Partial agonist activity of carteolol on atypical beta-adrenoceptors in the guinea pig duodenum

The partial agonist activities of carteolol were investigated on atypical beta-adrenoceptors of duodenum on the guinea pig. Carteolol produced a concentration-dependent relaxation of the guinea pig duodenum (pD(2)=4.85), which was not significantly affected by propranolol (1 microM). In the presence of propranolol (1 microM), however, the non-selective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist, bupranolol (30 microM), caused a rightward shift of the concentration-response curves for carteolol (apparent pA(2)=5.31). Moreover, carteolol (10 microM) weakly, but significantly, antagonized the relaxations in response to catecholamines (isoprenaline, noradrenaline and adrenaline), to a selective beta(3)-adrenoceptor agonist, (R*, R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]pheno xyacetic acid sodium salt (BRL37344), and to a non-conventional partial beta(3)-adrenoceptor agonist, [4-[3-[(1, 1-dimethylethyl)amino]-2-hydroxypropoxy]-1, 3-dihydro-2H-benzimidazol-2-one] hydrochloride (CGP12177A), also in the guinea pig duodenum (apparent pA(2)=5.77, 5.92, 6.05, 6.56 and 5. 58, respectively). These results suggest that the partial agonist effects of carteolol are mediated by atypical beta-adrenoceptors in the guinea pig duodenum.     

Characterization of atypical beta-adrenoceptors in the guinea pig duodenum.

The atypical beta-adrenoceptors mediating relaxation in the guinea pig duodenum were studied using catecholamines (isoprenaline, noradrenaline and adrenaline), a selective beta3-adrenoceptor agonist BRL37344 ((R*,R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phe noxyacetic acid sodium salt) and a non-conventional partial beta3-adrenoceptor agonist CGP12177A ((-)-4-(3-t-butylamino-2-hydroxypropoxy)benzimidazol-2-one)). Catecholamines and beta3-adrenoceptor agonists induced concentration-dependent relaxation in this preparation. Propranolol (1 microM) produced only small rightward shifts in the concentration-response curves of these agonists. In the presence of propranolol (1 microM), however, a non-selective beta1-, beta2- and beta3-adrenoceptor antagonist bupranolol caused a concentration-dependent rightward shift of the concentration-response curves for catecholamines and beta3-adrenoceptor agonists. Schild plot analyses of the effects of bupranolol against these agonists gave pA2 values of 6.02 (isoprenaline), 5.98 (noradrenaline), 5.93 (adrenaline), 6.51 (BRL37344) and 5.70 (CGP12177A), respectively, and all Schild slopes were not significantly different from unity. These results suggest that atypical beta-adrenoceptors are present in the guinea pig duodenum and involved in mediating the functional relaxant response.     

Partial agonistic properties of (+/-)-pindolol at atypical beta-adrenoceptors in the guinea pig gastric fundus.

(+/-)-Pindolol ([1-(1H-indol-4-yloxy)-3-[(1-methylethyl)- amino]-2-propanol)]) is a partial agonist at atypical beta-adrenoceptors in the guinea pig gastric fundus. (+/-)-Pindolol induced concentration-dependent relaxation in this tissue. However, the relaxant responses of (+/-)-pindolol were not antagonized by a combination of the selective beta(1)-adrenoceptor antagonist atenolol (10(-4) mol/l) and the selective beta(2)-adrenoceptor antagonist butoxamine (10(-4) mol/l). In the presence of both atenolol and butoxamine, the nonselective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist (+/-)-bupranolol (10(-5)-10(-4) mol/l) caused a concentration-dependent rightward shift of the concentration-response curves for (+/-)-pindolol. Schild plot analyses of (+/-)-bupranolol against (+/-)-pindolol gave the pA(2) value of 5.46 +/- 0.03 and Schild slope was not significantly different from unity. Furthermore, (+/-)-pindolol (10(-5) mol/l) weakly but significantly antagonized the relaxant responses to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), a selective beta(3)-adrenoceptor agonist BRL37344 ((R*,R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium salt) and a nonconventional partial beta(3)-adrenoceptor agonist (+/-)-CGP12177A ([4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride). These results suggest that (+/-)-pindolol acts as a partial agonist at atypical beta-adrenoceptors in the guinea pig gastric fundus.     

