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Adrenoceptor Subtypes (adrenoceptor + subtype)

Distribution by Scientific Domains

Medical Sciences	93%
Life Sciences	6%

Selected Abstracts

,1 -Adrenoceptor subtypes and lower urinary tract symptoms

INTERNATIONAL JOURNAL OF UROLOGY, Issue 3 2008
Debra A Schwinn
Abstract: Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging men leading to lower urinary tract symptoms (LUTS). ,1 -Adrenoceptors (,1ARs) antagonists (blockers) have become a mainstay of LUTS treatment because they relax prostate smooth muscle and decrease urethral resistance, as well as relieving bladder LUTS symptoms. A review of key recent clinical trials suggests new insights into the role of specific ,1AR subtypes in the treatment of LUTS. [source]

,2 -Adrenoceptor subtypes involved in the regulation of catecholamine release from the adrenal medulla of mice

BRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2006
E Moura
Background and purpose: This study was carried out to elucidate which ,2 -adrenoceptor subtypes mediated the inhibition of noradrenaline and adrenaline release from the adrenal medulla of mice. Experimental approach: Isolated adrenal medullae from wild-type and ,2A, ,2B and ,2C -adrenoceptor knockout (KO) mice were placed in superfusion chambers. Catecholamine overflow was evoked by 1,1-dimethyl-4-phenylpiperazinium (500 ,M) in absence or in presence of the ,2 -adrenoceptor agonist medetomidine. The effect of medetomidine was tested in presence of the ,-adrenoceptor antagonists rauwolscine, WB 4101, spiroxatrine, phentolamine and prazosin. Key results: In wild-type mice, medetomidine reduced noradrenaline and adrenaline overflow in a concentration-dependent manner (EC50 in nM: 1.54 and 1.92; Emax in % of inhibition: 91 and 94, for noradrenaline and adrenaline, respectively). The pKD values of the antagonists for noradrenaline overflow did not correlate with pKD values at ,2A, ,2B, or ,2C binding sites. The pKD values of the antagonists for adrenaline overflow correlated positively with pKD values at ,2C binding sites (opossum kidney cells). The effect of medetomidine (100 nM) on noradrenaline overflow was significantly reduced in all three ,2KO mice (57, 54, 44 % inhibition, for ,2A, ,2B, and ,2C, respectively), whereas the effect of medetomidine on adrenaline overflow was greatly reduced in ,2CKO mice (14 % inhibition). Conclusions and implications: In the adrenal medulla of mice, all three ,2 -adrenoceptor subtypes (,2A, ,2B, and ,2C) play an equal role in the inhibition of noradrenaline overflow, whereas the ,2C -adrenoceptor is the predominant ,2 -adrenoceptor subtype involved in the inhibitory mechanism controlling adrenaline overflow. British Journal of Pharmacology (2006) 149, 1049,1058. doi:10.1038/sj.bjp.0706950 Published online 30 October 2006 [source]

Relaxant effects of , -adrenergic agonists on porcine and human detrusor muscle

ACTA PHYSIOLOGICA, Issue 2 2005
J. K. Badawi
Abstract Aim:, Relaxant effects of different , -adrenoceptor agonists on porcine and human detrusor were examined. Thus, the , -adrenoceptor subtype mainly responsible for relaxation in the detrusor muscle of pigs was characterized. Additionally, different effects of several , -agonists in both species were shown. Methods:, Experiments were performed on muscle strips of porcine and human detrusor suspended in a tissue bath. The relaxant effects of the non-selective , -agonist isoprenaline, the selective ,2-agonists procaterol, salbutamol and the selective ,3-agonists BRL 37344, CL 316 243 and CGP 12177 on potassium-induced contraction were investigated. The inhibitory effect of different substances on the maximum contraction and the rank order of potency for endogenous catecholamines was determined in pigs. Furthermore, concentration-relaxation curves were performed for pigs and humans. Results:,Pigs: In the pre-treatment experiments isoprenaline and procaterol showed similar effects. The concentration,response experiments showed that the maximum relaxation induced by procaterol and salbutamol was more than 90%, not significantly different from isoprenaline, whereas the maximum relaxations of CL 316 243, BRL 37344 and CGP 12177 amounted to 68, 70 or 30%, respectively. Rank order of potencies was isoprenaline , adrenaline > noradrenaline. Humans: Isoprenaline, procaterol, salbutamol and CL 316 243 showed a maximum relaxation of 80, 41, 24 and 35% and pD2 values of 6.24, 5.65, 5.48 and 5.55, respectively. Conclusion:,,2-receptors play a main functional role in mediating relaxation of porcine detrusor. Selective ,2- and ,3-agonists similarly relax the human detrusor. Effects were smaller compared with the pig. [source]

