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

Serap Gur, Philip J. Kadowitz, Levent Gurkan, Surabhi Chandra, Sharon Y. Dewitt, Andrew Harbin, Suresh C. Sikka, Krishna C. Agrawal, Wayne J.G. Hellstrom

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24 Scopus citations

Abstract

Study Type - Aetiology (case control) Level of Evidence3b 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.

Original languageEnglish (US)
Pages (from-to)78-83
Number of pages6
JournalBJU International
Volume106
Issue number1
DOIs
StatePublished - Jul 2010

Keywords

  • Erectile dysfunction
  • Hypertension
  • L-NAME
  • Rat
  • Sildenafil

ASJC Scopus subject areas

  • Urology

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