Role of Chloride Channels in the Regulation of Corpus Cavernosum Tone: A Potential Therapeutic Target for Erectile Dysfunction

Abstract

Introduction Recent electrophysiological recordings have identified the existence of outward, excitatory chloride (Cl−) currents in rat, rabbit, and human corpus cavernosum (CC) muscle cells. Aim The aim of this study was to investigate the physiological role of Cl− currents in the maintenance of cavernosal muscle tone in isolated rabbit CC tissues. Methods CC strips (1 × 1 × 5 mm) were suspended in tissue bath chambers for isometric tension experiments. Spontaneous cavernosal tone and contractions elicited by field stimulation or administration of established smooth muscle constrictors were examined in the presence of chloride channel (ClC) blockers, ni umic acid (NFA), and anthracene-9-carboxylic acid (A9C). Main Outcome Measure Both spontaneous myogenic activity and contractile responses to field stimulation, norepinephrine, histamine, and endothelin-1 were reduced by ClC blockers. Results In CC strips exhibiting intrinsic myogenic tone, NFA (30 and 100 µM) and A9C (1 mM) caused a relaxation of the tone. In addition, spontaneous contractile activity in CC was abolished in the presence of either ClC blocker. In CC strips precontracted with norepinephrine, histamine, and endothelin-1, both ClC blockers significantly reversed the tone. The ability of NFA and A9C to reverse norepinephrine-induced tone was unaffected by N ω-nitro-L-arginine, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, and cis-N-[2-phenylcyclopentyl]-azacyclotridec-1-en-2-amine. In addition, neither indomethacin nor tetraethylammonium affected the relaxant response of NFA. NFA and A9C inhibited the neurogenic and norepinephrine-induced contractions in a concentration-dependent manner. While NFA exerted persistent inhibition on neurogenic contraction, inhibition of neurogenic contractions by A9C was readily reversible. On K+-depolarized CC, NFA induced a concentration-related relaxation, whereas A9C was inert, suggesting an additional mechanism of NFA on voltage-gated calcium channels. Conclusions These results underline the importance of Cl− currents as a mechanism in the maintenance of cavernosal tone produced by adrenergic and various endogenous constrictors. Thus, the modulation of Cl− current, as an attractive and effective approach to regulate penile erection, and specific ClC blockers, as potential erectogenic agents, merits further research.

Spontaneous Ca2+ Waves in Rabbit Corpus Cavernosum: Modulation by Nitric Oxide and cGMP

“…The dual patch clamp/ Ca 2+ imaging recordings in the present study demonstrated that each Ca 2+ wave was indeed associated with a substantial Clcurrent, suggesting that one of the functions of the waves is to stimulate the cell via membrane depolarization. This mechanism is likely to play a role in propagating the Ca 2+ signal across the syncytium in the whole tissue and is consistent with the increasing evidence that Clchannels are important for maintaining detumescent tone [14,24]. The Clchannel-mediated depolarization would also provide a suitable mechanism for activation of voltage-dependent Ca 2+ channels which have been shown to be important for contraction [11,12].…”

Voltage-Dependent Ca2+ Currents Contribute to Spontaneous Ca2+ Waves in Rabbit Corpus Cavernosum Myocytes

“…However, the idea that corpus cavernosum cells maintain a constantly high Ca 2+ by remaining depolarized within the window current range of potentials is at odds with a number of observations (see Introduction). There is growing evidence that Ca 2+ ‐activated Cl – currents are essential for maintaining corpus cavernosum tone, and that these currents are activated in response to oscillatory changes in intracellular Ca 2+ [12–15,25,26]. Calcium waves, similar to those reported here, were shown to activate the Cl – current in isolated rabbit corpus cavernosum myocytes [15].…”

Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction

“…The waves depended on an intact sarcoplasmic reticulum Ca 2ϩ store, because they were blocked by cyclopiazonic acid and agents that interfere with ryanodine receptors and IP 3 -mediated Ca 2ϩ release. Chu and Adaikan (2008) underlined the importance of Cl Ϫ currents as a mechanism in the maintenance of CC tone produced by adrenergic and various endogenous constrictors in strips of rabbit CC. They suggested that the modulation of Cl Ϫ1 current could be an attractive and effective approach to regulate penile erection.…”

“…The contribution of chloride channels/currents to the modulation of human corporal smooth muscle tone is less well understood than that of the other ion channels. Studies of calcium-activated Cl Ϫ (Cl Ca ) function in the smooth muscle of CC have shown these channels to be involved in both the maintenance of spontaneous tone and the contractile response to noradrenaline and other agonists (Fan et al, 1999;Karkanis et al, 2003;Craven et al, 2004;Williams and Sims., 2007;Chu and Adaikan, 2008;Chung et al, 2009b). Karkanis et al (2003) demonstrated an excitatory calcium Cl Ca current in both human and rat corporal myocytes.…”