The impact of chronic renal failure on nitric oxide synthase isoforms gene expression in the penis and pelvic ganglia of rats.
OBJECTIVE
Patients with chronic renal failure experience a variety of physical and metabolic alterations. Uremia is often accompanied by erectile dysfunction (ED). Little information is available concerning the underlying pathophysiological mechanisms by which chronic renal failure can lead to erectile dysfunction. In this study, chronic renal failure was induced by 5/6 nephrectomy in a rat model. Cavernous nerve stimulation was used to measure the intracavernous pressure (ICP) rise.


METHODS
Adult male Sprague-Dawley rats, aged between 10-12 weeks and weighing 200-250 gm. were divided into two groups. The first group (n = 20) served as a control (sham-operated) and underwent laparotomy with dissection of the perirenal fat around both kidneys. The second group (n = 40) were subjected to an excisional 5/6 nephrectomy (unilateral nephrectomy and contralateral upper and lower polar nephrectomy). Serum creatinine was measured 3 days post-operatively and at the end of the 12th week. Development of renal failure was considered if the animal had serum creatinine more than 120 microM/l. After 12 weeks, 10 animals per group were subjected to electric field stimulation (EFS) of the cavernous nerve with simultaneous recording of ICP-rise and systemic blood pressure. Northern and western blot analyses were used to determine the mRNA expression and protein contents of NOS isoforms (neuronal and endothelial) in the penile tissues and MPG.


RESULTS
This remnant kidney model resulted in renal failure in 20 of 40 animals. The ICP-rise after cavernous nerve stimulation in the renal failure group was significantly impaired, 7.7+/-2.9 cm. H2O, as compared to control rats, 55.5+/-1.2 cm. H2O (p<0.001). The latency period after cavernous nerve stimulation was significantly increased in renal failure rats (6.9+/-0.95 sec.) in comparison to controls (2.4+/-0.25 sec.). Six of ten uremic animals had significantly lower testosterone (<1 nmol./l.) levels compared to non-uremic rats (3.6 nmol./l.) (p<0.005). Northern blot analysis revealed that renal failure rats had significantly higher levels of nNOS mRNA in the MPG and penile tissues than controls. There was no change in eNOS mRNA in either group. Western blot analysis demonstrated that eNOS and nNOS protein contents in the MPG and penile tissues of renal failure rats were significantly higher than those of controls.


CONCLUSIONS
This report demonstrates that impairment of erection in renal failure rats, as determined by ICP-rise, was present in spite of elevated neuronal nitric oxide synthase mRNA and its protein in the MPG and penile tissues. Further studies are needed to determine whether erectile dysfunction is a result of post-translational changes, circulating inhibitory substances or other factors.
Abdel-Gawad
M
M
Department of Urology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Huynh
H
H
Brock
G B
GB
D000818:Animals; D005725:Ganglia, Autonomic / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D007527:Isoenzymes / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000201:enzymology* / Q000503:physiopathology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics*; D010410:Penile Erection / Q000502:physiology*; D010413:Penis / Q000201:enzymology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase