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

• 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
• DOI: 10.1111/j.1464-410X.2009.09104.x
• EISSN: 1464-410X
• ISSN: 1464-4096

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.