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At least 19 recordsLinked to original sources
PubMed1992

The positive chronotropic effect induced by BRL 37344 and CGP 12177, two beta-3 adrenergic agonists, does not involve cardiac beta adrenoceptors but baroreflex mechanisms.

The presence of a beta-3 adrenoceptor (in addition to the classical beta-1 and beta-2 adrenoceptors) and its involvement in the control of heart rate was investigated in the dog. Experiments were carried out in conscious normal and sinoaortic denervated dogs (i.e. animals deprived of baroreceptor pathways). In normal dogs, infusion of isoproterenol, BRL 37344 (4-[-[(2-hydroxy-(3-chlorophenyl) ethyl)-amino]propyl]phenoxyacetate) (a beta-3 adrenergic agonist) or CGP 12177 (4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2- one) (a beta-1 beta-2 adrenergic antagonist reported to act as an agonist for the beta-3 adrenergic receptor) increased heart rate with an order of potency: BRL 37344 > isoproterenol >> CGP 12177. [125I]Cyanopindolol binding (2-2000 pM) was saturable and Scatchard analysis indicated the presence of an homogenous population of binding sites. KD was 12.8 +/- 18.5 pM and maximum binding was 94.2 +/- 12.5 fmol/mg of protein. Competition binding studies on dog heart membranes using 150 pM [125I] cyanopindolol indicated an order of potency (CGP 12177 > isoproterenol > BRL 37344) different from that observed in cardiovascular studies. Isoproterenol stimulated adenylate cyclase activity in heart membranes from normal dogs, whereas CGP 12177 and BRL 37344 were without any stimulating action. The positive chronotropic effects of isoproterenol, BRL 37344 and CGP 12177 were accompanied with a reduction in arterial blood pressure. In sinoaortic denervated animals, isoproterenol infusion provoked tachycardia and hypotension. BRL 37344 and CGP 12177 were without any significant effect on heart rate but induced a rapid and dramatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1987

Alpha-1 adrenergic receptor binding in aortas from rat and dog: comparison of [3H]prazosin and beta-iodo-[125I]-4-hydroxyphenyl-ethyl-aminomethyl-tetralone.

We have identified and characterized pharmacologically alpha-1 adrenergic receptors in aorta from dog and rat utilizing two alpha-1 antagonists, [3H]prazosin and beta-3-iodo[125I]-4-hydroxyphenyl-ethyl-aminoethyl-tetralone [125I]HEAT, to determine receptor number and affinity. The rat and dog alpha-1 receptors were found to be very similar. In the dog, KD values were 27 and 11 pM for [3H]prazosin and [125I]HEAT, respectively, whereas maximum binding values were 89 and 65 fmol/mg of protein. KD values in rat aorta were 22 and 15 pM for [3H]prazosin and [125I]HEAT, respectively, whereas maximum binding values were 62 and 47 fmol/mg of protein. Both tissues demonstrated a rank order potency of antagonist inhibition of the two radioligands consistent with an alpha-1 adrenergic receptor with prazosin greater than phentolamine greater than yohimbine. A comparison between IC50 values for both the ligands and the tissues shows strong correlations suggesting the two radioligands are identifying a similar receptor population and that the receptor labeled by the ligands has similar pharmacologic characteristics in the two tissues.

Adrenergic alpha-Antagonists↗
PubMed1994

Beta-3 adrenoceptor-mediated increase in cutaneous blood flow in the dog.

Beta-3 adrenergic agonist administration decreases arterial blood pressure in the dog as previously shown. The putative presence of beta-3 adrenoceptors in peripheral microvascular muscle was studied in dogs through measurement of cutaneous blood flow and skin temperature changes. Experiments were carried out in normal and sinoaortic denervated dogs (i.e., animals deprived of baroreceptor pathways). In normal dogs, the infusion of 0.4 nmol/kg/min of 4-[-[(2-hydroxy-(3-chlorophenyl)ethyl)-amino]propyl] phenoxyacetate (BRL 37344) or (R,R-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3- benzodioxole-2,2-dicarboxylate (CL 316243) (two selective beta-3 adrenoceptor agonists), or 8 nmol/kg/min of 4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2-one (CGP 12177) (a beta-1/beta-2 adrenergic antagonist also reported to act as an agonist for the beta-3 adrenoceptor) induced an increase in heart rate and cutaneous blood flow (evaluated in the internal part of the ear) and a decrease in blood pressure. The skin and the buccal mucous membrane became purplish. The infusion of (-)-isoproterenol (0.4 nmol/g/min), a dose known to stimulate preferentially beta-1/beta-2 adrenoceptors, or sodium nitroprusside (12 micrograms/kg/min) increased heart rate and decreased blood pressure, but reduced cutaneous blood flow. In sinoaortic denervated dogs, similar effects on cutaneous blood flow and blood pressure were observed. However, in these animals, heart rate remained unchanged whatever the infused drug. BRL 37344 (but not isoproterenol) increased cutaneous temperature in normal dogs. This study suggests that beta-3 adrenoceptors exist in canine cutaneous vascular smooth muscles and that their stimulation induces vasodilatation.

