Selective inhibition of neurogenic, but not agonist‐induced contractions by phospholipase A₂ inhibitors points to presynaptic phospholipase A₂ functions in contractile neurotransmission to human prostate smooth muscle

Article

Author: Waidelich, Raphaela ; Huang, Ru ; Keller, Patrick ; Weinhold, Philipp ; Stief, Christian G ; Hennenberg, Martin ; Götz, Melanie ; Hu, Sheng ; Tamalunas, Alexander

AbstractBackgroundPhospholipases A2 (PLA2) may be involved in α1‐adrenergic contraction by formation of thromboxane A2 in different smooth muscle types. However, whether this mechanism occurs with α1‐adrenergic contractions of the prostate, is still unknown. While α1‐adrenoceptor antagonists are the first line option for medical treatment of voiding symptoms in benign prostatic hyperplasia (BPH), improvements are limited, probably by nonadrenergic contractions including thromboxane A2. Here, we examined effects of PLA2 inhibitors on contractions of human prostate tissues.MethodsProstate tissues were obtained from radical prostatectomy. Contractions were induced by electric field stimulation (EFS) and by α1‐adrenergic agonists in an organ bath, after application of the cytosolic PLA2 inhibitors ASB14780 and AACOCF3, the secretory PLA2 inhibitor YM26734, the leukotriene receptor antagonist montelukast, or of solvent to controls.ResultsFrequency‐dependent contractions of human prostate tissues induced by EFS were inhibited by 25% at 8 Hz, 38% at 16 Hz and 37% at 32 Hz by ASB14780 (1 µM), and by 32% at 16 Hz and 22% at 32 Hz by AACOCF3 (10 µM). None of both inhibitors affected contractions induced by noradrenaline, phenylephrine or methoxamine. YM26734 (3 µM) and montelukast (0.3 and 1 µM) neither affected EFS‐induced contractions, nor contractions by α1‐adrenergic agonists, while all contractions were substantially inhibited by silodosin (100 nM).ConclusionsOur findings suggest presynaptic PLA2 functions in prostate smooth muscle contraction, while contractions induced by α1‐adrenergic agonists occur PLA2‐independent. Lacking sensitivity to montelukast excludes an involvement of PLA2‐derived leukotrienes in promotion of contractile neurotransmission.

01 Oct 2008·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Simplified YM-26734 inhibitors of secreted phospholipase A2 group IIA

Q4 · MEDICINE

Article

Author: Verlinde, Christophe L. M. J. ; Oslund, Rob C. ; Gelb, Michael H. ; Cermak, Nathan

Simplified analogs of YM-26734, a known inhibitor of secreted phospholipase A(2) (sPLA(2)) group IIA, were synthesized and found to also display potent inhibition at low nanomolar concentrations. Analogs were based on the didodecanoylphloroglucinol portion of YM-26734 which contains the predicted active site calcium binding group.

01 Nov 2003·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Induction of distinct sets of secretory phospholipase A2 in rodents during inflammation

Article

Author: Masuda, Seiko ; Yoshihara, Kumiko ; Kuwata, Hiroshi ; Hamaguchi, Katsuhiko ; Murakami, Makoto ; Kudo, Ichiro ; Shimbara, Satoko ; Oh-ishi, Sachiko

Although the expression of the prototypic secretory phospholipase A(2) (sPLA(2)), group IIA (sPLA(2)-IIA), is known to be up-regulated during inflammation, it remains uncertain if other sPLA(2) enzymes display similar or distinct profiles of induction under pathological conditions. In this study, we investigated the expression of several sPLA(2)s in rodent inflammation models. In lipopolysaccharide (LPS)-treated mice, the expression of sPLA(2)-V, and to a lesser extent that of sPLA(2)-IID, -IIE, and -IIF, were increased, whereas that of sPLA(2)-X was rather constant, in distinct tissues. 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema, in which the expression of sPLA(2)-IID, -IIF and -V was increased, was significantly reduced by YM-26734, a competitive sPLA(2)-IIA inhibitor that turned out to inhibit sPLA(2)-IID, -IIE, -V and -X as well. In contrast, sPLA(2)-IIA was dominant in carageenin-induced pleurisy in rats, where the accumulation of exudate fluids and leukocytes was significantly ameliorated by YM-26734. These results indicate that distinct sPLA(2)s can participate in inflammatory diseases according to tissues, animal species, and types of inflammation.

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 2	JP	Yamanouchi Pharmaceutical Co., Ltd.	-
Inflammation	Preclinical	JP	Yamanouchi Pharmaceutical Co., Ltd.	19 Jul 2012

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