Antagonistic effects of selective ,1 -adrenoceptor antagonists MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine in rat thoracic aorta and rabbit iliac artery

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2001
Mitsutoshi Satoh
The antagonistic effects of MDL73005EF and tamsulosin and partial agonists clonidine and tizanidineat rat thoracic aorta and rabbit iliac artery ,1 -adrenoceptors were investigated in this study. Selective ,1 -adrenoceptor antagonists MDL73005EF and tamsulosin dose-dependently shifted the concentration-response curves for noradrenaline to the right. Schild plots of the results obtained from the inhibition by MDL73005EF (pA2 8.30 ± 0.04) and tamsulosin (pA2 10.51 ± 0.06) of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta. The slopes of Schild plots obtained from the inhibition by MDL73005EF and tamsulosin of noradrenaline were significantly different from unity in rabbit iliac artery. Schild plots of the results obtained from the inhibition by clonidine and tizanidine of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta (pA2 7.08 ± 0.04 and 7.32 ± 0.04, respectively). These results suggest that ,1D -adrenoceptors play a significant role in the ,1 -adrenoceptor-agonist-induced contraction of rat thoracic aorta and rabbit iliac artery, and that clonidine and tizanidine interact with the ,1D -adrenoceptor subtype as competitive antagonists in rat thoracic aorta. [source]

Vascular ,1 -adrenoceptors in isolated perfused rat kidney: influence of ageing

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2007
S. O. Awe
Summary 1 The present study identifies ,1 -adrenoceptor subtype(s) involved in constrictor responses of the kidney and how ageing influences it. 2 The study was conducted on kidneys from F344BNF1 rats, which unlike F344 or Wistar rats used by many previous investigators do not exhibit glomerulonephritis at advanced age. 3 Noradrenaline (NA) and phenylephrine (PHE) (non-selective ,1) and A61063 (selective ,1A) adrenoceptor agonists elicited constriction of perfused kidneys of young and old rats. The pD2 values (index of renovascular reactivity) were significantly higher for A61603 than for either PHE or NA, and significantly decrease across age groups. 4 BMY 7378 or RS 100329, ,1D - or ,1A -adrenoceptor antagonists, respectively antagonized the constrictor responses and suppressed the maximal responses to all agonists in young adult rat kidneys. However, antagonism of PHE or A61063 by BMY 7378 in old rat kidneys was surmountable. 5 This study suggests that: (i) ,1A and ,1D -adrenoceptor subtypes mediate vasoconstriction of perfused rat kidney; (ii) ,1A -adrenoceptor subtype appears to predominate in renal vasculature based on agonist relative potencies. (iii) Ageing significantly decreases ,1 -adrenoceptor-mediated vasoconstriction of rat kidney. [source]

Evidence showing that ,-adrenoceptor subtype responsible for the relaxation induced by isoprenaline is principally ,2 but not ,1 in guinea-pig tracheal smooth muscle

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2004
Y. Tanaka
Summary 1 The present study was carried out to pharmacologically identify the ,-adrenoceptor subtype that mediates isoprenaline-elicited relaxation in the isolated guinea-pig tracheal smooth muscle, to answer the question whether it is ,1 - or ,2 -subtype? 2 Isoprenaline as well as salbutamol, a well-known ,2 -selective adrenoceptor agonist, produced a concentration-dependent relaxation with a pD2 value of 8.12 vs. 7.54 for salbutamol. 3 Isoprenaline-elicited relaxation was not affected by ,1 -selective antagonists, atenolol and CGP-20,712A, within the concentration ranges supposed to antagonize ,1 -subtype: atenolol, ,10,6 m; CGP-20,712A, ,10,8 m. 4 By contrast, the concentration,response curves for isoprenaline as well as salbutamol were shifted rightwards in a competitive fashion by atenolol at the concentrations ,3 × 10,6 m. However, pA2 values of atenolol against isoprenaline (5.86) and salbutamol (5.71) were consistent with the value corresponding to ,2 - but not to ,1 -subtype (around 7.00), and these values were not significantly different from each other. 5 Competitive antagonism of the relaxations to isoprenaline and salbutamol were also obtained with ,2 -selective antagonists, butoxamine and ICI-118,551. Against isoprenaline and salbutamol, the pA2 values of butoxamine (6.51 vs. 6.81) and ICI-118,551 (8.83 vs. 8.90) were substantially identical. Thus the primary mediation of ,2 -receptor in the relaxations was strongly supported. 6 The present findings provide evidence that the ,-adrenoceptor which mediates isoprenaline-elicited relaxation of guinea-pig tracheal smooth muscle is essentially ,2 - but not ,1 -subtype. The present study also indicates the importance of using multiple receptor antagonists with different pA2 values to pharmacologically identify the responsible receptor subtype in smooth muscle mechanical responses. [source]

The functional ,-adrenoceptor in dog caudal vesical arteries is mainly an ,1A subtype

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 5-6 2002
M. Nakazawa
Summary 1 The present study attempted to pharmacologically characterize the subtypes of ,-adrenoceptors mediating the vasoconstriction in the isolated and perfused canine vesical artery. 2 Noradrenaline (NA) and phenylephrine (PE, an ,1 -adrenoceptor agonist) induced a dose-dependent vasoconstriction, whereas xylazine (an ,2 -agonist) did not induce any clear vascular constrictor response. 3 Prazosin at 0.01 ,m and rauwolscine at 0.1 ,m failed to affect the NA-induced vasoconstriction. Prazosin at 0.1 ,m antagonized the vasoconstrictor responses to NA, with pKB value of 7.8. 4 WB 4101 at 0.01,0.1 ,m dose-dependently inhibited the responses to NA, with a pKB value of 8.9. The vasoconstrictor responses to NA were not significantly affected by chloroethylclonidine (10,30 ,m) or BMY 7378 (0.1 ,m). 5 The present results indicate that the canine vesical arteries dominantly contain ,1 -adrenoceptors but have no ,2 -adrenoceptors, and the functional subtype of ,1 -adrenoceptor is characterized as an ,1A -adrenoceptor subtype. [source]

JP-1302: a new tool to shed light on the roles of ,2C -adrenoceptors in brain

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2007
M D Tricklebank
The discovery of JP-1302 as a selective, high affinity antagonist at the ,2C -adrenoceptor will enable researchers to probe the functional role and address the therapeutic utility of this potentially highly important adrenoceptor subtype. British Journal of Pharmacology (2007) 150, 381,382. doi:10.1038/sj.bjp.0707007 [source]

,2 -Adrenoceptor subtypes involved in the regulation of catecholamine release from the adrenal medulla of mice

Alpha-2 adrenoceptor subtypes: are more better?

BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2005
David B Bylund
The discovery of an additional duplicated alpha-2 adrenoceptor subtype in the zebrafish raises a pesky nomenclature issue, as well as questions about the functions of the alpha-2 adrenoceptors in the zebrafish and how many alpha-2 receptors does an organism really need. British Journal of Pharmacology (2005) 144, 159,160. doi:10.1038/sj.bjp.0706060 [source]

Different roles of ,1 -adrenoceptor subtypes in mediating cardiomyocyte protein synthesis in neonatal rats

