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- Adolfsson, Per, 1967-, et al.
(author)
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Changes in β2-adrenoceptor expression and in adenylyl cyclase and phosphodiesterase activity in human uterine leiomyomas
- 2000
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In: Molecular human reproduction. - : Oxford University Press (OUP). - 1360-9947 .- 1460-2407. ; 6:9, s. 835-842
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Journal article (peer-reviewed)abstract
- Uterine leiomyoma is a very common benign tumour with unclear pathophysiology in adult women. In the present study we have investigated the expression level of α2- and β2-adrenoceptors, and the adenylyl cyclase and phosphodiesterase activity in leiomyoma tissue compared with adjacent myometrium. Our results show that the α2/β2-adrenoceptor ratio is increased in leiomyoma, due to a significant decrease in β2-adrenoceptor expression. These changes were not due to an increased innervation, as the tumour tissue was completely devoid of nerve fibres. Moreover, the adenylyl cyclase activity of leiomyoma membranes was found to be ~50% lower, whereas the phosphodiesterase activity was significantly increased (by ~100%). We found that stimulating an increase in intracellular cyclic AMP, by adenylyl cyclase activity through β2-adrenoceptors (isoprenaline), by direct enzyme activation (forskolin), or by inhibition of phosphodiesterase activity (papaverine), potently blocked both protein and DNA synthesis in cultured leiomyoma smooth muscle cells. Our results imply the adrenoceptors might be involved in, or a consequence of, leiomyoma growth. The results also suggest a new interesting approach for leiomyoma pharmacotherapy.
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| 2. |
- Adolfsson, Per, 1967-
(author)
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Regulatory importance of cyclic nucleotides in smooth muscle growth of the urogenital tract
- 2001
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Doctoral thesis (other academic/artistic)abstract
- 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.
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