Binding and functional characterization of α1-adrenoceptor subtypes in the rat prostate

Hiraoka, Yasuko; Ohmura, Tsuyoshi; Oshita, Masafumi; Watanabe, Yoshinari; Morikawa, Kouji; Nagata, Osamu; Kobayashi, Hideo; Taniguchi, Tadatsugu; Muramatsu, Ikunobu

doi:10.1016/s0014-2999(98)00895-4

Cited by 37 publications

(28 citation statements)

References 36 publications

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“…In assays using rat prostate, in which the subtype a 1A -adrenoceptor is the most important for contraction (Hiraoka et al, 1999), our results indicate that LDT3, LDT5, and LDT8 have high affinity for a 1A -adrenoceptors, with K B values ranging from 0.17 to 2.62 nM ( Fig. 1A; Table 2), close to those for the anti-BPH drug tamsulosin and slightly smaller than the previous derivative LDT66 (Table 2).…”

Section: Ldt3 Ltd5supporting

confidence: 60%

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

Nascimento-Viana

Carvalho

Nasciutti

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Benign prostatic hyperplasia (BPH) is characterized by stromal cell proliferation and contraction of the periurethral smooth muscle, causing lower urinary tract symptoms. Current BPH treatment, based on monotherapy with a 1A -adrenoceptor antagonists, is helpful for many patients, but insufficient for others, and recent reports suggest that stimulation of a 1D -adrenoceptors and 5-hydroxytryptamine (serotonin) (5-HT) 1A receptors contributes to cell proliferation. In this study, we investigated the potential of three N-phenylpiperazine derivatives (LDT3, LDT5, and LDT8) as multi-target antagonists of BPH-associated receptors. The affinity and efficacy of LDTs were estimated in isometric contraction and competition-binding assays using tissues (prostate and aorta) and brain membrane samples enriched in specific on-or off-target receptors. LDTs' potency was estimated in intracellular Ca 21 elevation assays using cells overexpressing human a 1 -adrenoceptor subtypes. The antiproliferative effect of LDTs on prostate cells from BPH patients was evaluated by viable cell counting and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays. We also determined LDTs' effects on rat intraurethral and arterial pressure. LDT3 and LDT5 are potent antagonists of a 1A -, a 1D -adrenoceptors, and 5-HT 1A receptors (K i values in the nanomolar range), and fully inhibited phenylephrine-and 5-HT-induced proliferation of BPH cells. In vivo, LDT3 and LDT5 fully blocked the increase of intraurethral pressure (IUP) induced by phenylephrine at doses (ED 50 of 0.15 and 0.09 mg.kg 21 , respectively) without effect on basal mean blood pressure. LDT3 and LDT5 are multi-target antagonists of key receptors in BPH, and are capable of triggering both prostate muscle relaxation and human hyperplastic prostate cell growth inhibition in vitro. Thus, LDT3 and LDT5 represent potential new lead compounds for BPH treatment.

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Section: Ldt3 Ltd5supporting

confidence: 60%

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

Nascimento-Viana

Carvalho

Nasciutti

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Both K B and pA 2 gain their usefulness from the fact that they are agonistindependent values, and remain constant even between different tissues 11 . From the data in This value for prazosin is consistent with the values obtained when prazosin interacts with an α 1 adrenergic receptor 12,13 , suggesting that the adrenergic receptor mediating contraction to phenylephrine is the α 1 adrenergic receptor.…”

Section: Discussionsupporting

confidence: 84%

Measurement of Smooth Muscle Function in the Isolated Tissue Bath-applications to Pharmacology Research

Jespersen

Tykocki

Watts

et al. 2015

JoVE

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Isolated tissue bath assays are a classical pharmacological tool for evaluating concentration-response relationships in a myriad of contractile tissues. While this technique has been implemented for over 100 years, the versatility, simplicity and reproducibility of this assay helps it to remain an indispensable tool for pharmacologists and physiologists alike. Tissue bath systems are available in a wide array of shapes and sizes, allowing a scientist to evaluate samples as small as murine mesenteric arteries and as large as porcine ileum -if not larger. Central to the isolated tissue bath assay is the ability to measure concentration-dependent changes to isometric contraction, and how the efficacy and potency of contractile agonists can be manipulated by increasing concentrations of antagonists or inhibitors. Even though the general principles remain relatively similar, recent technological advances allow even more versatility to the tissue bath assay by incorporating computer-based data recording and analysis software. This video will demonstrate the function of the isolated tissue bath to measure the isometric contraction of an isolated smooth muscle (in this case rat thoracic aorta rings), and share the types of knowledge that can be created with this technique.

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“…On the other hand, MK017, a new α 1A -and α 1L -AR agonist, showed a high potency for both AR phenotypes. These agonist profiles of receptors expressed in cell lines were entirely in accord with the phenotypes observed in intact tissue preparations both for the α 1A -AR [rat tail artery (19,28)] and for the α 1L -AR [rat prostate (37)]. However, it should be noted that there are significant differences in the efficacies to MK017 and Ro 115-1240 between native and reconstituted receptors (Fig.…”

Section: Discussionsupporting

confidence: 74%

Identification of Cysteine-Rich Epidermal Growth Factor–Like Domain 1α (CRELD1α) as a Novel α1A-Adrenoceptor–Down-Regulating Protein and Establishment of an α1L-Adrenoceptor–Expressing Cell Line

et al. 2010

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Abstract. Two distinct α 1 -adrenoceptor phenotypes ( α 1A -and α 1L -ARs) are known to originate from a single ADRA1A( α 1a ) gene by an as-yet-unknown mechanism. We hypothesized that an α 1a -AR-interacting protein could generate the α 1L -AR phenotype and we sought to identify such a protein and to examine its effects on the expression of α 1A and α 1L phenotypes. Cysteine-rich epidermal growth factor-like domain 1 α (CRELD1 α ) was first identified using a yeast two-hybrid approach as an α 1a -AR-interacting protein. Transfection of α 1a -AR cDNA alone yielded Chinese hamster ovary (CHO) cells expressing α 1A -ARs having a predominant high affinity site for prazosin, with a low proportion (<10%) of prazosin-low affinity sites ( α 1L -AR). Knockdown of endogenous CHO-CRELD1 α [ α 1a -CKD( α 1A -enhanced) cells] enhanced the expression of α 1A -AR, whereas over-expression of CRELD1 α reduced α 1A -AR expression, yielding α 1a -COE( α 1L -dominant) cells expressing a high proportion (50%) of the α 1L -AR phenotype. The ligand binding and functional agonist and antagonist profiles in α 1a -CKD( α 1A -enhanced) and α 1a -COE( α 1L -dominant) cell lines were entirely in accord with the α 1A -AR and α 1L -AR phenotypes observed in intact tissues. CRELD1 α down-regulates expression of the α 1A -AR, thereby enhancing the proportion of expression of the α 1L -AR phenotype. The α 1L -AR-expressing α 1a -COE( α 1L -dominant) cell line reflects accurately the phenotype of this AR observed in vivo and will facilitate development of α 1L -AR-targeted drugs.

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Binding and functional characterization of α1-adrenoceptor subtypes in the rat prostate

Cited by 37 publications

References 36 publications

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

New Multi-target Antagonists of 1A-, 1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure

Measurement of Smooth Muscle Function in the Isolated Tissue Bath-applications to Pharmacology Research

Identification of Cysteine-Rich Epidermal Growth Factor–Like Domain 1α (CRELD1α) as a Novel α1A-Adrenoceptor–Down-Regulating Protein and Establishment of an α1L-Adrenoceptor–Expressing Cell Line

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