Effect of acute lithium administration on penile erection: involvement of nitric oxide system

Abstract

Background: Lithium has been the treatment of choice for bipolar disorder (BD) for many years. Although erectile dysfunction is a known adverse effect of this drug, the mechanism of action by which lithium affects erectile function is still unknown.

Objective: The aim was to investigate the possible involvement of nitric oxide (NO) in modulatory effect of lithium on penile erection (PE). We further evaluated the possible role of Sildenafil in treatment of lithium-induced erectile dysfunction.

Materials and methods: Erectile function was determined using rat model of apomorphine-induced erections. For evaluating the effect of lithium on penile erection, rats received intraperitoneal injection of graded doses of lithium chloride 30 mins before subcutaneous injection of apomorphine. To determine the possible role of NO pathway, sub-effective dose of N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, was administered 15 min before administration of sub-effective dose of lithium chloride. In other separate experimental groups, sub- effective dose of the nitric oxide precursor, L-arginine, or Sildenafil was injected into the animals 15 min before administration of a potent dose of lithium. 30 min after administration of lithium chloride, animals were assessed in apomorphine test. Serum lithium levels were measured 30 min after administration of effective dose of lithium.

Results: Lithium at 50 and 100 mg/kg significantly decreased number of PE (p<0.001), whereas at lower doses (5, 10 and 30 mg/kg) had no effect on apomorphine induced PE. The serum Li+ level of rats receiving 50 mg/kg lithium was 1±0.15 mmol/L which is in therapeutic range of lithium. The inhibitory effect of Lithium was blocked by administration of sub-effective dose of nitric oxide precursor L-arginine (100 mg/kg) (p<0.001) and sildenafil (3.5 mg/kg) (p<0.001) whereas pretreatment with a low and sub-effective dose of L-NAME (10mg/kg) potentiated sub-effective dose of lithium, (p<0.001).

Conclusion: These results suggest acute treatments with lithium cause erectile dysfunction in an in-vivo rat model. Furthermore it seems that the NO pathway might play role in erectile dysfunction associated with lithium treatment. Findings also suggest that Sildenafil may be effective in treatment of lithium-associated erectile dysfunction.

Keywords: Erectile dysfunction; Lithium; Nitric oxide.

Figure 1

Effect of acute administration of lithium (5-100mg/kg, i.p.) on apomorphine induced penile erection in rats. Lithium was administered 30 min before apomorphine. ***p<0.001 and **p<0.01 compared with the saline-treated control. Values are expressed as mean±SEM. (n=6) and were analyzed using a one-way or two-way ANOVA followed by Newman-Keuls test

Figure 2

Effect of acute administration of L-NAME (5-100mg/kg, i.p.) on apomorphine induced penile erection in rats. L-NAME was administered 45 min before apomorphine. *p<0.05, **p<0.01 and ***p<0.001 compared with the saline-treated control. Values are expressed as mean±SEM. (n=6) and were analyzed using a one-way ANOVA followed by Newman-Keuls test

Figure 3

Additive effect of Lithium and L-NAME when co-administered in sub-effective doses (30 and 10 mg/kg, respectively). L-NAME or saline was administered 15 min before i.p. injection of lithium chloride and 45 min before apomorphine test. *p<0.05 compared with the saline/lithium-treated group; ns non-significant. Values are expressed as mean±SEM. Each group consisted of six animals

Figure 4

Effect of acute administration of Sildenafil (0.5-7mg/kg, i.p.) on apomorphine induced penile erection in rats. Sildenafil was administered 45 min before apomorphine. *p<0.05 compared with the saline-treated control. Values are expressed as mean±SEM (n=6) and were analyzed using a one-way ANOVA followed by Newman-Keuls test

Figure 5

Pretreatment with a L-arginine (100 mg/kg, i.p.), or b Sildenafil (3.5 mg/kg, i.p.) 15 min before administration of lithium (50 mg/kg) abolished the inhibitory effect of lithium on penile erection. Lithium was administered 30 min before apomorphine. *** p<0.001 compared with the saline/lithium-treated group; ns non-significant. Values are expressed as mean±SEM Each group consisted of six animals