation with EC₅₀ value and intrinsic activity of 19 nmol/L and 1.0, respectively, in CHO cells expressing rat β₃-adrenoceptors. The EC₅₀ values and the intrinsic activities of mirabegron were 610 nmol/L and 0.6 for rat β₁-adrenoceptors and were sumless and 0.1 for β₂-adrenoceptors, respectively. Mirabegron showed concentration-dependent relaxant and full agonistic effects in rat bladder strips under passive tension with EC₅₀ value of 290 nmol/L. The concentration–response curve of mirabegron was affected neither by the β₁-adrenoceptor selective antagonist CGP-20712A nor by the β₂-adrenoceptor selective antagonist ICI-118,551. In in vivo studies with cerebral infarcted rats, a significant decrease in the volume voided per micturition compared with sham-operated rats was observed. Mirabegron dose-dependently increased the volume voided per micturition. In conclusion, we have extended the selectivity profile of mirabegron to rats and demonstrated that it is effective via stimulation of β₃-adrenoceptors in a rat cerebral infarction model of detrusor overactivity.     

Partial Agonism and Functional Selectivity: A Study on β-Adrenoceptor Mediated Effects in Tracheal,Cardiac and Skeletal Muscle

Abstract: Colterol, procaterol, sulfonterol, terbutaline and three monophenolic derivatives of terbutaline were examined with respect to their ability to react in vitro on β-adrenoceptors in tissues isolated from guinea-pig. The effects measured were a) relaxation of the tracheal smooth muscle (mostly β₂), b) depression of subtetanic contractions of the soleus muscle (β₂), and c) increase in the force of the papillary muscle of the left ventricle (β₁). Antagonistic effects were measured against isoprenaline as an agonist. The compounds studied showed a wide variation in selectivity, potency and intrinsic activity. All agonists showed a pronounced β₂-selectivity, in general characterized by a higher intrinsic activity at β₂- than at β₁-adrenoceptors, while differences in affinity, as judged from the pA₂-values were small. Partial agonists, such as sulfonterol, which did not cause a complete relaxation of a moderately contracted tracheal muscle, produced identical concentration-response curves from the trachea and soleus muscle. It is concluded that partial agonism at β₁-adrenoceptors is an important factor for functional selectivity of β₂-adrenoceptor agonists. On the other hand there seems to be no useful differences between the maximum effect elicited by a partial β₂-adrenoceptor agonist on the skeletal muscle as compared with airway smooth muscle.     

Chronic β-AR activation-induced calpain activation and impaired eNOS–Akt signaling mediates cardiac injury in ovariectomized female rats

Objective: To address the pathophysiological relevance of ovarian hormones in chronic β-adrenergic stimulation-induced myocardial injury, we assessed impairments of Ca²⁺-mediated cell signaling in the left ventricle of ovariectomized female rats. Research design/methods: Female Wistar rats were subjected to bilateral ovariectomy and sham operation. Six weeks after ovariectomy (OVX), both OVX and sham rats were treated with isoproterenol (5mg/kg, intraperitoneally), a nonselective β-adrenergic agonist, once a day for 28 days. Results: We found that chronic β-adrenergic stimulation caused enhanced breakdown of sarcolemmal proteins such as dystrophin and utrophin in OVX rats compared to sham-operated rats. Generation of calpain-mediated 150 kDa-breakdown product of spectrin confirmed calpain activation following isoproterenol treatment. Marked breakdown of endogenous calpain inhibitor, calpastatin, in OVX rats was consistent with the calpain activation following chronic β-adrenergic stimulation. In addition to calpain activation, we also found marked reduction of endothelial nitric oxide synthase (eNOS) activity with concomitant deregulation by heat shock proteins 90 kDa and caveolin 3, both of which are eNOS-associated proteins. Finally, we documented decreased Akt phosphorylation with concomitant increased glycogen synthase kinase 3β phosphorylation underlying cell injury following chronic β-adrenergic stimulation. Conclusion: Taken together chronic β-adrenergic stimulation caused severe cardiac injury in OVX rats through calpain activation and impairments of Akt and eNOS signaling pathways.     

β2-adrenoceptor agonists reverse the leukotriene C4-induced release response of macrophages

The experiments concerned the effects of β-adrenoceptor agonists and antagonists on the leukotriene-C₄ (LTC₄)-induced secretory release response from carrageenan-elicited rat peritoneal macrophages. Both the non-selective β-adrenoceptor agonist isoprenaline and the selective β₂-adrenoceptor agonist salbutamol reversed the LTC₄-induced release response. Addition of the non-selective β-adrenoceptor antagonist sotalol or the β₂-selective antagonist H3525 abolished these effects. Practolol, a selective β₁-adrenoceptor antagonist was without any effect on the isoprenaline-LTC₄ interaction. These results are consistent with the presence of β₂-adrenoceptors on macrophages. The results of this study are discussed in view of a possible, cyclic adenosine 3′5′-monophosphate (cAMP)-mediated interaction between prostaglandin E₂ and LTC₄ in modulating macrophage function.     