Functional properties of atypical beta-adrenoceptors on the guinea pig duodenum

In this study, we attempted to further characterize atypical beta-adrenoceptors on the guinea pig duodenum. (-)-Enantiomers of isoprenaline and noradrenaline were more potent than its (+)-enantiomers. The isomeric activity ratios ((+)/(-)) were less than those obtained in the guinea pig atria and trachea. The concentration-response curves to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), to the selective beta(3)-adrenoceptor agonist, BRL37344 ((R*, R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium), and to the non-conventional partial beta(3)-adrenoceptor agonist, (+/-)-CGP12177A ((+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride), were resistant to blockade by (+/-)-pindobind, the beta-adrenoceptor alkylating agent. (-)-Noradrenaline and (-)-adrenaline were more potent than dopamine and (-)-phenylephrine, respectively. Selective beta(2)-adrenoceptor agonists possess agonistic activities at atypical beta-adrenoceptors. (+/-)-Propranolol and (+/-)-bupranolol had no agonistic effect, whereas (+/-)-alprenolol, (+/-)-pindolol, (+/-)-nadolol, (+/-)-CGP12177A and (+/-)-carteolol exhibited agonistic activities at atypical beta-adrenoceptors. These results suggest that pharmacological properties of atypical beta-adrenoceptors differ from those of conventional beta(1)- and beta(2)-adrenoceptors on the guinea pig.     

Agonistic activity of SR59230A at atypical beta-adrenoceptors in guinea pig gastric fundus and duodenum

We have recently suggested that atypical beta-adrenoceptors are present in guinea pig gastric fundus and duodenum. In the present study, we have shown that SR59230A (3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate), a selective beta(3)-adrenoceptor antagonist, possesses agonistic activities at atypical beta-adrenoceptors in these tissues. SR59230A caused concentration-dependent relaxations. However, (+/-)-propranolol (1 microM) did not affect SR59230A-induced relaxations. Pretreatment of with a combination of (+/-)-propranolol (1 microM) and the non-selective beta(1)-, beta(2)-, beta(3)- and beta(4)-adrenoceptor antagonist, (+/-)-bupranolol (30 microM), significantly antagonized the relaxant effects induced by SR59230A. The results clearly indicate that SR59230A acts as an atypical beta-adrenoceptor agonist on guinea pig gastric fundus and duodenum.     

Pharmacological analysis of atypical beta-adrenoceptors in the guinea pig gastrointestinal tissue systems

The purpose of the present study was to characterize the atypical beta-adrenoceptors involved in relaxant responses in guinea pig gastric fundus, duodenum and ileum in functional experiments with catecholamines (isoprenaline, noradrenaline and adrenaline), beta 3-adrenoceptor agonists (BRL37344 and CGP12177A) and a non-selective beta 1-, beta 2- and beta 3-adrenoceptor antagonist bupranolol, and to obtain further evidence to clarify whether there is a tissue difference in atypical beta-adrenoceptors in the guinea pig gastrointestinal tissue systems. The atypical beta-adrenoceptors are present in gastric fundus, duodenum and ileum of guinea pig. In the presence of propranolol (1 microM) or atenolol (100 microM) plus butoxamine (100 microM), bupranolol caused a concentration-dependent rightward shift of the concentration-response curves for catecholamines and beta 3-adrenoceptor agonists. There was not a significant difference of pA2 values for bupranolol against these agonists between gastric fundus, duodenum and ileum of guinea pig. These results suggest that guinea pig gastric fundus, duodenum and ileum relaxation are mediated predominantly by an atypical beta-adrenoceptor population whereas the classical beta 1- or/and beta 2-adrenoceptors play a subordinate function role and that the receptors of three tissues are pharmacological identified by functional approaches. There is not a tissue difference in atypical beta-adrenoceptors in the guinea pig gastrointestinal tissue systems between stomach and ileum.     

Partial agonistic effects of carteolol on atypical beta-adrenoceptors in the guinea pig gastric fundus

The properties of the beta1-/beta2-adrenoceptor partial agonist carteolol were investigated in atypical beta-adrenoceptors on the guinea pig gastric fundus. Carteolol induced concentration-dependent relaxation in this tissue (pD2 = 5.55, intrinsic activity = 0.94). However, a combination of the selective beta1-adrenoceptor antagonist atenolol (100 microM) and the selective beta2-adrenoceptor antagonist butoxamine (100 microM) produced only small rightward shifts in the concentration-response curves of carteolol in the gastric fundus (pD2 = 4.91, intrinsic activity = 0.94). In the presence of both atenolol (100 microM) and butoxamine (100 microM), the non-selective beta1-, beta2- and beta3-adrenoceptor antagonist (+/-)-bupranolol (10-100 microM) caused a concentration-dependent right-ward shift of the concentration-response curves for carteolol in the guinea pig gastric fundus. Schild plot analyses of the effects of (+/-)-bupranolol against carteolol gave the pA2 value of 5.29 and the Schild slope was not significantly different from unity. Furthermore, carteolol (10 microM) weakly but significantly antagonized the relaxant responses to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), a selective beta3-adrenoceptor agonist BRL37344 ((R*,R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxy-acetic acid sodium salt) and a non-conventional partial beta3-adrenoceptor agonist (+/-)-CGP12177A ([4-[3-[(1,1dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride) in the guinea pig gastric fundus. These results suggest that the partial agonistic effects of carteolol are mediated by atypical beta-adrenoceptors in the guinea pig gastric fundus.     

Regulation of beta-adrenoceptors in the guinea pig left ventricle and skeletal muscle following chronic agonist treatment

Pretreatment of guinea pigs with adrenaline, isoprenaline or terbutaline for 7 days significantly reduced the Bmax for the radioligand [125I]cyanopindolol (ICYP) in the gastrocnemius muscle (beta 2-adrenoceptors). Pretreatment of guinea pigs with terbutaline reduced the responsiveness of gastrocnemius muscle slices adenylate cyclase to isoprenaline (10(-4) M). In the left ventricle (predominantly beta 1-adrenoceptors) pretreatment of guinea pigs with isoprenaline or adrenaline for 7 days did not alter the Bmax for ICYP. The responsiveness of adenylate cyclase to isoprenaline (10(-4) M) in left ventricle slices was significantly reduced following isoprenaline pretreatment of the guinea pigs. Thus desensitisation of beta-adrenoceptors in left ventricle and skeletal muscle developed following chronic agonist pretreatment. Reduction of beta 2-adrenoceptors in the skeletal muscle could be responsible for the desensitisation of adenylate cyclase. In the left ventricle the receptors were resistant to agonist induced down-regulation. It is proposed that other mechanisms which are tissue- and species-specific independent of the receptor subtype can be responsible for agonist-induced desensitisation in the left ventricle of the guinea pig in vivo.     

Putative partial agonist 1-aminocyclopropanecarboxylic acid acts concurrently as a glycine-site agonist and a glutamate-site antagonist at N-methyl-D-aspartate receptors

1-Aminocyclopropanecarboxylic acid (ACPC) has been shown to protect against neuronal cell death after ischemic insult in vivo. Such results can be correlated with in vitro assays in which ACPC protected neurons against glutamate-induced neurotoxicity by reducing the activity of N-methyl-D-aspartate (NMDA) channel activation. Electrophysiological studies have determined that ACPC inhibits NMDA receptor activity by acting as a glycine-binding site partial agonist. In this study, rapid drug perfusion combined with whole-cell voltage-clamp was used to elicit and measure the effects of ACPC on NMDA receptor-mediated responses from cultured hippocampal neurons and cerebellar granule cells. The ACPC steady-state dose-response curve had both stimulatory and inhibitory phases. Half-maximal activation by ACPC as a glycine-site agonist was 0.7 to 0.9 microM. Half-maximal inhibition by ACPC was dependent on NMDA concentration. Peak responses to a >100 microM ACPC pulse in the presence of 1 microM glutamate were similar to those of glycine but decayed to a steady-state amplitude below that of glycine. The removal of ACPC initially caused an increase in inward current followed by a subsequent decrease to baseline levels. This suggests that relief of low-affinity antagonism occurs before high-affinity agonist dissociation. Simulations of ACPC action by a two glutamate-binding site/two glycine-binding site model for NMDA channel activation in conjunction with the concurrent role of ACPC as a glycine-site full agonist and glutamate-site competitive antagonist were able to successfully approximate experimental results.     