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2004
Yongzhen Zhang
Summary 1.,Three different ,1 -adrenoceptor subtypes, designated ,1A, ,1B and ,1D, have been cloned and identified pharmacologically in cardiomyocytes. In vitro studies have suggested that ,1 -adrenoceptors play an important role in facilitating cardiac hypertrophy. However, it remains controversial as to which subtype of ,1 -adrenoceptors is involved in this response. In the present study, we investigated the different role of each ,1 -adrenoceptor subtype in mediating cardiomyocyte protein synthesis, which is a most important characteristic of cardiac hypertrophy in cultured neonatal rat cardiomyocytes. 2.,Cardiomyocyte hypertrophy was monitored by the following characteristic phenotypic changes: (i) an increase in protein synthesis; (ii) an increase in total protein content; and (iii) an increase in cardiomyocyte size. 3.,The role of each ,1 -adrenoceptor subtype in mediating cardiomyocyte protein synthesis was investigated by the effect of specific ,1 -adrenoceptor subtype-selective antagonists on noradrenaline-induced [3H]-leucine incorporation. In addition, pKB values for ,1 -adrenoceptor subtype-selective antagonists were calculated and compared with the corresponding pKi values to further identify their effects. 4.,Activation of ,1 -adrenoceptors by phenylephrine or noradrenaline in the presence of propranolol significantly increased [3H]-leucine incorporation, protein content and cell size. 5.,Pre-incubating cardiomyocytes with 5-methyl-urapidil, RS 17053 or WB 4101 significantly inhibited noradrenaline-induced [3H]-leucine incorporation. However, there was no effect when cardiomyocytes were pre-incubated with BMY 7378. The correlation coefficients between pKB values for ,1 -adrenoceptor subtype-selective antagonists and pKi values obtained from cloned ,1A -, ,1B - or ,1D -adrenoceptors were 0.92 (P < 0.01), 0.66 (P > 0.05) and 0.24 (P > 0.05), respectively. 6.,Our results suggest that the ,1 -adrenoceptor is dominantly responsible for adrenergic hypertrophy of cultured cardiomyocytes in neonatal rats. The efficiency in mediating cardiomyocyte protein synthesis is ,1A > ,1B , ,1D. [source]

Activation Of ,1 -Adrenoceptors Is Not Essential For The Mediation Of Ischaemic Preconditioning In Rat Heart

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2002
E Vasara
SUMMARY 1. The aim of the present study was to clarify the role of ,1 -adrenoceptors in the mechanism of ischaemic preconditioning (IP). 2. Rat isolated perfused hearts were either non- preconditioned, preconditioned with 5 min ischaemia or treated for 5 min with ,1 -adrenoceptor agonists (50 ,mol/L phenylephrine; 0.1, 0.5 and 1 ,mol/L methoxamine) before being subjected to 45 min of sustained ischaemia followed by 60 min reperfusion. 3. Within each of the above protocols, hearts were divided into groups to which ,1 -adrenoceptor antagonists (prazosin, 5,-methyl urapidil and chloroethylclonidine (CEC)) were administered. Functional recovery and infarct size were used as indices of the effects of ischaemia. Ischaemic contracture characteristics and maximal diastolic pressure during reflow were also assessed. 4. Blockade of ,1 -adrenoceptors with prazosin or the subtype-selective antagonists 5,-methyl urapidil and CEC did not abolish the protective effect of IP with respect to both functional recovery and infarct size reduction. 5. Protection afforded by phenylephrine was attenuated in hearts treated with prazosin or the ,1B -adrenoceptor- selective antagonist CEC, but not in those treated with the ,1A -adrenoceptor-selective antagonist 5,-methyl urapidil. 6. Treatment with low concentrations of methoxamine, considered to be ,1A -adrenoceptor selective, did not confer any protection to the ischaemic myocardium. 7. A close relationship between accelerated ischaemic contracture and enhanced cardioprotection was observed. 8. The results suggest that ,1 -adrenoceptor stimulation mimics IP, but it is not an essential component in the mechanism behind the protective effect of IP in rat heart. In addition, the present study demonstrates that stimulation of the ,1B - but not the ,1A -adrenoceptor subtype is responsible for the catecholamine-induced protection of ischaemic myocardium in rat. [source]

Existence Of ,1A - and ,1B -Adrenoceptor Subtypes In Canine Mandibular Alveolar Arteries

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2001
Yuichi Taguchi
SUMMARY 1. The present study attempted to pharmacologically characterize the , -adrenoceptor subtypes mediating vasoconstriction in canine isolated and perfused mandibular alveolar artery (MAA). 2. Noradrenaline (NA) and phenylephrine (PE) induced a strong vasoconstriction in a dose-dependent manner. The PE-induced vascular constriction was significantly inhibited by treatment with prazosin. Xylazine evoked a moderate vascular constriction and the xylazine-induced response was suppressed by rauwolscine. The NA-induced response was partially inhibited by rauwolscine and the remaining response to NA was abolished by subsequent administration of prazosin. 3. Treatment of MAA with WB4101 produced a dose- dependent inhibition of NA-induced vasoconstriction. Pretreatment of tissues with 10 ,mol/L chloroethylclonidine produced a slight and statistically significant inhibition of NA-induced responses. BMY 7378, a selective ,1D -adrenoceptor antagonist, failed to significantly affect vasoconstrictor responses to NA. 4. The present results suggests that: (i) both ,1 - and ,2 -adrenoceptors are involved in vasoconstrictor responses in the canine MAA; and (ii) the ,1 -adrenoceptors involved in the vasoconstrictor responses in the MAA are characterized as mainly of the ,1A - and partially of the ,1B -adrenoceptor subtype. [source]

