Erectile dysfunction in a murine model of sleep apnea

Abstract

Rationale: Erectile dysfunction (ED) is frequent in obstructive sleep apnea syndrome (OSAS). Chronic intermittent hypoxia (CIH), one of the hallmarks of OSAS, could mediate ED.

Objectives: To determine whether intermittent hypoxia during sleep affects erectile dysfunction in mice.

Methods: Three groups of C57BL/6 mice were exposed to CIH for 5 or 24 weeks. Sexual function was evaluated by in vivo telemetry of corpus spongiosum pressure. Spontaneous erections, sexual activity during mating, and noncontact tests were assessed after 5 weeks of CIH and after treatment with tadalafil. Plasma testosterone was measured after 8 and 24 weeks of CIH, and the expression of nitric oxide synthase (NOS) isoforms was examined in penile tissue.

Measurements and main results: Noncontact, spontaneous, and contact sexual activity in the mice was suppressed after CIH. Spontaneous erection counts decreased after the first week of CIH by 55% (P < 0.001) and remained unchanged thereafter. Recovery of erectile activity during normoxia for 6 weeks was incomplete. Compared with control mice, latencies for mounts and intromissions increased by 60- and 40-fold, respectively (P < 0.001), and the sexual activity index decreased sixfold. Tadalafil treatment significantly attenuated these effects. Immunoblot analyses of NOS proteins in the erectile tissue showed decreased expression of endothelial NOS after CIH (P < 0.01), with no changes in plasma testosterone levels after 8 and 24 weeks of CIH.

Conclusions: CIH during sleep is associated with decreased libido in mice. The decreased expression of endothelial NOS protein in erectile tissue and the favorable response to tadalafil suggest that altered nitric oxide mechanisms underlie CIH-mediated ED. No changes in testosterone emerge after intermittent hypoxia.

Figure 1.

Schematic timeline for the various groups of mice exposed to either room air (RA) or chronic intermittent hypoxia (CIH) and the various tests administered at each time point. Number of animals per time point in indicated in parentheses. NOS = nitric oxide synthase.

Figure 2.

Effect of chronic intermittent hypoxia (CIH) on nitric oxide synthase (NOS) isoform protein levels in the penile tissue of mice. (A) Representative Western blots are shown for control (room air [RA]) and CIH for 8 weeks in mice. Blots were reprobed with a monoclonal antibody against β-actin for standardization of loading inequalities. (B) Quantification of immunoreactivity in the penile tissue from mice exposed to CIH (n = 12) and RA (n = 8). Immunoreactivity is expressed in mean densitometry units corrected for β-actin (relative units). eNOS = endothelial NOS; nNOS = neuronal NOS; iNOS = inducible NOS. *P < 0.01.

Figure 3.

Spontaneous erections in mice during exposure and recovery from chronic intermittent hypoxia (CIH). Effects of CIH on spontaneous erectile activity were measured on Weeks 1, 5, and 8, and during normoxic (room air [RA]) recovery on Weeks 1, 3, and 6. n = 8/group.

Figure 4.

Effects of tadalafil on spontaneous erections in mice exposed to chronic intermittent hypoxia (CIH) for 8 weeks and in control mice. RA = room air. n = 8 mice/group. *P < 0.01, **P < <0.001.

Figure 5.

Effects of chronic intermittent hypoxia (CIH) and tadalafil on the number of corpus spongiosum pressure (CSP) peaks recorded in male mice during noncontact tests with an estrous female mouse. Data represent counts per minute of CSP peaks (80–120 mm Hg and 0.4–05-s duration; n = 8 mice/group). Solid squares, baseline (RA); solid circles, 5 weeks of CIH; open circles, 1 hour after tadalafil administration in CIH mice. *P < 0.0001 room air versus CIH.

Figure 6.

Latencies to mounts, intromissions, ejaculations, and I(I+M) index measured during mating test. CIH = chronic intermittent hypoxia (5 wk); I = intromission; M = mounting; RA = room air. Tadalafil was used at the standard dose of 0.014 mg/25 g body weight; n = 8/group. *P < 0.001 CIH versus CIH + tadalafil; ^†CIH versus RA.