Adrenergic beta-Agonists↗
PubMed1996

Phenotypic characterization of the Trp64Arg polymorphism in the beta 3-adrenergic receptor gene in normal weight and obese subjects.

The beta 3-adrenergic receptor, located mainly in fat cells of visceral adipose tissue, is involved in the regulation of lipolysis and thermogenesis. Recently, a mutation in the corresponding gene resulting in the replacement of tryptophan by arginine in position 64 (Trp64Arg) has been demonstrated, which associated with obesity and metabolic complications of obesity. We have investigated whether this polymorphism is associated with changes in beta 3-adrenergic receptor function or clinical characteristics in 40 non-obese and 43 obese non-diabetic subjects who underwent elective abdominal surgery. The beta-adrenergic receptor gene polymorphism was examined by restriction-enzyme cleavage conformation. Beta 3-adrenergic receptor function was investigated by measuring lipolysis in isolated visceral white fat cells incubated with noradrenaline (natural ligand) or (CGP) 12,177 (selective beta 3-agonist). No homozygotes for the mutation were found. The allelic frequency of Trp64Arg was similar in obese and non-obese subjects (9.4 and 12.5%, respectively). In obese and non-obese subjects there was no change in body mass index, body fat distribution, fat cell size, fasting circulating levels of insulin, glucose or lipids, blood pressure or adipocyte lipolysis induced by noradrenaline or CGP 12,177 when Trp64Arg heterozygotes were compared with Trp64A homozygotes. Our results suggest that the Trp64Arg mutation in its heterozygous form is not a major determinant of beta 3-adrenergic receptor function (when assessed by lipolysis in white adipose tissue) or of the pathophysiology of obesity.

Adipocytes↗
PubMed1995

Beta 2- but not beta 3-adrenoceptors mediate prejunctional inhibition of non-adrenergic non-cholinergic contraction of guinea pig main bronchi.

We studied the effects of selective beta-adrenoceptor agonists on the cholinergic and non-adrenergic non-cholinergic (excitatory NANC) contractions elicited by electrical field stimulation of guinea pig main bronchi in vitro. Addition of the selective beta 2-adrenoceptor agonists, fenoterol and salbutamol, and the selective beta 3-adrenoceptor agonist, BRL 37344 (4-[2-[(2-hydroxy-2-(3-chlor-phenyl)ethyl)amino]-propyl]-phenoxyac etic acid), induced a dose-dependent inhibition of the cholinergic contraction (pD2 7.89, 6.71 and 4.56, respectively) and the excitatory NANC response (pD2 9.11, 8.16 and 7.42, respectively). Fenoterol- and BRL 37344-induced inhibition of the excitatory NANC response was blocked with high potency (pKB 8.77 and 9.07, respectively) by the selective beta 2-adrenoceptor antagonist, ICI 118,511 (erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamino)-but an-2-ol). A comparable contraction induced by neurokinin A (2 or 5 nM) was also inhibited by fenoterol, salbutamol and BRL 37344, but at significantly higher concentrations than for the inhibition of the excitatory NANC response (pD2 8.72, 7.56 and 6.66, respectively). Such a preferential inhibition of electrical field stimulation- versus agonist-induced effects was not observed for cholinergic contractions (pD2 versus methacholine-induced tone 7.86, 6.93 and 5.10, respectively). The results clearly exclude the involvement of beta 3-adrenoceptors in these responses. Furthermore they show that beta 2-adrenoceptors are involved in the prejunctional inhibition of excitatory NANC contractions, presumably via modulation of tachykinin release from sensory nerves, and solely in the postjunctional inhibition of cholinergic contractions.

Adrenergic beta-Agonists↗
PubMed1996

Developmental expression and functional activity of beta 1- and beta 3-adrenoceptors in murine 3T3-F442A differentiating adipocytes.

Beta 1- and beta 3-adrenoceptor mRNA and protein expression, and contribution of each subtype to the catecholamine-sensitive adenylyl cyclase system were studied during the adipose conversion of the murine 3T3-F442A cell line. Northern and reverse transcriptase-polymerase chain reaction analyses indicated that emergence of beta 3-adrenoceptor transcripts was concomittant with that of the gene encoding adipsin, a very late marker of adipose differentiation. Conversely, the induction of the beta 1-adrenoceptor mRNA occurred early after cell commitment towards adipose conversion. Changes in beta-subtype gene expression were accompanied by parallel modifications in receptor expression and function. 125I-cyanopindolol saturation and competition binding experiments showed a 3-fold increase in beta 1-adrenoceptor density in day 3 post-confluent cells. The beta 3-subtype population became detectable later and represented approximately 95% of total beta-adrenoceptors in day 8 and day 12 post-confluent cells. Adenylyl cyclase activity in response to the beta 3-adrenoceptor-selective agonists CGP12177 (4-(3-t-butylamino-2-hydroxypropoxy)-benzimidazol-2-one), ICI201651 ([(R)-4-(2 hydroxy-3-phenoxypropylamino-ethoxy)-N-(2- methoxyethyl)phenoxy-acetamide]) and cyanopindolol was virtually absent in young adipocytes, but dramatically increased in mature cells. The respective contributions of the beta 1- and the beta 3-subtypes to the production of cAMP were resolved by an Eadie-Hofstee computer analysis of isoproterenol and norepinephrine concentration-response curve of adenylyl cyclase activity. Agonist response curves in the presence of beta 1- and beta 2-adrenoceptor antagonist indicated that the beta 1-subtype accounted for the totality of beta-adrenoceptor-mediated adenylyl cyclase activation in young adipocytes. In mature adipose cells approximately 90% of this response was due to an activation of the beta 3-adrenoceptor. In addition, approximately 84% of the maximal norepinephrine-stimulated lipolysis was mediated by the beta 3-adrenoceptor in fully differentiated adipocytes. The differentiation-dependent expression of beta-subtypes in adipocytes is a biphasic process involving an initial and moderate induction of beta 1-adrenoceptors followed by the emergence of a prominent beta 3-adrenoceptor population. Compared analysis of both receptor occupancy and cAMP production shows that the beta 3-subtype is more efficiently coupled to the adenylyl cyclase system than the beta 1-adrenoceptor. Thus in mature adipose cells this receptor subtype represents the core of cAMP-dependent regulation of the lipolytic, antilipogenic and thermogenic effects of catecholamines.

Adenylyl Cyclases↗
PubMed1996

A specific beta 3-adrenoceptor agonist induces increased pancreatic islet blood flow and insulin secretion in rats.

In order to study the role of beta 3-adrenoceptor stimulation on insulin secretion in rats, plasma insulin level and islet blood flow were measured during treatment with CL 316243 which is chemically named disodium (R,R)-5-[2-[[2,3-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1, 3-benzodioxole-2,2-dicarboxylate, a specific beta 3-adrenoceptor agonist. CL 316243 induced a marked increase in both islet blood flow and plasma insulin concentration without changes in whole pancreatic blood flow. This increase was totally prevented when the rats were pretreated with bupranolol, a beta 1, beta 2, beta 3-adrenoceptor antagonist, but not with nadolol, a beta 1, beta 2-adrenoceptor antagonist. We conclude that beta 3-adrenoceptor stimulation provokes a marked vasodilatation of microvessels in the islets of Langerhans, which in turn could contribute to the increase in insulin secretion.

Adrenergic beta-Agonists↗
PubMed1996

Effect of selective beta-adrenoceptor stimulation on UCP synthesis in primary cultures of brown adipocytes.

