The α1D-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction

Tanoue, Akito; Nasa, Yoshihisa; Koshimizu, Taka‐aki; Shinoura, Hitomi; Oshikawa, Sayuri; Kawai, Takayuki; Sunada, Sachie; Takeo, Satoshi; Tsujimoto, Gozoh

doi:10.1172/jci14001

Cited by 95 publications

(96 citation statements)

References 38 publications

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“…It was recently shown that α 1D -AR stimulation has no direct influence on myocardial (3,12,18 and 24 months) of rats. bp Base pairs; MWM Molecular weight marker inotropic and chronotropic effects (14), but can impair myocardial contractility by reducing coronary flow (7). The downregulation of cardiac α 1D -AR expression in middle age and presenescence demonstrated in our experiments might be an adaptive response to senescence, which could contribute to maintain normal coronary flow by means of decreasing α 1D -AR gene transcription activity and receptor content, to prevent the occurrence of myocardial ischemia.…”

Section: Discussionmentioning

confidence: 74%

Alteration of messenger RNA and protein levels of cardiac alpha(1)-adrenergic receptor and angiotensin II receptor subtypes during aging in rats

Cao¹,

Li²

2009

Canadian Journal of Cardiology

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S everal receptor systems coexist in the heart, including the adrenergic receptor (AR) and the angiotensin II receptor (ATR). Among the cardiac adrenoceptor subtypes, it is well known that beta (β)-AR is predominant with respect to mediating positive inotropic and chronotropic effects (it accounts for approximately 75% of the inotropic response); however, a vast body of evidence has accumulated showing that the alpha(1)-AR (α 1 -AR) also plays an important role in causing positive inotropic effects (it accounts for approximately 25% of the inotropic response). A recent finding (1) indicates that, in addition to the regulation of myocardial contractility, α 1 -AR is involved in mediating the hypertrophic response of cardiomyocytes. Moreover, it has been shown that the ATR not only influences hemodynamics, but also regulates the growth and hypertrophic response of cardiomyocytes, vascular smooth muscle cells and fibroblasts, which are related to cardiovascular remodelling and functional alteration.The endogenetic ligands of α 1 -AR are noradrenaline and adrenaline, while the ATR is always activated by angiotensin II (Ang II). According to its pharmacological characteristics, α 1 -AR is divided into three subtypes: α 1A -AR, α 1B -AR and α 1D -AR. ATRs can be grouped into AT 1 R and AT 2 R. Structural and functional alterations in the senile heart have been associated with an activated sympathetic system and a regional cardiac renin-angiotensin system. However, the influence of aging on the expression of cardiac α 1 -AR and ATR subtypes has remained uncertain. Previous investigations (2-4) focused on comparing the expression of α 1 -AR and ATR subtypes between young adulthood and senescence, but to date, limited information has been expeRImeNtAl studIes ©2009 Pulsus Group Inc. All rights reserved BACKGROUND: Structural and functional alterations in the senescent heart have been associated with an activated sympathetic nervous system and a regional cardiac renin-angiotensin system. To date, however, limited information related to their expression alteration during the whole procress of growth and development has been reported. OBJECTIVES: To examine the expression of alpha(1)-adrenergic receptor (α 1 -AR) and angiotensin II receptor (ATR) subtypes in the left ventricle of hearts from young adult, middle-aged, presenescent and senescent rats. METHODS: Semiquantitative reverse transcriptase polymerase chain reaction and Western blot were used to quantitate the messenger RNA and protein of α 1 -AR and ATR subtypes, respectively, in the left ventricles of three-(young adult), 12-(middle age), 18-(presenescent) and 24-month-old (senescent) Wistar rats. RESULTS AND CONCLUSIONS: α 1A -AR expression decreased gradually with age, and α 1D -AR expression was repressed in middle age and presenescence, while the expression of α 1B -AR remained unchanged during senescence. AT 1 R expression was unaffected by aging from young adulthood to presenescence, but exhibited a remarkable upregulation in senescence. There were no signific...

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Section: Discussionmentioning

confidence: 74%

Alteration of messenger RNA and protein levels of cardiac alpha(1)-adrenergic receptor and angiotensin II receptor subtypes during aging in rats

Cao¹,

Li²

2009

Canadian Journal of Cardiology

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“…Its lack of effect in the cavernous arteries argues against an involvement of the a 1B -AR subtype. BMY 7378 is a tried and tested a 1D -AR antagonist and was used at concentrations of 1-100 nM, covering its known affinity for the a 1D -AR (pK B B8.7, Kenny et al, 1995;Satoh et al, 1999;Daly et al, 2002;Tanoue et al, 2002;Deighan et al, 2005) while avoiding its affinity at the a 1A -AR (pK B B6.6; Lachnit et al, 1997;Zacharia et al, 2004;Deighan et al, 2005). As no effect on the PE response was observed over this range of concentrations, it would be reasonable to conclude that the a 1D -AR subtype is not the predominant functional subtype in cavernous penile arteries.…”

Section: Discussionmentioning

confidence: 99%

“…Concentration ratios lay between 1.0270.38 and 1.9170.67 (n ¼ 6). BMY 7378 is a wellcharacterized a 1D -AR selective compound that has been shown to be potent at a 1D -ARs in various tissues with pA 2 / pK B 's of 8.3 to 9.6 (Kenny et al, 1995;Satoh et al, 1999;Daly et al, 2002;Tanoue et al, 2002;Deighan et al, 2005). Therefore, 100 nM should be expected to produce a significant shift of approximately 50-fold of an a 1D -AR-mediated response even at the insensitive end of this spectrum.…”

