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Characterization of α2-Adrenoceptor Subtypes in Pregnant Human Myometrium
Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
1998 (Engelska)Ingår i: Gynecologic and Obstetric Investigation, ISSN 0378-7346, E-ISSN 1423-002X, Vol. 45, nr 3, s. 145-150Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The aim of the present investigation was to determine which subtypes of the α2-adrenoceptors are being expressed in the human pregnant myometrium at term pregnancy. In radioligand binding studies, the specific binding of [3H]rauwolscine to human myometrial membranes was specific and of high affinity with Kd of 2.8 ± 0.6 nM and Bmax of 95 ± 5 fmol/mg protein. Results from competition for the binding of [3H]rauwolscine using subtype-selective ligands, oxymetazoline (α2A-subptype), chlorpromazine (α2B-subtype) and prazosin (α2B-α2C-subtype), suggested that the α2A- and α2B-subtypes are being co-expressed. In order to examine if also the α2C-subtype is being expressed we used an optimal concentration of oxymetazoline or chlorpromazine which would block the high-affinity site, equivalent to the α2A- and α2B-subtype respectively. Competition curves of both oxymetazoline and chlorpromazine still showed a significantly better fit using a two-site model, suggesting that the α2C-subtype also is being expressed. The expression of α2C-subtype mRNA was confirmed using reverse transcription-polymerase chain reaction on mRNA isolated from myometrial biopsies.

In conclusion, our results suggest that all three subtypes of α2-adrenoceptors are being coexpressed in the human myometrium at term pregnancy and that α2-expression is dominated by the α2A-subtype.

Ort, förlag, år, upplaga, sidor
1998. Vol. 45, nr 3, s. 145-150
Nyckelord [en]
α2-Adrenergic receptors, Subtype, Myometrium, Human, Pregnancy, [3H]rauwolscine, Reverse transcription-polymerase chain reaction
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-80081DOI: 10.1159/000009944OAI: oai:DiVA.org:liu-80081DiVA, id: diva2:545451
Tillgänglig från: 2012-08-20 Skapad: 2012-08-20 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Ingår i avhandling
1. Regulatory importance of cyclic nucleotides in smooth muscle growth of the urogenital tract
Öppna denna publikation i ny flik eller fönster >>Regulatory importance of cyclic nucleotides in smooth muscle growth of the urogenital tract
2001 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Smooth muscle hyperplasia/hypertrophy is, if not responsible for, so at least involved in those diseases, which impair life quality for most people in today's society.

This thesis, presents a pharmacological investigation, related to the regulatory role of cyclic nucleotides, of smooth muscle hyperplasia/hypeitrophy in human uterine leiomyoma and benign prostate hyperplasia (BPH).

Four main aspects, with cAMP as a connecting thought, have been analyzed, namely expression and characterization of the adrenergic receptors (AR), determination of adenylyl cyclase (AC)- and phosphodiesterase (PDE)-activity, and finally the connection between mentioned issues and proliferation of cultured smooth muscle cells (smc).

In the frrst paper, characterization of the a 2-adrenergic receptor (az-AR) subtypes in human myometrium at term pregnancy was examined by combining radioligand binding-studies with reverse transcriptase-polymerase chain reaction (RT-PCR). Results demonstrated a significant eo-expression of α2A and α2B, and a weak indication of the α2C-AR, which however was identified at the mRNA level by the RT-PCR analysis.

In the next investigatio~ smooth muscle tissue of human uterine leiomyoma (benign smooth muscle tumor) was compared with surrounding myometrial tissue (control). The expression of AR, AC- and PDE-activity was analyzed, as well as the effect of cAMP with respect to growth regulation of cultured leiomyoma smc. Primarily, a significantly reduced ß2-AR expression and AC-activity was detected in leiomyoma compared to control tissue, whereas the PDE-activity was approximately 100% higher. In addition, the α2-AR population in leiomyoma was slightly increased. When cultured leiomyoma smc was treated with cAMP increasing agents as forskolin, an AC stimulating agent, or papaverin, a general PDE inhibitor, a considerable inhibition of DNA replication and protein synthesis was obtained.

In the thh·d paper, a proliferation study was made on cultured benign prostate hyperplasia smc, were the mitogen effect of lysophosphatidic acid (LPA) and cAMP/cGMP increasing agents was investigated. LPA generated a dose-dependent mitogen response, which was efficiently inhibited, both by forskolin, and by papaverin. In addition, sildenafil (Viagra®), which serve as a potent and selective PDE5 inhibitor, also decreased the LPA mediated growth promotion in a dose dependent manner.

The last study, demonstrate primarily the expression pattem of LPA receptors (Edg) in BPH smc. Further, the intracellular cAMP changes in LPA stimulated BPH smc and the proliferative effect of the LPA analogue sphingosine 1-phosphate (SIP) was considered. First, all Edg was identified with exception of Edg6. Moreover, the cAMP level was unchanged by LPA per se, whereas co-incubation with forskolin generated a rapid and transient response. Further, SIP generated a divergent response including a LPA equivalent mitogen effect at low concentrations whereas inhibition of DNA replication was obtained at higher concentrations.

In summary, this project demonstrates that cyclic nucleotides inhibit smooth muscle hyperplasia/hypertrophy in the luogenital tract. These results also suggest that manipulation of cyclic nucleotide level using tissue specific PDE inhibitors might constitute a new therapeutic approach for hyperplasia/hypertrophy related diseases in the urogenital tract.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2001. s. 45
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 694
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-27452 (URN)12105 (Lokalt ID)91-7373-136-6 (ISBN)12105 (Arkivnummer)12105 (OAI)
Disputation
2001-11-02, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Svenska)
Opponent
Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2012-10-22Bibliografiskt granskad

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Adolfsson, Per I.Berg, GöranSvensson, Samuel P. S.

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