,-Adrenoceptor gene variation and intermediate physiological traits: prediction of distant phenotype

EXPERIMENTAL PHYSIOLOGY, Issue 7 2010
John H. Eisenach
Intermediate physiological phenotype is the genetic and environmental influence on functional physiological characteristics with direct prognostic relevance to distant, more complex phenotypes, such as cardiovascular and metabolic disease. Increasingly available and affordable genotyping techniques have created an explosion of information on candidate gene variation and its relationship to intermediate physiological traits. Variation in ,-adrenoceptor genes is an intense focus of investigation because ,-adrenoceptors are: (1) ubiquitous in organ system distribution; (2) integral to a multitude of physiological processes; (3) well described in cardiovascular and metabolic disease; and (4) major pharmacological treatment targets. Furthermore, knowledge of functional gene variants in these receptors predates the description of the human genome. This review highlights the influence of common gene variation in the three ,-adrenoceptor subtypes on intermediate physiological phenotype predictive of cardiovascular disease and obesity. Although further information is needed to replicate this information across populations, this review condenses and summarizes growing trends in specific pleiotropic effects of ,-adrenoceptor polymorphisms and suggests which variants may be predictive of distant phenotype. [source]

Influence of high dietary sodium intake on the functional subtypes of ,1 -adrenoceptors in the renal cortical vasculature of Wistar,Kyoto rats

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1-2 2009
R. N. Kazi
Summary 1,Increased renal vascular resistance is one renal functional abnormality that contributes to hypertension, and ,1 -adrenoceptors play a pivotal role in modulating this renal vascular resistance. This study investigates the functional contribution of ,1 -adrenoceptor subtypes in the renal cortical vasculature of Wistar,Kyoto rats on a normal sodium diet (WKYNNa) compared with those given saline to drink for 6 weeks (WKYHNa). 2,The renal cortical vascular responses to the adrenergic agonists noradrenaline (NA), methoxamine (ME) and phenylephrine (PE) were measured in WKYHNa and WKYNNa rats either in the absence (the control phase) or presence of chloroethylclonidine (CEC), an ,1B -adrenoceptor antagonist, 5-methylurapidil (5-MeU), an ,1A antagonist, or BMY7378, an ,1D antagonist. 3,Results showed a greater renal cortical vascular sensitivity to NA, PE and ME in the WKYHNa compared with WKYNNa rats (P < 0.05). Moreover, 5-MeU and BMY7378 attenuated adrenergically induced renal cortical vasoconstriction in WKYHNa and WKYNNa rats; this response was largely blunted in CEC-treated WKYHNa rats (all P < 0.05) but not in CEC-treated WKYNNa rats. 4,The data suggest that irrespective of dietary sodium content, in Wistar,Kyoto rats ,1A - and ,1D -subtypes are the major ,1 -adrenoceptors in renal cortical vasculature; however, there appears to be a functional involvement of ,1B -adrenoceptors in the WKYHNa rats. [source]

Vascular ,1 -adrenoceptors in isolated perfused rat kidney: influence of ageing

Alpha1A/L -adrenoceptors mediate contraction of the circular smooth muscle of the pig urethra

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2006
K. Bagot
Summary 1 Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional ,1 -adrenoceptors. This study characterizes the ,1 -adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. 2 The potency order of a number of agonists and the affinities of several receptor selective antagonists were determined on pig-isolated circular smooth muscle strips in the presence of cocaine (1 ,m) and corticosterone (10 ,m) to inhibit amine uptake and propranolol (1 ,m) to antagonize , -adrenoceptors. 3 The potency order for agonists was N -[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulphonamide (A61603) > noradrenaline = phenylephrine = M6434 > methoxamine with pEC50 values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The ,1D -adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY7378) caused rightward shifts of the concentration,response curves to noradrenaline, yielding a low affinity estimate (6.6) for the urethral receptor. The ,1A -adrenoceptor-selective antagonists, RS100329 and 5-methylurapidil, gave relatively high affinity estimates (9.6 and 8.8 respectively) for this receptor. All three antagonists produced Schild plots with slopes close to unity but did reduce maximum responses at higher concentrations. Prazosin antagonized responses of the urethra to noradrenaline, yielding a mean affinity estimate of 9.0. Although the Schild plot for prazosin again had a slope of unity, this drug also reduced maximum responses to noradrenaline at all concentrations examined (10,100 nm). N -[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro- ,,, -dimethyl-1H-indole-3-ethanamide (RS17053), which discriminates between responses mediated via ,1A (high affinity) and ,1L -adrenoceptors (low affinity) at concentrations up to 3 ,m, failed to antagonize responses of the urethra. 5 These results suggest that contraction of urethral circular smooth muscle in the pig is mediated via a single population of adrenoceptors with the pharmacological characteristics of the ,1A/L -adrenoceptor, most probably the ,1L -adrenoceptor. [source]