Given the co-existence of the three beta-adrenoceptor (beta AR) subtypes (beta 1AR, beta 2AR and beta 3AR) in brown adipocytes, the present study was undertaken to determine the relative importance of these in the induction of UCP synthesis in mouse BAT precursor cells in primary culture. Cells at different stages of differentiation were exposed to different beta AR agonists: prenalterol (a selective beta 1AR agonist), salbutamol or clenbuterol (selective beta 2AR agonists), or BRL 37344 (a selective beta 3AR agonist). As with the endogenous agonist, noradrenaline, and the non-selective beta AR agonist, isoprenaline, all four beta AR agonists induced UCP in the confluent stage of the cells, but with different potencies, and with the highest induction being seen after clenbuterol or BRL 37344 treatment. Cells in the confluent stage of development were the most sensitive to the effects of the agonists, although clenbuterol and BRL 37344 induced a weak UCP synthesis in pre-confluent cells. None of these beta AR agonists were able to induce UCP synthesis in the post-confluent period. The responses to prenalterol and salbutamol were inhibited by propranolol at relatively low concentrations, suggesting their effects were mediated by beta 1AR and beta 2AR, respectively. However, propranolol was a particularly weak antagonist of BRL 37344 and, unexpectedly, of the clenbuterol UCP responses, which suggests that both induce UCP synthesis via the beta 3AR. In summary, the beta 3AR is the most important adrenoceptor coupled to the induction of UCP synthesis, although both beta 1AR and beta 2AR activation may make a contribution. However, all three beta AR subtypes do not become fully functional until cultured cells become confluent.

Adipose Tissue, Brown↗
PubMed1995

Effect of bupranolol on CGP 12177-induced relaxation and cAMP accumulation in the guinea pig taenia caecum.

1. The effect of bupranolol on CGP 12177-induced relaxation and cAMP accumulation in the guinea pig taenia caecum was examined. 2. The relaxant response to CGP 12177 was unaffected by propranolol (approximately 10(-6) M), whereas that to CGP 12177 was antagonized in a concentration-dependent manner by bupranolol; Schild plot of the data revealed the pA2 value of 5.61. 3. CGP 12177 significantly increased cyclic AMP level in this preparation. Bupranolol (10(-4) M) significantly decreased the cyclic AMP level that was elicited by CGP 12177, whereas propranolol (10(-5) M) produced no effect. 4. These results suggest that bupranolol appears to be an efficient beta3-antagonist in the guinea pig taenia caecum and confirm that the response to CGP 12177 is mediated by beta3-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1996

Endogenous beta 3- but not beta 1-adrenergic receptors are resistant to agonist-mediated regulation in human SK-N-MC neurotumor cells.

Although there is considerable interest in the regulation of the different beta-adrenergic receptor (AR) subtypes, most previous studies have utilized stably transfected cells expressing recombinant receptors under the control of viral promoters. Human SK-N-MC neurotumor cells appear to be novel, since they express both endogenous beta 1AR and beta 3AR based on radioligand binding and on functional response. Saturation binding of either the hydrophilic ligand (-)-[3H]CGP-12177 or the more hydrophobic (-)-[125I]iodocyanopindolol indicated the presence of two populations of binding sites with high and low affinities. With either ligand, the beta 1AR antagonist CGP-20712A preferentially inhibited binding to the high-affinity sites. This is consistent with the latter representing beta 1AR whereas the low-affinity sites represent beta 3AR. Both subtypes appeared to be functional on the basis of isoproterenol stimulation of cyclic adenosine monophosphate (cAMP) in intact cells and adenylyl cyclase activity in cell membranes in the absence and presence of CGP-20712A. SK-N-MC-IXC cells, derived by twice subcloning the parental cells, also expressed both beta AR subtypes, indicating that they co-exist in the same cell. SK-N-MC cells exposed to isoproterenol exhibited a rapid sequestration and a slower downregulation of beta 1AR. The latter subtype also underwent desensitization, as indicated by a rightward shift to less sensitivity in the EC50 for isoproterenol stimulation of adenylyl cyclase activity. In contrast, the beta 3AR subtype was resistant to agonist-mediated sequestration, downregulation, and desensitization. Thus, when endogenously expressed in the same cell line, human beta 1AR and beta 3AR display differences in their ability to be regulated by agonist.

Adrenergic beta-1 Receptor Agonists↗
PubMed1997

Beta3-adrenoceptors mediate relaxation of guinea pig taenia caecum by BRL37344A and BRL35135A.

Beta-adrenoceptor-mediated relaxation of guinea pig taenia caecum was investigated by studying the effects of the beta3-adrenoceptor agonists, BRL37344A [(R*,R*)-(+/-)-4-[2'-[2-hydroxy-2-(3-chlorophenyl) ethylamino] propyl] phenoxyacetic acid sodium salt sesquihydrate] and BRL35135A [(R*,R*)-(+/-)-methyl-4-[2-[2-hydroxy-2-(3-chlorophenyl) ethylamine] propyl] phenoxyacetate hydrobromide]. BRL37344A and BRL35135A caused dose-dependent relaxation of the guinea pig taenia caecum. The concentration-response curves for BRL37344A and BRL35135A were unaffected by propranolol, ICI118551 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-but an-2-ol], atenolol, butoxamine, prazosin, yohimbine and phentolamine. Bupranolol produced shifts of the concentration-response curves for BRL37344A and BRL35135A. Schild regression analyses carried out for bupranolol against BRL37344A and BRL35135A gave pA2 values of 5.79 and 5.84, respectively. These results suggest that the relaxant response to BRL37344A and BRL35135A of the guinea pig taenia caecum is mediated by beta3-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1996

Function and regulation of the beta 3-adrenoceptor.

The cloning, sequencing and expression in model systems of the previously unidentified beta 3-adrenoceptor recently led to an extensive functional characterization. Ligand binding and adenylate cyclase activation studies helped define a specific profile that is quite distinct from that of the beta 1- and beta 2-adrenoceptors, but strongly reminiscent of most of the 'atypical' beta-adrenoceptor-mediated responses reported in earlier pharmacological studies. More recently, a naturally occurring variation in the human beta 3-adrenoceptor has been correlated with hereditary obesity and with increased dynamic capacity to add on weight and develop non-insulin dependent diabetes in Western obese patients. Donny Strosberg and France Pietri-Rouxel describe how results now provide a consistent picture of an important role for the human beta 3-adrenoceptor in the regulation of lipid metabolism and as an obvious target for drugs to treat some forms of obesity and diabetes.

Adrenergic beta-Agonists↗
PubMed1997

Characteristics of [3H]CGP12177 binding sites at beta 2- and beta 3-adrenoceptors in the guinea pig taenia caecum.

1. Experiments were carried out to characterize the [3H]CGP12177 binding sites in the microsomal fraction from the guinea pig taenia caecum. 2. The Scatchard plot in the absence of butoxamine (10(-4) M) or bupranolol (10(-4) M) was concave, suggesting two affinity sites: high and low affinity binding sites. 3. The Scatchard plot in the presence of butoxamine gave a straight line, indicating only the low affinity site. 4. The Scatchard plot in the presence of bupranolol was undetectable. 5. These results suggest that the high affinity binding sites for [3H]CGP12177 correspond to beta 2-adrenoceptors in the microsomal fraction from the guinea pig taenia caecum, whereas the low affinity binding sites represent beta 3-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1998

Neural inhibition in the rat lower esophageal sphincter: role of beta 3-adrenoceptor activation.

1. Electrical field stimulation (EFS) of the rat lower esophageal sphincter produced tetrodotoxin-sensitive relaxant responses. 2. The relaxant responses were not significantly affected by propranolol but were attenuated by 6-hydroxydopamine and cyanopindolol, indicating beta 3-adrenoceptor activation. 3. The relaxant responses were significantly reduced in tissues previously exposed to BRL 37344, a beta 3-adrenoceptor agonist. 4. It was concluded that EFS-induced relaxation was adrenergic in origin and was mediated by beta 3-adrenoceptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMedDate not supplied

Comparison between beta 3 and beta 2 adrenoceptor agonists as inhibitors of gastric acid secretion.

