Premium
Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects
Author(s) -
WERKSTRÖM VIKTORIA,
SVENSSON ANNA,
ANDERSSON KARLERIK,
HEDLUND PETTER
Publication year - 2006
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2006.06217.x
Subject(s) - urethra , cgmp specific phosphodiesterase type 5 , sildenafil , vardenafil , medicine , erectile tissue , endocrinology , nitric oxide , phosphodiesterase , zaprinast , cgmp dependent protein kinase , anatomy , tadalafil , biology , smooth muscle , enzyme , cyclic gmp , biochemistry , cancer , cell cycle , cyclin dependent kinase 2
OBJECTIVES To characterize the distribution of phosphodiesterase 5 (PDE‐5), cGMP and cGMP‐dependent protein kinase I (PKG1), and to evaluate the effect of pharmacological inhibition of PDE‐5 in isolated preparations of pig and human urethra, as the nitric oxide (NO)/cGMP pathway generates the main inhibitory signals to reduce resistance in the bladder outlet and urethra during emptying of the bladder. MATERIALS AND METHODS After obtaining ethics committee approval, urethral specimens were obtained from three female patients during cystectomy, and from young female pigs. The specimens were prepared for immunohistochemical investigations and for functional studies in organ baths. Effects of sildenafil, vardenafil and tadalafil (1 n m to 30 µ m ) were studied in l ‐noradrenaline (1 µ m )‐activated or spontaneously contracted preparations, and on relaxations induced by electrical‐field stimulation (EFS). Levels of cGMP were determined by radioimmunoassay. RESULTS After stimulation with the NO donor, DETA NONO‐ate (1 m m ), there was greater cGMP‐immunoreactivity (IR) in urethral and vascular smooth muscles. There was a wide distribution of cGMP‐ and vimentin‐positive interstitial cells between pig urethral smooth muscle bundles. There was also cGMP‐IR within NO‐synthase‐IR endothelium. There was PDE‐5 IR within the urethral and vascular smooth muscle cells, but also in vascular endothelial cells that expressed cGMP‐IR. In pig and human sections, there was strong PKG1‐IR in α‐actin‐IR urethral smooth muscle cells that also contained IR for cGMP. Sildenafil, vardenafil and tadalafil caused mean ( sem ) concentration‐dependent relaxations of the pig urethra which, at 30 µ m , were 80 (3)% (11 samples), 81 (5)% (12 samples) and 64 (4)% (10 samples) of the spontaneous tone. The relaxation of L‐noradrenaline‐contracted female human urethra was 100% in response to 10 µ m sildenafil, and 85 (15)% and 47 (13)% for 30 µ m of vardenafil and tadalafil, respectively (three samples). Vardenafil or sildenafil (30 µ m ) doubled cGMP levels in pig specimens. There were no effects on cGMP levels with tadalafil. EFS (1–32 Hz) caused l ‐NG‐nitroarginine‐sensitive relaxations of pig urethral muscle that were increased in amplitude and duration by PDE‐5 inhibition. At 0.1 µ m , sildenafil, vardenafil or tadalafil significantly prolonged the mean ( sem ) duration of the relaxation at 4 Hz by 55 (19)%, 45 (14)% and 51 (12)%, respectively. CONCLUSIONS PDE‐5‐, cGMP‐ and PKG1‐IR is widely distributed in human and pig urethral tissues. Nerve‐induced relaxations of urethral preparations were enhanced at low concentrations of sildenafil, vardenafil and tadalafil, whereas there were direct smooth muscle‐relaxant actions of the PDE‐5 inhibitors at high concentrations. Inhibition of PDE‐5 might be an interesting option to facilitate cGMP‐mediated relaxation of the outflow region.