Pharmacological characterization of ,2 -adrenoceptor-mediated responses in pig nasal mucosa

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2003
M. R. Corboz
Summary 1 Pig nasal mucosal strips were incubated with ,-adrenoceptor antagonists followed by ,2 -adrenoceptor agonist concentration,response curves. 2 Contractions elicited by the ,2 -adrenoceptor agonists BHT-920 (pD2 = 6.16 ± 0.07), UK 14,304 (pD2 = 6.89 ± 0.13) and PGE-6201204 (pD2 = 7.12 ± 0.21) were blocked by the ,2 -adrenoceptor antagonist yohimbine (0.1 ,m). In contrast, the ,1 -adrenoceptor antagonist prazosin (0.03 ,m) had no effect on the BHT-920-, UK 14,304- and PGE-6201204-induced contractions, but blocked the contractile response to the ,1 -adrenoceptor agonist phenylephrine (pD2 = 5.38 ± 0.04) and the mixed ,1 - and ,2 -adrenoceptor agonist oxymetazoline (pD2 = 6.30 ± 0.22). 3 The ,2 -adrenoceptor antagonist yohimbine (0.01,0.1 ,m, pA2 = 8.04), ,2B/C -adrenoceptor antagonist ARC 239 (10 ,m, pKb = 6.33 ± 0.21), ,2A/C -adrenoceptor antagonist WB 4101 (0.3 ,m, pKb = 8.01 ± 0.24), ,2A -adrenoceptor antagonists BRL44408 (0.1 ,m, pKb = 6.82 ± 0.34) and RX 821002 (0.1 ,m, pKb = 8.31 ± 0.35), ,2C -adrenoceptor antagonists spiroxatrine (1 ,m, pKb = 7.32 ± 0.32), rauwolscine (0.1 ,m, pKb = 8.16 ± 0.14) and HV 723 (0.3 ,m, pKb = 7.68 ± 0.14) inhibited BHT-920-induced contractions in pig nasal mucosa. 4 The present antagonist potencies showed correlations with binding affinity estimates (pKi) obtained for these antagonists at the human recombinant ,2A - and ,2C -adrenoceptors (r = 0.78 and 0.83, respectively) and with binding affinity estimates (pKd) obtained in pig native ,2A - and ,2C -monoreceptor assays (r = 0.85 and 0.78, respectively). No correlation was observed for the ,2B -subtype. 5 In conclusion, contractile responses to phenylephrine, BHT-920, UK 14,304, PGE-6201204 and oxymetazoline indicate that ,1 - and ,2 -adrenoceptors are present and mediate vasoconstriction in pig nasal mucosa. Furthermore, correlation analysis comparing antagonist potency in pig nasal mucosa with affinities for human recombinant ,2 -adrenoceptors and native pig ,2 -adrenoceptors suggest that ,2A - and ,2C -adrenoceptor subtypes constrict pig nasal mucosa vasculature. [source]

The effect of streptozotocin-induced diabetes on cardiac ,-adrenoceptor subtypes in the rat

AUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2001
D. J. Sellers
1,The present study investigates the effect of short-term experimental diabetes of 14-days duration on the ,-adrenoceptor subtypes of the rat heart. 2,,-adrenoceptor-mediated functional responses to submaximal doses of isoprenaline were enhanced in Langendorff-perfused hearts from diabetic rats, manifested as greater changes in tension, heart rate and rates of tension development (+dT/dt) and decline (,dT/dt). 3,Radioligand binding data demonstrated that total cardiac ,-adrenoceptor density and affinity for [3H]-dihydroalprenolol was unchanged by diabetes, although a decrease in ,1 -adrenoceptor density and increase in ,2 -adrenoceptor density was observed. 4,In conclusion, hearts from 14-day streptozotocin-induced diabetic rats demonstrate a number of alterations within the ,-adrenoceptor system. However, the enhanced ,-adrenoceptor-mediated responses to isoprenaline were not caused by an overall increase in density of ,-adrenoceptors, but were accompanied by changes in the ratio of the ,-adrenoceptor subtypes. [source]

Antinociceptive Synergism of MD-354 and Clonidine.

