Effect of hydrogen sulphide-donating sildenafil (ACS6) on erectile function and oxidative stress in rabbit isolated corpus cavernosum and in hypertensive rats.
OBJECTIVE To study the effect of the H(2)S-donating derivative of sildenafil (ACS6) compared to sildenafil citrate and sodium hydrosulphide (NaHS) on relaxation, superoxide formation and NADPH oxidase and type 5 phosphodiesterase (PDE5) expression in isolated rabbit cavernosal tissue and smooth muscle cells (CSMCs), and in vivo on indices of oxidative stress induced with buthionine sulphoximine (BSO). MATERIALS AND METHODS Relaxation was studied in an organ bath in response to carbachol and after incubation with interleukin-1beta for 12 h. CSMCs were incubated with tumour-necrosis factor-alpha or the thromboxane A(2) (TXA(2)) analogue, U46619, with or with no sildenafil citrate, ACS6 or NaHS for 16 h. Superoxide formation and the expression of p47(phox) (an active subunit of the NADPH oxidase complex) and PDE5 protein was then assessed using Western blotting. Rats were also treated with BSO (with or with no sildenafil citrate or ACS6) for 7 days; cavernosal cGMP, cAMP, glutathionine and plasma TXA(2) and 8-isoprostane F(2alpha) was measured by enzyme-linked immunosorbent assay. RESULTS ACS6 and sildenafil citrate relaxed cavernosal smooth muscle equipotently; NaHS alone had little effect at up to 100 microm. The formation of superoxide and expression of p47(phox) and PDE5 was reduced by ACS6, sildenafil citrate and NaHS (order of potency: ACS6 > sildenafil citrate > NaHS). The effects of ACS6 were blocked by inhibitors of protein kinase A (PKA) and PKG. In rats treated with BSO, both ASC6 and sildenafil citrate reduced the increased plasma levels of TXA(2) and 8-isoprostane F(2alpha) but increased cGMP, cAMP and glutathionine levels in corpus cavernosum. CONCLUSIONS By virtue of a dual action on PKA and PKG activation, ACS6 not only promotes erection, acutely, but might also have a long-term beneficial effect through inhibition of oxidative stress and downregulation of PDE5.
Shukla
Nilima
N
Department of Urology, University of Bristol, UK.
Rossoni
Giuseppe
G
Hotston
Matthew
M
Sparatore
Anna
A
Del Soldato
Piero
P
Tazzari
Valerio
V
Persad
Raj
R
Angelini
Gianni D
GD
Jeremy
Jamie Y
JY
D000818:Animals; D015153:Blotting, Western; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D015536:Down-Regulation; D007172:Erectile Dysfunction / Q000188:drug therapy*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D010410:Penile Erection / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines; D011817:Rabbits; D051381:Rats; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
C534144:1-piperazineacetic acid 4-((3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-4-ethoxyphenyl)sulfonyl)-4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl ester; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5