Erectile dysfunction (ED) affects 30% of men >40 years old worldwide ^[1] and is often treated with phosphodiesterase-5 inhibitors (PDE5Is, e.g. Viagra^TM) which prevent degradation of cyclic guanosine monophosphate (cGMP). cGMP promotes relaxation of the corpus cavernosum smooth muscle (CCSM) of the penis to form an erection. However, >50% of diabetic men are resistant to treatment with PDE5Is ^[2]. Therefore, there is a need to develop new therapies for ED. Approaches include exploration of the pathways downstream of formation of cGMP, or alternative pathways that cause relaxation. KCNQ‐encoded voltage‐dependent potassium (K_v7) channels are present on CCSM cells ^[3,4]. Here we examine the role of K_v7 channels in the control of contractility of the mouse corpus cavernosum smooth muscle.

Isometric tension recordings were made from CCSM crura dissected from C57BL/6 mice euthanised via pentobarbital injection. Intracellular Ca²⁺ was imaged from single CCSM cells incubated with the Ca²⁺ indicator, Fluo-4-AM.

PCR revealed the expression of KCNQ1,3,4 and 5 within cDNA isolated from mouse corpus cavernosum (n=3). Furthermore, qPCR results indicated dominant expression of KCNQ5 transcripts (n=3). Isometric tension recording showed that addition of a₁-agonist, phenylephrine (PE), to CCSM crura generates phasic contractions, whilst displaying large tonic contractions only at higher concentrations. The K_v7 channel blocker, XE-991 (10µM), increased the amplitude of the phasic contractions (from 0.9±0.2mN to 1.3±0.3mN; P=0.0205, paired t-test) and their frequency (from 4.0±0.6min^-1 to 10.1±1.0min^-1;  P<0.001, paired t-test) when CCSM crura were precontracted with 300 nM PE (n=6). In contrast, the K_v7 channel activator, retigabine (10µM), abolished the phasic contractions (control frequency: 6.2±1.2min^-1; P=0.0312, Wilcoxon test; control amplitude: 0.9±0.3mN; P=0.0312, Wilcoxon test; n=6) induced by 300 nM PE . Furthermore, both retigabine (n=8) and an L-type Ca²⁺ channel blocker, nifedipine (1µM; n=6), abolished only the phasic activity, whilst the tonic responses remained at higher concentrations (3µM, 10µM and 30µM) of PE.

Ca²⁺ imaging experiments revealed that isolated CCSM cells developed spontaneous phasic Ca²⁺ oscillations. XE-991 increased the frequency of these oscillations (from 1.0±0.6min^-1 to 17.0±3.3min^-1; P= 0.0018, Friedman test; n=6). In contrast, the oscillations were abolished by retigabine (control frequency: 13.5±3.3min^-1; P=0.0030, Friedman test; n=6) or nifedipine (control frequency: 10.7±1.4min^-1; P=0.0187, Friedman test; n=6). Furthermore, 100 nM PE caused Ca²⁺ oscillations, which were abolished by both retigabine (n=6) and nifedipine (n=6). Application of XE-991 increased the amplitude and frequency of the PE-induced Ca²⁺ oscillations (n=6).

Taken together with the effects found in isometric tension recording, these data suggest that alterations in membrane potential are the basis for the phasic activity in tension recording and Ca²⁺ oscillations in single cells. Therefore, K_v7 channels could be utilised as potential therapeutic target for ED.