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2010
Part II.
In the present investigation, a possible role for ,2 -adrenoceptors was examined. Mechanistic studies using yohimbine (a subtype non-selective ,2 -adrenoceptor antagonist), BRL 44408 (a preferential ,2A -adrenoceptor antagonist) and imiloxan (a preferential ,2B/C -adrenoceptor antagonist) on the antinociceptive actions of a MD-354/clonidine combination were conducted. Subcutaneous pre-treatment with all three antagonists inhibited the antinociceptive synergism of MD-354 and clonidine in the mouse tail-flick assay in a dose-dependent manner (AD50 = 0.33, 2.1, and 0.17 mg/kg, respectively). Enhancement of clonidine antinociception by MD-354 did not potentiate clonidine's locomotor suppressant activity in a mouse locomotor assay. When [ethyl- 3H]RS-79948-197 was used as radioligand, MD-354 displayed almost equal affinity to ,2A - and ,2B -adrenoceptors (Ki = 110 and 220 nM) and showed lower affinity at ,2C -adrenoceptors (Ki = 4,700 nM). MD-354 had no subtype-selectivity for the ,2 -adrenoceptor subtypes as an antagonist in functional [35S]GTP,S binding assays. MD-354 was a weak partial agonist at ,2A -adrenoceptors. Overall, in addition to the 5-HT3 receptor component, the present investigation found MD-354 to be a weak partial ,2A -adrenoceptor agonist that enhances clonidine's thermal antinociceptive actions through an ,2 -adrenoceptor-mediated mechanism without augmenting sedation. [source]

Catecholamine synthesis and metabolism in the central nervous system of mice lacking ,2 -adrenoceptor subtypes

BRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2009
MA Vieira-Coelho
Background and purpose:, This study investigates the role of ,2 -adrenoceptor subtypes, ,2A, ,2B and ,2C, on catecholamine synthesis and catabolism in the central nervous system of mice. Experimental approach:, Activities of the main catecholamine synthetic and catabolic enzymes were determined in whole brains obtained from ,2A -, ,2B - and ,2C -adrenoceptor knockout (KO) and C56Bl\7 wild-type (WT) mice. Key results:, Although no significant differences were found in tyrosine hydroxylase activity and expression, brain tissue levels of 3,4-dihydroxyphenylalanine were threefold higher in ,2A - and ,2C -adrenoceptor KO mice. Brain tissue levels of dopamine and noradrenaline were significantly higher in ,2A and ,2CKOs compared with WT [WT: 2.8 ± 0.5, 1.1 ± 0.1; ,2AKO: 6.9 ± 0.7, 1.9 ± 0.1; ,2BKO: 2.3 ± 0.2, 1.0 ± 0.1; ,2CKO: 4.6 ± 0.8, 1.5 ± 0.2 nmol·(g tissue),1, for dopamine and noradrenaline respectively]. Aromatic L-amino acid decarboxylase activity was significantly higher in ,2A and ,2CKO [WT: 40 ± 1; ,2A: 77 ± 2; ,2B: 40 ± 1; ,2C: 50 ± 1, maximum velocity (Vmax) in nmol·(mg protein),1·h,1], but no significant differences were found in dopamine ,-hydroxylase. Of the catabolic enzymes, catechol- O -methyltransferase enzyme activity was significantly higher in all three ,2KO mice [WT: 2.0 ± 0.0; ,2A: 2.4 ± 0.1; ,2B: 2.2 ± 0.0; ,2C: 2.2 ± 0.0 nmol·(mg protein),1·h,1], but no significant differences were found in monoamine oxidase activity between all ,2KOs and WT mice. Conclusions and implications:, In mouse brain, deletion of ,2A - or ,2C -adrenoceptors increased cerebral aromatic L-amino acid decarboxylase activity and catecholamine tissue levels. Deletion of any ,2 -adrenoceptor subtypes resulted in increased activity of catechol- O -methyltransferase. Higher 3,4-dihydroxyphenylalanine tissue levels in ,2A and ,2CKO mice could be explained by increased 3,4-dihydroxyphenylalanine transport. [source]

,2 -Adrenoceptor subtypes involved in the regulation of catecholamine release from the adrenal medulla of mice

Alpha-2 adrenoceptor subtypes: are more better?