Pharmacological analysis of atypical beta-adrenoceptors in the guinea pig gastric fundus using the beta(3)-adrenoceptor antagonist bupranolol

Atypical beta-adrenoceptor-mediated relaxations to catecholamines (isoprenaline, noradrenaline and adrenaline) and beta(3)-adrenoceptor agonists, BRL37344 [(R*, R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]-propyl]phen oxyacetic acid sodium salt] and CGP12177A [(-)-4-(3-t-butylamino-2-hydroxy- propoxy)benzimidazol-2-one] in guinea pig gastric fundus were investigated. The five agonists induced concentration-dependent relaxation of the gastric fundus. In the presence of both atenolol and butoxamine only small rightward shifts of the concentration-response curves to these agonists were observed. Under this condition, however, bupranolol caused a concentration-dependent rightward shift of the concentration-response curve to catecholamines and beta(3)-adrenoceptor agonists. Schild plot analyses of bupranolol against these agonists gave pA(2) values of 6.08 (isoprenaline), 6. 04 (noradrenaline), 5.90 (adrenaline), 6.50 (BRL37344) and 5.80 (CGP12177A), respectively. These results clearly suggest that the existence of functional atypical beta-adrenoceptors in the guinea pig gastric fundus and the relaxation of these agonists in this tissue are mediated via atypical beta-adrenoceptors. Copyright Copyright 1999 S. Karger AG, Basel     

Oxotremorine acts as a partial nicotinic agonist on cultured chick myotubes

Oxotremorine, a compound widely used as a muscarinic agonist, was found to inhibit binding of 125I-alpha-bungarotoxin to chick myotube nicotinic acetylcholine receptors, IC50 = 79 +/- 5 microM. Oxotremorine also induced a d-tubocurarine sensitive influx of 86Rb in the myotubes (EC50 = 50 +/- 15 microM). Comparative ion-flux studies with carbachol suggested a partial agonist mode of action of oxotremorine.     

Aripiprazole acts as a selective dopamine D2 receptor partial agonist

Aripiprazole has made a significant contribution to the treatment of schizophrenia and related disorders with an improved safety and tolerability profile, which has been attributed to its unique pharmacological profile. It has been claimed that partial agonism of the dopamine D₂ and 5-HT_1A receptors and antagonism of the 5-HT₂ receptor contribute to the clinical profile of aripiprazole, a so-called dopamine- and 5-HT stabiliser. However, recent studies have questioned the role of the 5-HT-mediated systems in the mechanism of action of aripiprazole. This report reviews published and unpublished data that suggest that aripiprazole acts as a selective partial agonist at the dopamine D₂ receptor and does not affect 5-HT receptors at therapeutic doses.     

Aripiprazole acts as a selective dopamine D2 receptor partial agonist

Aripiprazole has made a significant contribution to the treatment of schizophrenia and related disorders with an improved safety and tolerability profile, which has been attributed to its unique pharmacological profile. It has been claimed that partial agonism of the dopamine D(2) and 5-HT(1A) receptors and antagonism of the 5-HT(2) receptor contribute to the clinical profile of aripiprazole, a so-called dopamine- and 5-HT stabiliser. However, recent studies have questioned the role of the 5-HT-mediated systems in the mechanism of action of aripiprazole. This report reviews published and unpublished data that suggest that aripiprazole acts as a selective partial agonist at the dopamine D(2) receptor and does not affect 5-HT receptors at therapeutic doses.     

Chronic heart failure in the guinea pig increases cardiac alpha 1- and beta-adrenoceptors

Compared with sham-operated guinea pigs, chronic heart failure produced by aortic constriction resulted in a 79% increase in alpha 1-adrenoceptor density as measured by [3H]prazosin binding (73 +/- 15 vs. 131 +/- 20 fmol/mg protein, P < 0.05); beta-adrenoceptor number, measured by (-)-[3H]dihydroalprenolol binding, increased by 93% (28 +/- 3.4 vs. 54 +/- 5.2 fmol/mg protein, P < 0.01). For each radioligand KD values were unchanged. Thus, congestive heart failure due to chronic pressure overload results in compensatory augmentation of alpha 1- and beta-adrenoceptor numbers.     