In order to investigate the role of beta 3 adrenoceptors in the regulation of gastric acid secretion we studied the effects of compound SR58611A (a selective agonist for atypical beta adrenoceptors), alone or in combination with beta-adrenoceptor antagonists, in the gastric fistula of a conscious cat. The effects of SR58611A were compared with those of clenbuterol, a selective agonist for beta 2 adrenoceptors. Intravenous infusion of SR58611A (0.3-3 mumol/kg/h) caused a dose-dependent, but partial, inhibition of the acid secretory response to 2-deoxy-D-glucose 100 mg/kg i.v., maximum effect not exceeding 40%. Clenbuterol (0.03-0.1 mumol/kg/h) caused a similar effect (maximum inhibition about 50%) at doses approximately 30 times lower. The acid secretion induced by the histamine H2-receptor agonist dimaprit (1 mumol/kg/h) was minimally affected by both beta adrenoceptor agonists. The inhibitory effect of SR58611A (3 mumol/kg/h) on 2-deoxy-D-glucose-induced acid secretion was not modified by pretreatment with the non-selective beta 1- and beta 2-adrenoceptor blocker propranolol, administered at doses (1.5 mumol/kg iv) that completely blocked the inhibitory effect of clenbuterol (0.1 mumol/kg/h). In contrast, bupranolol (10 mumol/kg i.v.) (a drug endowed with beta 3 antagonistic properties) prevented the inhibitory effects of both SR58611A and clenbuterol. The present data provide functional evidence that, besides beta 2-, also beta 3-adrenoceptors can have negative effects on gastric acid secretion, particularly when it is stimulated by indirect stimuli, like 2-deoxy-D-glucose. This gastric antisecretory activity may represent an additional mechanism for the physio-pharmacological control of gastric acid secretion.

Adrenergic beta-2 Receptor Agonists↗
PubMed1997

Effects of (-)-RO363 at human atrial beta-adrenoceptor subtypes, the human cloned beta 3-adrenoceptor and rodent intestinal beta 3-adrenoceptors.

1. Chronic treatment of patients with beta-blockers causes atrial inotropic hyperresponsiveness through beta 2-adrenoceptors, 5-HT4 receptors and H2-receptors but apparently not through beta 1-adrenoceptors despite data claiming an increased beta 1-adrenoceptor density from homogenate binding studies. We have addressed the question of beta 1-adrenoceptor sensitivity by determining the inotropic potency and intrinsic activity of the beta 1-adrenoceptor selective partial agonist (-)-RO363 and by carrying out both homogenate binding and quantitative beta-adrenoceptor autoradiography in atria obtained from patients treated or not treated with beta-blockers. In the course of the experiments it became apparent that (-)-RO363 also may cause agonistic effects through the third atrial beta-adrenoceptor. To assess whether (-)-RO363 also caused agonistic effects through beta 3-adrenoceptors we studied its relaxant effects in rat colon and guinea-pig ileum, as well as receptor binding and adenylyl cyclase stimulation of chinese hamster ovary (CHO) cells expressing human beta 3-adrenoceptors. 2. beta-Adrenoceptors were labelled with (-)-[125I]-cyanopindolol. The density of both beta 1- and beta 2-adrenoceptors was unchanged in the 2 groups, as assessed with both quantitative receptor autoradiography and homogenate binding. The affinities of (-)-RO363 for beta 1-adrenoceptors (pKi = 8.0-7.7) and beta 2-adrenoceptors (pKi = 6.1-5.8) were not significantly different in the two groups. 3. (-)-RO363 increased atrial force with a pEC50 of 8.2 (beta-blocker treated) and 8.0 (non-beta-blocker treated) and intrinsic activity with respect to (-)-isoprenaline of 0.80 (beta-blocker treated) and 0.54 (non-beta-blocker treated) (P < 0.001) and with respect to Ca2+ (7 mM) of 0.65 (beta-blocker treated) and 0.45 (non-beta-blocker treated) (P < 0.01). The effects of (-)-RO363 were resistant to antagonism by the beta 2-adrenoceptor antagonist, ICI 118,551 (50 nM). The effects of 0.3-10 nM (-)-RO363 were antagonized by 3-10 nM of the beta 1-adrenoceptor selective antagonist CGP 20712A. The effects of 20-1000 nM (-)-RO363 were partially resistant to antagonism by 30-300 nM CGP 20712A. 4. (-)-RO363 relaxed the rat colon, partially precontracted by 30 mM KCl, with an intrinsic activity of 0.97 compared to (-)-isoprenaline. The concentration-effect curve to (-)-RO363 revealed 2 components, one antagonized by (-)-propranolol (200 nM) with pEC50 = 8.5 and fraction 0.66, the other resistant to (-)-propranolol (200 nM) with pEC50 = 5.6 and fraction 0.34 of maximal relaxation. 5. (-)-RO363 relaxed the longitudinal muscle of guinea-pig ileum, precontracted by 0.5 microM histamine, with intrinsic activity of 1.0 compared to (-)-isoprenaline and through 2 components, one antagonized by (-)-propranolol (200 nM) with pEC50 = 8.7 and fraction 0.67, the other resistant to (-)-propranolol with pEC50 = 4.9 and fraction 0.33 of maximal relaxation. 6. (-)-RO363 stimulated the adenylyl cyclase of CHO cells expressing human beta 3-adrenoceptors with pEC50 = 5.5 and intrinsic activity 0.74 with respect to (-)-isoprenaline (pEC50 = 5.9). (-)-RO363 competed for binding with [125I]-cyanopindolol at human beta 3-adrenoceptors transfected into CHO cells with pKi = 4.5. (-)-Isoprenaline (pKi = 5.2) and (-)-CGP 12177A (pKi = 6.1) also competed for binding at human beta 3-adrenoceptors. 7. We conclude that under conditions used in this study, (-)-RO363 is a potent partial agonist for human beta 1- and beta 3-adrenoceptors and appears also to activate the third human atrial beta-adrenoceptor. (-)-RO363 relaxes mammalian gut through both beta 1- and beta 3-adrenoceptors. (-)-RO363, used as a beta 1-adrenoceptor selective tool, confirms previous findings with (-)-noradrenaline that beta 1-adrenoceptor-mediated atrial effects are only slightly enhanced by chronic treatment of patients with beta-blockers. Chronic treatment with

