Lysophosphatidic acid stimulates proliferation of cultured smooth muscle cells from human BPH tissue: sildenafil and papaverin generate inhibition.
BACKGROUND
The endogenous substance lysophosphatidic acid (LPA) has been found to generate proliferation of cultured smooth muscle cells (SMC). Therefore, the effect of LPA on human benign prostate hyperplasia (BPH) could be of interest.


METHODS
The proliferative effect of LPA on cultured human prostatic SMC from specimens obtained at trans-urethral resection of the prostate (TURP) because of BPH, was analyzed by [3H]-thymidine and [35S]-methionine incorporation. In addition, LPA stimulated BPH SMC were treated with papaverin, forskolin, sildenafil or zaprinast, well known to increase the intracellular level of cAMP or cGMP.


RESULTS
LPA produced a dose-dependent increase in BPH SMC, both regarding DNA- and protein-synthesis with EC50 values of 3 and 10 microM, respectively. Furthermore, both papaverin, a general phosphodiesterase inhibitor regarding cAMP hydrolyzes, and forskolin, an adenylyl cyclase stimulating agent, inhibited the LPA-stimulated DNA replication in a dose dependent manner with IC50 = 2.5, and 0.35 microM, respectively. cGMP increasing agents, such as the NO-donors SIN-1 and SNAP, produced a weak anti-proliferative response. However, both phosphodiesterase 5 inhibitors sildenafil (Viagra) and zaprinast efficiently blocked DNA replication. In addition, when the protein synthesis was examined, we found that the LPA response was significantly inhibited by forskolin and papaverin.


CONCLUSIONS
The major conclusion of this investigation is that the endogenous serum component LPA, is able to promote human BPH SMC growth. In addition, our study indicates that cyclic nucleotides can inhibit this effect. Future clinical studies will be needed to determine if different specific phosphodiesterase inhibitors per se or in combination could represent a new therapeutic possibility for the treatment of BPH.
Adolfsson
Per I
PI
Department of Medicine and Care, Division of Pharmacology, Faculty of Health Science, Linköping University, Linköping, Sweden. per.adolfsson@far.liu.se
Ahlstrand
Christer
C
Varenhorst
Eberhard
E
Svensson
Samuel P S
SP
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology; D004247:DNA / Q000032:analysis / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000473:pathology; D010208:Papaverine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011470:Prostatic Hyperplasia / Q000473:pathology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000032:analysis; D011687:Purines; D011688:Purinones / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013268:Stimulation, Chemical; D013450:Sulfones
D006131:Growth Inhibitors; D008246:Lysophospholipids; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011506:Proteins; D011687:Purines; D011688:Purinones; D013450:Sulfones; D005576:Colforsin; D004247:DNA; D000068677:Sildenafil Citrate; D010208:Papaverine; D000242:Cyclic AMP; C011145:zaprinast; D006152:Cyclic GMP