The effects of (+/-)-, (+)- and (-)-celiprolol and bromoacetylalprenololmentane at the beta-adrenoceptors of rat isolated cardiovascular preparations

The effects of (+/-)-, (+)- and (-)-celiprolol and of bromoacetylalprenololmentane (BAAM, an irreversible beta-adrenoceptor antagonist) on the contractile responses of the electrically driven rat right ventricle strip to isoprenaline and on the relaxant responses of the rat aorta to procaterol, have been studied. Racemic and (-)-celiprolol or BAAM treatment of the ventricle produced non-parallel rightward shifts of the isoprenaline response curves with a reduction in the maximal response. Sotalol produced parallel rightward displacements of the procaterol response curves of the aorta with no effect on the maximal relaxations. Racemic and (+)- and (-)-celiprolol or BAAM treatment of the aorta produced non-parallel rightwards shifts of the procaterol relaxant curves with a reduction in the maximal relaxation. The BAAM data was used to demonstrate that the KA (dissociation constant) for isoprenaline at beta 1-adrenoceptors was 1.46 x 10(-7) M and for procaterol at beta 2-adrenoceptors was 2.34 x 10(-5) M. Calculation of receptor occupancy demonstrated that to produce a maximal response of the rat right ventricle, had to occupy 87% of the beta 1-adrenoceptors. Likewise, for a maximal response of the rat aorta, procaterol had to occupy 81% of the beta 2-adrenoceptors. It is suggested that the use of tissues with small beta-adrenoceptor reserves has shown that (+/-)- and (-)-celiprolol are slowly dissociating, rather than readily reversible, beta-adrenoceptor antagonists.     

Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig

We have previously shown that N/OFQ, the endogenous peptide ligand for the 'opioid-like' NOP receptor, inhibits cough in guinea pigs and cats. In the present study we sought to continue our characterization of the cough-suppressant effects of NOP stimulation by profiling the pulmonary and antitussive effects of a novel non-peptide NOP agonist, Ro-64-6198, in guinea pigs. In receptor-binding assays, we confirmed that Ro-64-6198 selectively binds to NOP receptors over other opioid receptors. The Ki values for Ro-64-6198 at NOP, MOP, KOP and DOP receptors was 0.3, 36, 214 and 3,787 nmol/l, respectively. In GTPgammaS-binding assays, Ro-64-6198 displayed >900-fold functional selectivity at NOP relative to MOP receptors. We evaluated the effects of Ro-64-6198 (3 and 10 micromol/l) in isolated guinea pig nodose ganglia cells on the increases in intracellular Ca2+ concentration evoked by capsaicin stimulation (1 x 10(-8)-1 x 10(-6) mol/l). Similar to previously reported data with N/OFQ, Ro-64-6198 (3 and 10 micromol/l) significantly attenuated Ca2+ responses in nodose ganglia cells produced by exposure to capsaicin. The effect of Ro-64-6198 (3 micromol/l) on capsaicin-induced intracellular Ca2+ responses was blocked by the NOP antagonist, J113397 (3 micromol/l). In guinea pig in vivo studies, aerosolized capsaicin (10-300 micromol/l) produced a dose-dependent increase in cough number. Ro-64-6198 given i.p. significantly inhibited cough due to capsaicin (300 micromol/l) exposure. In a duration study we found that the maximum antitussive effect (42 +/- 8% inhibition) of Ro-64-6198 (3 mg/kg) was observed at 1 h after i.p. administration. Also at 1 h after administration, Ro-64-6198 (0.003-3.0 mg/kg, i.p.) produced a dose-dependent inhibition of cough. The antitussive effect of Ro-64-6198 (3 mg/kg, i.p.) was blocked by J113397 (12 mg/kg, i.p.) but not by the classical opioid antagonist naltrexone (10 mg/kg, i.p.). Although the antitussive action of Ro-64-6198 may be mediated by a central and/or a peripheral site of action, we hypothesize that selective oral NOP agonists that do not penetrate the blood-brain barrier may provide a novel approach for the treatment of cough. Moreover, because these drugs do not interact at MOP receptors, they may be devoid of codeine-like side effects such as respiratory depression, sedation, constipation or proclivities for addictive liabilities.     