Sympathectomy reveals ,1A - and ,1D -adrenoceptor components to contractions to noradrenaline in rat vas deferens

BRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2004
Linda Cleary
We have previously demonstrated that contractions of rat vas deferens to exogenous noradrenaline involve predominantly ,1A -adrenoceptors, but that contractions to endogenous noradrenaline involve predominantly ,1D -adrenoceptors. In this study, we have examined the effects of sympathectomy on the subtypes of ,1 -adrenoceptor in rat vas deferens in radioligand binding and functional studies. In vehicle-treated tissues, antagonist displacement of [3H]prazosin binding to ,1 -adrenoceptors was consistent with a single population of ,1 -adrenoceptors. Binding affinities for a range of ,1 -adrenoceptor antagonists were expressed as pKi values and correlated with known affinities for ,1 -adrenoceptor subtypes. The correlation was significant only with ,1A -adrenoceptors. In tissues from rats sympathectomised with 6-hydroxy-dopamine (2 × 100 mg kg,1 i.p.), binding affinity for the ,1D -adrenoceptor antagonist BMY 7378 fitted best with a two-site model. In functional studies, the potency of noradrenaline at producing total (phasic plus tonic) but not tonic contractions was increased in tissues from sympathectomised rats. Results obtained from sympathectomised rats suggest that phasic contractions are mainly ,1D -adrenoceptor mediated, whereas tonic contractions are mainly ,1A -adrenoceptor mediated, based on the effects of BMY 7378 and the ,1A -adrenoceptor antagonist RS 100329. It is concluded that the predominant ,1 -adrenoceptor in vehicle-treated rat vas deferens is the ,1A -adrenoceptor, both in terms of ligand binding and contractions to exogenous agonists. The ,1D -adrenoceptor is only detectable by ligand binding following chemical sympathectomy, but is involved in noradrenaline-evoked contractions, particularly phasic contractions, of rat vas deferens. British Journal of Pharmacology (2004) 143, 745,752. doi:10.1038/sj.bjp.0705987 [source]

A comparison of agonist-specific coupling of cloned human ,2 -adrenoceptor subtypes

BRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2000
Jane E Rudling
The agonist-specific coupling properties of the three cloned human ,2 -adrenoceptor subtypes have been compared, when expressed at similar levels in Chinese hamster ovary (CHO) cell lines, using noradrenaline and (±)- meta -octopamine as agonists. Noradrenaline can couple the receptor to both the inhibition and stimulation of forskolin-stimulated cyclic AMP production in all three receptor subtypes, with the relative strength of the coupling to the pathways varying for each of the receptor subtypes. meta -Octopamine selectively couples the ,2A -adrenoceptor only to the inhibition of forskolin-stimulated cyclic AMP production. However, meta -octopamine couples the ,2B - and ,2C -adrenoceptors to both the inhibition and stimulation of forskolin-stimulated cyclic AMP production. The relative potency of meta -octopamine to noradrenaline varies between the different ,2 -adrenoceptor subtypes. The effects of meta -octopamine are around two orders of magnitude less potent than those of noradrenaline on both the ,2A - and ,2B -adrenoceptor subtypes. In contrast, in the case of the ,2C -adrenoceptor, meta -octopamine is only one order of magnitude less potent than noradrenaline in the stimulation of forskolin-stimulated cyclic AMP production and, in addition, is equipotent with noradrenaline in the inhibition of forskolin-stimulated cyclic AMP production and has an increased maximal response. This raises the possibility that meta -octopamine may have physiologically important actions via ,2C -adrenoceptors in vivo. The results show that the modulation of cyclic AMP production occurs in both a subtype- and agonist-specific manner for ,2A -adrenoceptors and in a subtype specific manner for ,2B - and ,2C -adrenoceptors. British Journal of Pharmacology (2000) 131, 933,941; doi:10.1038/sj.bjp.0703644 [source]