Alpha‐adrenoceptors: A critical review

McGrath, J.C.; Brown, C. M.; Wilson, V.G.

doi:10.1002/med.2610090403

Cited by 100 publications

(58 citation statements)

References 443 publications

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“…They are involved in the regulation of blood pressure by mediating contraction of vascular smooth muscle and induction of coronary vasoconstriction in humans (Civantos Calzada and Aleixandre de Artinano 2001; Comings et al 2000). These receptors also modulate sedation, analgesia, insulin release, renal function, cognition, memory, and behavior (Berthelsen and Pettinger 1977;McGrath et al 1989;Timmermans and van Zwieten 1981). Three distinct subtypes of a 2 -AR-a2A, a2B, and a2C-have been identified in multiple mammalian species by molecular and pharmacological research.…”

Section: Introductionmentioning

confidence: 99%

Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene

et al. 2004

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The alpha 2-adrenergic receptors (a 2 -AR) mediate physiological effects of epinephrine and norepinephrine. Three genes encode a 2 -AR subtypes carrying common functional polymorphisms (ADRA2A Asn251Lys, ADRA2B Ins/Del301-303 and ADRA2C Ins/Del322-325). We genotyped these functional markers plus a panel of single nucleotide polymorphisms evenly spaced over the gene regions to identify gene haplotype block structure. A total of 24 markers were genotyped in 96 Caucasians and 96 African Americans. ADRA2A and ADRA2B each had a single haplotype block at least 11 and 16 kb in size, respectively, in both populations. ADRA2C had one haplotype block of 10 kb in Caucasians only. For the three genes, haplotype diversity and the number of common haplotypes were highest in African Americans, but a similar number of markers (3-6) per block was sufficient to capture maximum diversity in either population. For each of the three genes, the haplotype was capable of capturing the information content of the known functional locus even when that locus was not genotyped. The a 2 -AR haplotype maps and marker panels are useful tools for genetic linkage studies to detect effects of known and unknown a 2 -AR functional loci.

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Section: Introductionmentioning

confidence: 99%

Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene

et al. 2004

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“…The cloned a 2 C10 gene corresponds to the a 2A -pharmacological subtype (Kobilka et al, 1987), whilst the cloned a 2 C4 gene corresponds to the a 2C -pharmacological subtype (Regan et al, 1988) and the a 2 C2 gene corresponds to the a 2B -pharmacological subtype (Lomasney et al, 1990). a 2 -Adrenoceptors are widely distributed in peripheral tissues and in the central nervous system where they carry out a wide range of functions (McGrath et al, 1989;Bylund et al, 1994;MacDonald et al, 1997;Docherty, 1998). Recent results from knock-out mouse strains suggest that a 2A -adrenoceptors are likely to mediate most, but not all, of the classical e ects ascribed to a 2 -adrenoceptor agonists.…”

Section: Introductionmentioning

confidence: 99%

A comparison of agonist‐specific coupling of cloned human α₂‐adrenoceptor subtypes

Rudling

Richardson

Evans

2000

British J Pharmacology

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1 The agonist-speci®c coupling properties of the three cloned human a 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. 2 Noradrenaline can couple the receptor to both the inhibition and stimulation of forskolinstimulated 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. 3 meta-Octopamine selectively couples the a 2A -adrenoceptor only to the inhibition of forskolinstimulated cyclic AMP production. However, meta-octopamine couples the a 2B -and a 2C -adrenoceptors to both the inhibition and stimulation of forskolin-stimulated cyclic AMP production. 4 The relative potency of meta-octopamine to noradrenaline varies between the di erent a 2 -adrenoceptor subtypes. The e ects of meta-octopamine are around two orders of magnitude less potent than those of noradrenaline on both the a 2A -and a 2B -adrenoceptor subtypes. In contrast, in the case of the a 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 a 2C -adrenoceptors in vivo. 5 The results show that the modulation of cyclic AMP production occurs in both a subtype-and agonist-speci®c manner for a 2A -adrenoceptors and in a subtype speci®c manner for a 2B -and a 2C -adrenoceptors.

