Chronic inhibition of nitric‐oxide synthase induces hypertension and erectile dysfunction in the rat that is not reversed by sildenafil

Study Type – Aetiology (case control) Level of Evidence 3b OBJECTIVE To evaluate the effect of N(G)‐nitro‐l‐arginine methyl ester (L‐NAME)‐induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)‐5 inhibitor, sildenafil, can reverse the effects of nitric...

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Published in:	BJU international Vol. 106; no. 1; pp. 78 - 83
Main Authors:	Gur, Serap, Kadowitz, Philip J., Gurkan, Levent, Chandra, Surabhi, DeWitt, Sharon Y., Harbin, Andrew, Sikka, Suresh C., Agrawal, Krishna C., Hellstrom, Wayne J.G.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-07-2010 Wiley-Blackwell
Subjects:	Animals Arterial hypertension. Arterial hypotension Biological and medical sciences Blood and lymphatic vessels Blotting, Western Cardiology. Vascular system Enzyme-Linked Immunosorbent Assay erectile dysfunction Erectile Dysfunction - drug therapy Erectile Dysfunction - etiology hypertension Hypertension - complications L‐NAME Male Medical sciences Nephrology. Urinary tract diseases NG-Nitroarginine Methyl Ester - administration & dosage Nitric Oxide Synthase - antagonists & inhibitors Nitric Oxide Synthase - drug effects Nitric Oxide Synthase - metabolism Nitric Oxide Synthase Type I - metabolism Nitric Oxide Synthase Type II - metabolism Nitric Oxide Synthase Type III - metabolism Penile Erection - drug effects Phosphodiesterase Inhibitors - therapeutic use Piperazines - therapeutic use Purines - therapeutic use rat Rats Rats, Sprague-Dawley sildenafil Sildenafil Citrate Sulfones - therapeutic use Up-Regulation Nephrology Vasodilator agent Rat 3',5'-Cyclic-GMP phosphodiesterase Impotence Sexual dysfunction Cardiovascular disease Esterases Phosphoric diester hydrolases Urology erectile dysfunction Inhibition Male genital diseases Hypertension L-NAME Erection disorders Enzyme Rodentia Enzyme inhibitor Nitric-oxide synthase Phosphodiesterase inhibitor Phosphodiesterase 5 inhibitor Vertebrata Chronic Mammalia Animal Hydrolases Oxidoreductases Sildenafil
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Summary:	Study Type – Aetiology (case control) Level of Evidence 3b OBJECTIVE To evaluate the effect of N(G)‐nitro‐l‐arginine methyl ester (L‐NAME)‐induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)‐5 inhibitor, sildenafil, can reverse the effects of nitric oxide (NO) deficiency, as HT is a risk factor for erectile dysfunction (ED) and the NO synthase (NOS) inhibitor L‐NAME induces NO‐deficient HT. MATERIALS AND METHODS Thirty‐six adult Sprague‐Dawley male rats were divided into three groups, i.e. a control, L‐NAME‐HT (40 mg/rat/day in the drinking water for 4 weeks), and sildenafil‐treated L‐NAME‐HT (1.5 mg/rat/day sildenafil, by oral gavage concomitantly with L‐NAME). The erectile response expressed as a ratio of intracavernosal pressure (ICP)/mean arterial pressure (MAP), evaluated after electrical stimulation of the right cavernous nerve. The isometric tension of corpus cavernosum smooth muscle (CCSM) was measured in organ‐bath experiments. NOS expression was determined immunohistochemically for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein. cGMP levels were evaluated by enzyme‐linked immunosorbent assay. RESULTS The erectile response was diminished in the HT group. Nitrergic and endothelium‐dependent relaxation was reduced, while the relaxation response to sodium nitroprusside and contractile response to phenylephrine were not altered in CCSM from L‐NAME‐treated rats. HT rats showed decreased expression of nNOS, whereas eNOS and iNOS protein expression was increased. Sildenafil partly restored endothelial and molecular changes in CCSM from HT rats, but did not reverse the decreased erectile response, even as cGMP levels returned to normal levels. CONCLUSIONS Sildenafil treatment did not correct the ED in L‐NAME‐treated HT rats. Under sustained high blood pressure, up‐regulation of PDE5 expression failed to reverse the depletion of neuronal NO and/or impaired nNOS activity. However, endothelium‐dependent relaxation was restored. Drug targeting of neuronal dysfunction might delay the onset of ED in HT.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1464-4096 1464-410X
DOI:	10.1111/j.1464-410X.2009.09104.x