Chronic terbutaline treatment desensitizes β-adrenergic inhibition of lymphocyte activation in healthy volunteers

1 A substantial body of evidence has accumulated that β-adrenoceptor mediated increases in human lymphocyte cyclic AMP can inhibit activation of resting lymphocytes. The aim of this study was to determine whether this effect might desensitize during chronic β-adrenoceptor agonist treatment. We assessed the effects of 2 weeks treatment with the β₂-adrenoceptor agonist terbutaline (3 × 5 mg day^?1 p.o.) on isoprenaline-induced inhibition of concanavalin A-evoked lymphocyte activation in nine healthy male volunteers. Lymphocyte activation was determined by [³H]-thymidine incorporation (as a measure of proliferation), and inositol phosphate formation was assessed in [³H]-myo-inositol prelabelled lymphocytes in the presence of 10 mm LiCl. 2 Terbutaline treatment caused a significant reduction in isoprenaline (1 nm – 10 μm )-induced increases in lymphocyte cyclic AMP content; the maximal increase was 14 ± 3 pmol/10⁶ cells before and 7 ± 2 pmol/10⁶ cells (n= 9, P < 0.05) after terbutaline treatment. 3 The mitogen concanavalin A (Con A, 1–32 μg ml^?1)-induced increase in inositol phosphate formation was significantly enhanced after terbutaline treatment (max. increase before treatment: 255 ± 25% above basal; after treatment 453 ± 16% above basal; n= 9, P < 0.001), while isoprenaline (1 nm – 10 μm )-induced inhibition of Con A (16 μg ml^?1)-evoked increases in inositol phosphate formation was significantly reduced after the terbutaline treatment (max. inhibition before treatment: 22 ± 4%; after treatment 9 ± 1%, n= 9, P < 0.01). 4 Con A (1.25 – 10 μg ml^?1)-induced increases in [³H]-thymidine incorporation into the lymphocytes (as a measure of proliferation) was not affected by the terbutaline treatment. On the other hand, isoprenaline (1 nm – 1 μm )-induced inhibition of Con A (5 μg ml^?1)-evoked lymphocyte proliferation (max. inhibition: 33 ± 7%, n= 9) was almost completely abolished after the terbutaline treatment. 5 We conclude that chronic treatment with terbutaline desensitizes lymphocyte β₂-adrenoceptors and, therefore, the inhibitory effect of cyclic AMP on lymphocyte activation.     

Hypertrophic cardiomyopathy: A desensitized cardiac \-adrenergic system in the presence of normal plasma catecholamine concentrations

Only few data are available concerning the biochemical and functional state of the \-adrenergic system in hypertrophied human myocardium. The present study was to investigate the myocardial \-adrenergic signal transduction system in hypertrophic obstructive cardiomyopathy (HOCM).Thin myocardial strips were prepared from surgically excised, septal myocardium from 7 patients with HOCM and their force of contraction was measured in vitro. The positive inotropic effects of calcium and dihydro-ouabain, both acting independently of \-adrenoceptors and cAMP, were similar in these preparations to those, previously published, seen with nonfailing myocardium. In contrast, the \-adrenoceptor agonist isoprenaline and the phosphodiesterase inhibitor 3-isobutyl-l-methylxanthine (IBMX) had reduced positive inotropic effects. Their EC₅₀-values were about 10 fold higher than the respective EC₅₀-values published for nonfailing myocardium. The positive inotropic potencies of isoprenaline and IBMX were reduced in HOCM by as much as they were in the additionally investigated myocardium from 6 patients with severe mitral regurgitation (MR, NYHA III). In order to clarify whether the functional alterations are related to changes in the \-adrenoceptors, \-adrenoceptor density and \₁:\₂-adrenoceptor subtype distribution were determined in the same myocardium using ¹²⁵I-Iodocyanopindolol saturation binding.Myocardial \-adrenoceptor density was reduced to 68% in HOCM and to 56% in MR compared to nonfailing myocardium controls (NF: 64.8 ± 6.5 fmol/mg protein). In HOCM, this reduction was due to a selective down regulation of \₁-adrenoceptors (24.9 ± 3.7 fmol/mg protein vs NF: 46.4 ± 6.8 fmol/mg protein, P < 0.05), whereas \₂-adrenoceptor density was unchanged (19.0 ± 1.9 fmol/mg protein vs NF: 18.4 ± 3.3 fmol/mg protein, n.s.). In MR both \-adrenoceptor subtypes were reduced (\₁: 26.9 ± 1.4 fmol/mg protein, \₂: 9.6 ± 1.7 fmol/mg protein; both P < 0.05 vs NF). Electrochemically determined plasma catecholamine levels were elevated in MR. However, plasma catecholamine levels were normal or slightly below normal in HOCM.In summary, myocardial \-adrenoceptors are downregulated and their function is impaired in HOCM. This desensitization is not caused by a negative feedback regulation due to increased plasma catecholamines. The present results show that the desensitizations of the \-adrenergic system associated with HOCM has characteristics that indicate a major deviation in its development from that of the \-adrenergic desensitization previously described to occur in congestive heart failure.     