Propylbenzilycholine mustard (PrBCM)-sensitive cholinoceptors and contractile response to partial agonist in guinea pig ileal muscle

Pilocarpine, a partial agonist, activates propylbenzilylcholine mustard (PrBCM)-sensitive cholinoceptors in the guinea pig ileal longitudinal muscle, while carbachol, a full agonist, predominantly activates PrBCM-resistant ones. Carbachol behaves as a partial agonist in the preparation treated with phenoxybenzamine and mainly activates PrBCM-sensitive cholinoceptors, as phenoxybenzamine preferably blocks PrBCM-resistant ones. The receptor occupancy-response curve for carbachol became a rectangular hyperbola, while pilocarpine showed a linear relation. After occlusion of cholinoceptors with phenoxybenzamine, carbachol showed a linear receptor occupancy-response relation, suggesting that its contraction mechanisms after occlusion of cholinoceptors resemble those for pilocarpine. Both the agonists induced an increase in cytosolic Ca2+ concentration [( Ca2+]i) and tension development in a concentration-dependent manner under the conditions used herein. The slopes of the regression lines between [Ca2+]i and tension development for pilocarpine in the untreated preparation and for carbachol in the preparation treated with phenoxybenzamine were significantly steeper than that for carbachol in the untreated preparation, suggesting that carbachol in the phenoxybenzamine-treated preparation and pilocarpine induced a greater tension for a given increase in low [Ca2+]i than did carbachol. Thus an activation of PrBCM-sensitive cholinoceptors might enhance the Ca2+-sensitivity of the contractile elements.     

Impromidine (SK & F 92676) acts as a partial agonist on the isolated whole stomach of the rat

The present secretory studies on the isolated stomach of the rat provide evidence that impromidine acts as a partial agonist at the histamine H2-receptors. It was found to be 100 times more potent than histamine but with a maximal response only 50% that obtained with histamine.     

Pipequaline acts as a partial agonist of benzodiazepine receptors: An electrophysiological study in the hippocampus of the rat

Pipequaline (PK 8165), a quinoline derivative and a ligand of the benzodiazepine binding site, is a clinically-effective anxiolytic, which is devoid of sedative and anticonvulsant properties. Several biochemical and behavioral studies have indicated that this molecule shares some properties with both agonists and antagonists of benzodiazepine receptors. The present in vivo electrophysiological studies were undertaken to determine the effects of microiontophoretic applications and of intravenous injections of pipequaline on hippocampal pyramidal neurons, activated by kainate, glutamate or acetylcholine and to characterize the effects of pipequaline on the action of benzodiazepines. Intravenously administered pipequaline exerted a partial suppression of activations by kainate, glutamate and acetylcholine. Microiontophoretic applications of pipequaline reduced the neuronal activation by kainate. This effect was blocked by RO 15-1788. In small intravenous doses, pipequaline potentiated the effect of microiontophoretically-applied flurazepam whereas, in larger doses, it suppressed the effects of microiontophoretically-applied flurazepam and of intravenously administered lorazepam on kainate-induced activation. Similarly, microiontophoretic applications of pipequaline blocked the suppressant effect of microiontophoretically-applied flurazepam on kainate-induced activation. These results constitute further evidence that the selective anxiolytic activity of pipequaline might be ascribed to its partial agonistic action on benzodiazepine receptors.     

Identification and subclassification of rat adipocyte beta-adrenoceptors using (+/-)-[125I]cyanopindolol

The ligand binding characteristics of beta-adrenoceptors on membranes derived from rat whole fat pads and isolated adipocytes have been compared to those present on lung membranes using the specific ligand (+/-)-[125I]cyanopindolol [(125I]CYP). The equilibrium dissociation constant (KD) of [125I]CYP was similar in all three preparations, whilst the degree of stereospecificity displayed by the isomers of propranolol varied between lung and isolated adipocyte membranes. The rank order of potency in displacing [125I]CYP binding was isoprenaline greater than adrenaline greater than noradrenaline in lung and whole fat pads, suggesting an overall beta 2-receptor subtype, and isoprenaline greater than noradrenaline greater than adrenaline in isolated adipocytes, suggesting a beta 1-receptor. Pharmacological characterisation of receptor subtype with selective beta-adrenoceptor agents indicated that all three preparations contained a heterogeneous receptor population (lung 80% beta 2, 20% beta 1; whole fat pad 62% beta 2, 38% beta 1; isolated adipocyte 15% beta 2, 85% beta 1). In view of the high proportion of beta 2-receptors on whole fat pad membranes, the overall amount of beta 2-receptors on isolated adipocytes may reflect contamination from other cell types. The nature of the beta 1-receptors present on fat cells is discussed in relation to the apparently atypical beta-receptor involved in mediating the functional lipolytic response.