Inhibition of neuroeffector transmission in human vas deferens by sildenafil

Abstract

Sildena®l (0.1 ± 30 mM), a cyclic GMP phosphodiesterase 5 (PDE 5) inhibitor, induced inhibition of electrically evoked contractions of ring segments of human vas deferens from 34 vasectomies. Zaprinast (0.1 ± 100 mM), another PDE 5 inhibitor, and the nitric oxide (NO) donor sodium nitroprusside (SNP) (0.1 ± 100 mM) had no e ect on neurogenic contractions. The inhibition induced by sildena®l was not modi®ed by the inhibitor of guanylate cyclase 1H-[1,2,4]oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) (1 ± 30 mM) but it was abolished by the K + channel blockers tetraethylammonium (TEA, 1 mM), iberiotoxin (0.1 mM) and charybdotoxin (0.1 mM). Sildena®l, zaprinast and SNP did not a ect the contractions induced by noradrenaline. SNP (10 mM) caused elevation of cyclic GMP levels that was potentiated by sildena®l (10 mM) and zaprinast (100 mM). ODQ (10 mM) inhibited the increase in cyclic GMP. Sildena®l inhibits adrenergic neurotransmission in human vas deferens. The inhibition is not related to accumulation of cyclic GMP but is probably due to activation of prejunctional large-conductance Ca 2+ -activated K + channels.

Modulation of Adrenergic Responses of Human Vas Deferens by K+ Channel Inhibitors

“…14 Furthermore, it has been previously demonstrated that sildenafil, a phosphodiesterase 5 inhibitor, has inhibitory effects on smooth muscle of human vas deferens by activation of presynaptic large-conductance Ca 2ϩ -activated K ϩ channels. 15 Thus, a link between adrenergic contraction of vas deferens and modulation of K ϩ channels is becoming apparent.…”

Role of Ca2+-activated K+ channels and Na+,K+-ATPase in prostaglandin E1- and E2-induced inhibition of the adrenergic response in human vas deferens

“…Furthermore, it has been shown that K + channels are involved in the prejunctional inhibitory effects of atrial natriuretic factor in the rabbit isolated vas deferens [12] and in the a 2 -adrenoceptor-mediated inhibition in rat vas deferens [13]. In the human vas deferens, sildenafil, an inhibitor of phosphodiesterase 5, inhibits adrenergic contractions through activation of presynaptic K Ca 1.1 channels [14]. Glibenclamide has been shown to block K ATP channels [21] with an IC 50 in the micromolar range for smooth muscle preparations [26].…”

“…In vas deferens, it has been demonstrated that K + channels are involved in the prejunctional inhibitory effects of atrial natriuretic factor [12], a 2 -adrenoceptor agonists [13] and sildenafil, an inhibitor of phosphodiesterase 5 [14]. Activation of K + channels stimulates cellular K + efflux [15].…”

The Role of PDE5 Inhibitors in the Treatment of Testicular Dysfunction

“…It has been suggested that sildenafil activates the opening of prejunctional potassium channels to reduce adrenergic neurotransmission by using NO-independent mechanisms (Medina et al, 2000). If this is true, this sildenafil induced reduction in adrenergic neurotransmission in smooth muscular fibers may alter the adrenergic tone in vas deferens muscular fiber and may reduce its pattern of contraction.…”