Adenylyl Cyclases↗
PubMed1997

Lipolytic effects of conventional beta 3-adrenoceptor agonists and of CGP 12,177 in rat and human fat cells: preliminary pharmacological evidence for a putative beta 4-adrenoceptor.

1. The nature of rat and human fat cell beta 3-adrenoceptors was investigated by studying the effects of the new beta 3-adrenoceptor selective antagonist, SR 59,230A, on lipolysis induced by the conventional beta 3-adrenoceptor agonists, CL 316,243 and SR 58,611A, and by the non-conventional partial beta 3-adrenoceptor agonist CGP 12,177 (a potent beta 1- and beta 2-adrenoceptor antagonist with partial beta 3-adrenoceptor agonist property). 2. In rat fat cells, the rank order of potency of agonists was: CL 316,243 > isoprenaline > SR 58,611A > CGP 12,177. The three former agents were full agonists whereas CGP 12,177 was a partial agonist (intrinsic activity of 0.70). In human fat cells, the lipolytic effect of CGP 12,177 reached 25% of isoprenaline effect. CL 316,243 was a poor inducer of lipolysis and SR 58,611A was ineffective. 3. In rat fat cells, lipolysis induced by CL 316,243 and SR 58,611A was competitively antagonized by SR 59,230A. Schild plots were linear with pA2 value of 6.89 and 6.37, respectively. Conversely, 0.1, 0.5 and 1 microM SR 59,230A did not modify the concentration-response curve of CGP 12,177. A rightward shift of the curve was however observed with 10 and 100 microM of SR 59,230A. The apparent pA2 value was 5.65. The non-selective beta-adrenergic antagonist, bupranolol, competitively displaced the concentration-response curve of CGP 12,177 and CL 316,243. Schild plots were linear with pA2 values of 6.70 and 7.59, respectively. CL316,243-mediated lipolytic effect was not antagonized by CGP 20,712A. In human fat cells, CGP 12,177-mediated lipolytic effect was antagonized by bupranolol and CGP 20,712A. SR 59,230A (0.1, 1 and 10 microM) did not modify the concentration-response curve of CGP 12,177. A rightward shift was however observed at 100 microM leading to an apparent pA2 value of 4.32. 4. The results suggest that the non-conventional partial agonist CGP 12,177 can activate lipolysis in fat cells through the interaction with a beta-adrenoceptor pharmacologically distinct from the beta 3-adrenoceptor, i.e. through a putative beta 4-adrenoceptor. They suggest that the two subtypes coexist in rat fat cells whereas only the putative beta 4-adrenoceptor mediates lipolytic effect of CGP12,177 in human fat cells.

Adipocytes↗