Section: Agonist Profilesmentioning

confidence: 99%

α_1A‐Adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries

Morton

Daly

Jackson

et al. 2007

British J Pharmacology

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Background and purpose: Maintained penile erection depends on the absence of a-adrenoceptor (a-AR) activation and so can be facilitated by a-blockers. This study seeks the a 1 -AR subtypes involved in order to inform the pro-erectile consequences of subtype selective blockade. Experimental approach: Wire myography was used with dorsal (nutritional supply) and cavernous (erectile inflow) penile arteries; standard a-AR-selective agonists and antagonists were employed to classify responses. Key results: In both penile arteries noradrenaline (NA) and phenylephrine (PE, a 1 -AR agonist) caused concentrationdependent contractions. Sensitivity to NA was increased by NA uptake blockers, cocaine (3 mM) and corticosterone (30 mM). PE responses were antagonised by phentolamine (non-selective a-AR: dorsal pK B 8.00, cavernous 8.33), prazosin (nonsubtype-selective a 1 -AR: dorsal 8.60, cavernous 8.41) and RS100329 (a 1A -AR selective: dorsal 9.03, cavernous 8.80) but not by BMY7378 (a 1D -AR selective: no effect at 1-100 nM) or Rec15/2615 (a 1B -AR selective: no effect at 1-100 nM). Schild analysis was straightforward in cavernous artery, indicating that PE activates only a 1A -AR. In dorsal artery Schild slopes were low, though a 1A -AR was still indicated. Analysis using UK 14,304 and rauwolscine indicated an a 2 -AR component in dorsal artery that may account for low slopes to a 1 -AR antagonists. Conclusions and implications: Penile arteries have a predominant, functional a 1A -AR population with little evidence of other a 1 -AR subtypes. Dorsal arteries (nutritional supply) also have a 2 -ARs. Thus, a-AR blockers with affinity for a 1A -AR or a 2 -AR would potentially have pro-erectile properties; the combination of these perhaps being most effective. This should inform the design of drugs to assist/avoid penile erection.

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“…Although all three ␣ 1 -AR subtypes signal through the same G q/11 signaling pathway (11), ␣ 1 -AR subtypes can differ in their tissue distributions (1), cellular localization (12,13), activation of transcriptional responses (14), and association with intracellular proteins (15)(16)(17), suggesting that ␣ 1 -AR subtypes perform specific physiological functions. Furthermore, recent data obtained from both ␣ 1 -AR overexpressed (18 -21) and knockout mice (22)(23)(24)(25) indicate that ␣ 1 -ARs play important physiological roles in the cardiovascular system and central nervous system. However, attempts to pharmacologically isolate specific responses to particular subtypes have proven difficult because of the lack of highly ␣ 1B -AR-selective antagonists.…”

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confidence: 99%

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Chen

Rogge

Hague

et al. 2004

Journal of Biological Chemistry

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The 19-amino acid conopeptide ( -TIA) was shown previously to antagonize noncompetitively ␣ 1B -adrenergic receptors (ARs). Because this is the first peptide ligand for these receptors, we compared its interactions with the three recombinant human ␣ 1 -AR subtypes (␣ 1A , ␣ 1B , and ␣ 1D ). Radioligand binding assays showed that -TIA was 10-fold selective for human ␣ 1B -over ␣ 1A -and ␣ 1D -ARs. As observed with hamster ␣ 1B -ARs, -TIA decreased the number of binding sites (B max ) for human ␣ 1B -ARs without changing affinity (K D ), and this inhibition was unaffected by the length of incubation but was reversed by washing. However, -TIA had opposite effects at human ␣ 1A -ARs and ␣ 1D -ARs, decreasing K D without changing B max , suggesting it acts competitively at these subtypes. -TIA reduced maximal NE-stimulated [ 3 H]inositol phosphate formation in HEK293 cells expressing human ␣ 1B -ARs but competitively inhibited responses in cells expressing ␣ 1A -or ␣ 1D -ARs. Truncation mutants showed that the amino-terminal domains of ␣ 1B -or ␣ 1D -ARs are not involved in interaction with -TIA. Alanine-scanning mutagenesis of -TIA showed F18A had an increased selectivity for ␣ 1B -ARs, and F18N also increased subtype selectivity. I8A had a slightly reduced potency at ␣ 1B -ARs and was found to be a competitive, rather than noncompetitive, inhibitor in both radioligand and functional assays. Thus -TIA noncompetitively inhibits ␣ 1B -ARs but competitively inhibits the other two subtypes, and this selectivity can be increased by mutation. These differential interactions do not involve the receptor amino termini and are not because of the charged nature of the peptide, and isoleucine 8 is critical for its noncompetitive inhibition at ␣ 1B -ARs.

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The α1D-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction

Cited by 95 publications

References 38 publications

Alteration of messenger RNA and protein levels of cardiac alpha(1)-adrenergic receptor and angiotensin II receptor subtypes during aging in rats

Alteration of messenger RNA and protein levels of cardiac alpha(1)-adrenergic receptor and angiotensin II receptor subtypes during aging in rats

α_1A‐Adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

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The α1D-adrenergic receptor directly regulates arterial blood pressure via vasoconstriction

Cited by 95 publications

References 38 publications

Alteration of messenger RNA and protein levels of cardiac alpha(1)-adrenergic receptor and angiotensin II receptor subtypes during aging in rats

Alteration of messenger RNA and protein levels of cardiac alpha(1)-adrenergic receptor and angiotensin II receptor subtypes during aging in rats

α1A‐Adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

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α_1A‐Adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries