Ca²⁺‐activated K⁺ channel (K_Ca) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

Abstract

Background and PurposeWe have evaluated the influence of calcium‐activated potassium channels (KCa) activation on cGMP‐mediated relaxation in human penile tissues from non‐diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats.Experimental ApproachCavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non‐diabetic rats.Key ResultsConcentration‐dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS‐8 (10 μM) significantly potentiated sildenafil‐induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 μM). In HCC, sildenafil‐induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large‐conductance KCa (BK) and intermediate‐conductance KCa (IK) contribute to NS‐8‐induced effects and were immunodetected in human and rat penile arteries. NS‐8 potentiated sildenafil‐induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes‐induced ED in rats only when combined with KCa activation.Conclusions and ImplicationsActivation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non‐diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED.

Effect of the Novel BKCa Channel Opener LDD175 on the Modulation of Corporal Smooth Muscle Tone

“…A recent report also showed that the activation of BK Ca improve vasodilatory capacity of PDE5 in the human penile vessels and enhance erectile responses in vivo. They concluded that therapeutic potential of BK Ca channel activator might improve the efficacy of PDE5 in the management of ED [29]. We also verified that 10 −5 M LDD175 plus 10 −6 M udenafil had more relaxation effects than 10 −5 M LDD175 or 10 −6 M udenafil only.…”

“…Penile erection is mainly mediated by the cyclic guanosine monophosphate/nitric oxide (NO) pathway. The vasodilator effects of NO are partly mediated by the activation of BK Ca channels [27–29]. Kun et al.…”

“…Penile erection is mainly mediated by the cyclic guanosine monophosphate/nitric oxide (NO) pathway. The vasodilator effects of NO are partly mediated by the activation of BK Ca channels [27][28][29]. Kun et al reported that the relaxant responses elicited by sildenafil involve the activation of BK Ca channels in both the intracavernosal artery and human CSM strips [30].…”

BK channel β1-subunit deficiency exacerbates vascular fibrosis and remodelling but does not promote hypertension in high-fat fed obesity in mice

“…Previous studies indicated that vascular BK channel dysfunction causes tissue hypoperfusion and related complications in humans[13], and in animal models of metabolic diseases, due to increased VSMC contractility and insensitivity to endothelium-dependent NO. [14,15,35,36] There is no literature showing an association of BK channel deficiency with vascular remodeling and fibrosis in obesity.…”

“…[13] Animal models of metabolic disorders such as insulin resistance[14], diabetes[15], and genetic[16]or high-fat diet-induced obesity[17-19] also show vascular BK channel dysfunction. Reduced expression[17-19] or increased degradation of BK β1-subunit protein caused by oxidative signaling[14,15] appears responsible for vascular BK channel dysfunction, as α-subunit protein expression is unchanged.…”