Characterization of Mechanical Effects and β-Adrenoceptor Binding of Prenalterol in Rat Myocardium

Abstract: The partial β-agonist prenalterol has been found to differ from the full agonist isoprenaline in some aspects of its cardiac action. We therefore studied in rat myocardium whether prenalterol elicited the same qualitative changes of the contraction-relaxation cycle as was previously found for isoprenaline. We also measured binding of prenalterol to β-adrenoceptors. Prenalterol augmented relaxation more than contraction and thus evoked the same qualitative changes of the contraction-relaxation cycle as did isoprenaline. However, the response developed slowlier than that to isoprenaline, and the effect on relaxation followed a more protracted time course than the effect on contraction. Prenalterol bound non-selectively to β₁- and β₂-adrenoceptors in both heart and lung broken cell preparations. pK_d for binding to β-adrenoceptors and pD₂ values for functional effects in heart were similar, i.e. prenalterol had to occupy half the amount of β-adrenoceptors in order to evoke half-maximal functional effects. The non-selective α-blocker phentolamine potentiated the effects of prenalterol on contraction, but did not change the equilibrium binding of prenalterol to cardiac β-adrenoceptors. Phentolamine did not change the potency and efficacy of isoprenaline. Thus, although prenalterol qualitatively evoked the same response as isoprenaline, it also exhibited some properties which differed.     

COMPARISON OF THE ATTENUATING EFFECTS OF FOUR β-ADRENOCEPTOR AGONISTS ON RAT ISOLATED UTERUS AND AORTA

1. The ability of four 8-adrenoceptor agonists to attenuate oxytocin (0.2,2 and 20 nmol/L) or KCI (20,40 and 80 mmol/L)-induced Contractions of the uterus (n= 5–8 for each agonist) and the KCI (18 mmol/L)-induced contractions of the aorta (n = 9 for each agonist) from rats, pretreated with oestradiol has been compared. 2. Isoprenaline, salbutamol, terbutaline and procaterol (0.1–10μmol/L) attenuated the contractions of the uterus and the aorta. All four agonists had similar attenuating potencies on the uterus. 3. Procaterol caused the same maximal attenuation (33%) on the aorta as the other β-adrenoceptor agonists and is thus acting as a full β₂-adrenoceptor agonist under these experimental conditions. Isoprenaline and procaterol were much more potent than salbutamol and terbutaline in attenuating the aorta responses. 4. This study showed that isoprenaline and procaterol were potent attenuants on both the uterus and aorta whereas salbutamol and terbutaline were potent uterine but only modest aorta attenuants. This preliminary study indicates that the responsiveness of uterine and vascular tissue to certain β₂-adrenoceptors differs.     

Facilitation of noradrenaline release from rat brain slices by \-adrenoceptors

The present study examined whether stimulation of \-adrenoceptors facilitated noradrenaline release in the rat brain. Electrical stimulation-evoked overflow of tritium from rat cerebral cortical, hypothalamic and hippocampal slices labelled with ³H-noradrenaline was measured during superfusion for 100 min. Tissue slices were electrically simulated (1 Hz, 20 mA, 2 ms, 2 min), at 20(S1) and 70(S2) min after the onset of superfusion. The nonselective \-adrenoceptor agonist isoproterenol (0.1 – 10 nM) enhanced stimulation-evoked overflow of tritium from slices of cerebral cortex, hypothalamus and hippocampus in a concentration-dependent manner; mean S2/S1 ratios with 10 nM isoproterenol were 161 +- 11%, 142 +- 15% and 143 - 12% of control, respectively, in the three brain regions. The facilitatory effect of isoproterenol in cerebral cortical slices was antagonized by propranolol (50 nM), a nonselective \sb-adrenoceptor antagonist, and by the \sb₁- and \sb₂-selective adrenoceptor antagonists ICI 89,406 (1 nM) and ICI 118,551(1 nM), respectively. The \sb₁- and \sb₂-selective adrenoceptor agonists prenalterol and albuterol (0.1 \2- 10 nM), respectively, also increased stimulation-evoked overflow of tritium from cerebral cortical slices; these effects were antagonized by \sb-adrenoceptor antagonists. These findings suggest that stimulation of \sb-adrenoceptors enhance noradrenaline release from rat cerebral cortical, hypothalamic and hippocampal slices; this release mechanism appears to involve both \sb₁- and \sb₂-adrenoceptor subtypes. These facilitating presynaptic receptors may be involved in mediating the antidepressant-like behavioral effects of \sb₂-adrenoceptor agonists.