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“…A comparative study by Nielsen et al (1991) examined the pharmacological characteristics of x-adrenoceptor-mediated contractions to noradrenaline in similar sized mesenteric arteries (200 fym diameter) from the rat, rabbit, pig and man and found a2-adrenoceptor-mediated contractions detectable only in porcine and human blood vessels. Further, there are reports that indicate that ml-and a2-adrenoceptors participate in sympathetically mediated vasoconstriction of human vessels (Stevens & Moulds, 1985;Parkinson et al, 1992), yet a-adrenoceptor mediated constrictor responses in small arteries from the rat, guinea-pig and rabbit appear to be exclusively via al-adrenoceptors (Angus et al, 1988;McGrath et al, 1989). It seems likely that in small mammals, neuronally activated x2-adrenoceptors reside on blood vessels too small for routine experimentation (see Ohyanagi et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

The relationship between density of α‐adrenoceptor binding sites and contractile responses in several porcine isolated blood vessels

Wright

Blaylock

Kendall

et al. 1995

British J Pharmacology

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1 The aim of this study was to investigate constrictor x-adrenoceptors in three isolated blood vessles of the pig, the thoracic aorta (TA), the splenic artery (SA) and marginal ear vein (MEV) and then compare the functional response with the densities of a,-and M2-adrenoceptor binding sites in these and several other porcine vascular tissues, palmar common digital artery (PCDA), palmar lateral vein (PLV) and ear artery (EA).2 Noradrenaline (NA), phenylephrine (PE) and UK14304 (all at 0.03-10gM) elicited concentrationdependent contractions in the TA and MEV, with a rank order of potency of UK14304>NA>PE. UK14304 produced maximal responses which were 58% (TA) and 65% (MEV) of that of NA. In the SA, UK14304 and PE produced maximal responses which were less than 10% and 50% of the NA-induced maximal response respectively, with an order of potency of NA>PE. In the SA, NAinduced contractions were competitively antagonized by prazosin (pA2 = 8.60 ± 0.15). Further, rauwolscine (1-1O M) antagonized NA-induced contractions with an apparent pKB of 6.09 ± 0.11 (n = 6), indicating an action at al-adrenoceptors. The combination of the two antagonists at concentrations selective for al-(0.1 JLM) and a2-adrenoceptors (1 J4M) had no greater effect than either antagonist alone.This suggests that the SA expresses only post-junctional a1-adrenoceptors.3 In the TA, prazosin produced non-parallel shifts in the NA-induced CRC and this was also observed with rauwolscine, where reductions in the maximal responses were also observed. In the MEV, prazosin was largely inactive in antagonizing NA-induced contractions. In both these vessels a combination of these two antagonists had a greater effect than either alone, indicating the presence of functional a,-and M2-adrenoceptors. The post-junctional x2-adrenoceptors in all of these vessels were resistant to prazosin, suggesting the a2-adrenoceptor to be of the a2A/2D subtype. mg-', n = 4), followed by the PCDA (256.7 ± 22.7 fmol mg', n = 4), the PLV and SA having approximately equal density (143.6 ± 3.9 and 159.1 ± 7.0 fmol mg-' respectively, n = 4 for both), followed by the EA (91.3 ± 10.5 fmol mg-', n = 3) and the MEV had the lowest density (48.9 ± 11.4 fmol mg-', n = 3).7 In saturation studies using [3H]-RX821002, all tissues produced single site saturation curves with no differences in the Kd values (range 1.31 ± 2.16 nM) but the highest densities were found in the TA and MEV (545.3 ± 36.2 and 531.0 ± 40.9 fmol mg-' respectively), followed by the PLV (418.4 ± 39.4 fmol mg-'), then the EA (266.3 ± 40.0 fmol mg-'), and low densities of [3H]-RX821002 binding being found in the PCDA and SA (155.9 ± 18.1 and 117.5 ± 19.3 fmol mg-' respectively). 8 The pattern of binding site distribution for ol-and C2-adrenoceptors is in reasonable agreement with functional studies carried out in these porcine vascular tissues; the TA has the highest densities of a,-and X2-adrenoceptors; in the SA and PCDA there is a predominance (although small) of al-adrenoceptor binding sites, the reverse of which is obse...

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Alpha‐adrenoceptors: A critical review

Cited by 100 publications

References 443 publications

Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene

Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene

A comparison of agonist‐specific coupling of cloned human α₂‐adrenoceptor subtypes

The relationship between density of α‐adrenoceptor binding sites and contractile responses in several porcine isolated blood vessels

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Alpha‐adrenoceptors: A critical review

Cited by 100 publications

References 443 publications

Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene

Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene

A comparison of agonist‐specific coupling of cloned human α2‐adrenoceptor subtypes

The relationship between density of α‐adrenoceptor binding sites and contractile responses in several porcine isolated blood vessels

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A comparison of agonist‐specific coupling of cloned human α₂‐adrenoceptor subtypes