Effect of hydrogen sulphide‐donating sildenafil (ACS6) on erectile function and oxidative stress in rabbit isolated corpus cavernosum and in hypertensive rats

Q2 · MEDICINE

Article

Author: Valerio Tazzari ; Nilima Shukla ; Anna Sparatore ; Giuseppe Rossoni ; Jamie Y. Jeremy ; Matthew Hotston ; Piero Del Soldato ; Gianni D. Angelini ; Raj Persad

OBJECTIVETo study the effect of the H2S‐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 METHODSRelaxation was studied in an organ bath in response to carbachol and after incubation with interleukin‐1β for 12 h. CSMCs were incubated with tumour‐necrosis factor‐α or the thromboxane A2 (TXA2) analogue, U46619, with or with no sildenafil citrate, ACS6 or NaHS for 16 h. Superoxide formation and the expression of p47phox (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 TXA2 and 8‐isoprostane F2α was measured by enzyme‐linked immunosorbent assay.RESULTSACS6 and sildenafil citrate relaxed cavernosal smooth muscle equipotently; NaHS alone had little effect at up to 100 µm. The formation of superoxide and expression of p47phox 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 TXA2 and 8‐isoprostane F2α but increased cGMP, cAMP and glutathionine levels in corpus cavernosum.CONCLUSIONSBy 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.

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Indication	Highest Phase	Country/Location	Organization	Date
Respiratory Distress Syndrome, Adult	Discovery	Italy	CTG Pharma Ltd.	-

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