Abstract
We studied the mechanisms involved in the human corpora cavernosa (HCC) relaxation induced by a new metal-based nitric oxide (NO) donor, the ruthenium complex cis-[Ru(bpy)2Imn(NO)](+3) (FOR0811). FOR0811 produced relaxation in phenylephrine (PE)-precontracted HCC with a maximal response that achieved 112.9 ± 10.6%. There was no difference between the maximal relaxation induced by FOR0811 when compared with sodium nitroprusside (SNP) (106.8 ± 7.3%), BAY41-2272 (107.6 ± 4.1%) or vardenafil (103.4 ± 3.8%), however, FOR0811 was less potent than SNP and vardenafil. L-N(G)-nitroarginine methyl ester (L-NAME), a NO synthase inhibitor, had no effect in the concentration-response curve elicited by FOR0811. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a heme-site inhibitor of soluble guanylyl cyclase (sGC) was able to either block or reverse the relaxation induced by FOR0811. On the other hand, the relaxation induced by FOR0811 was not affected by glibenclamide, a blocker of ATP-sensitive potassium channels. FOR0811 (10 μM) was able to increase cyclic guanosine monophosphate (cGMP) levels in corpora cavernosa strips. FOR0811 completely relaxes HCC by a sGC-cGMP-dependent mechanism and can be a lead compound in the development of new stable NO donors.
Highlights
ED is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual activity.[1]
Moncada et al.[6] showed by using a superfusion cascade bioassay that nitric oxide (NO) released from endothelial cells was indistinguishable from endotheliumderived relaxing factor (EDRF) and suggested that EDRF was NO
NO activates the soluble guanylyl cyclase, which catalyzes cyclic guanosine monophosphate production from guanosine triphosphate. cGMP acts on intracellular effectors leading to reduced intracellular calcium levels, dissociation of actin and myosin fibers, and smooth muscle relaxation.[8]
Summary
ED is defined as the inability to achieve or maintain an erection sufficient for satisfactory sexual activity.[1]. The normal erectile function is achieved when three simultaneous and synergic processes occur: increase of arterial blood influx in penis, relaxation of corpus cavernosum smooth muscle and restriction of venous blood outflow.[4]. Ignarro et al.[7] showed that NO released from non-adrenergic non-cholinergic fibers was the main neurotransmitter involved in penile erection in both rabbit and HCC. NO is released from the cavernous nerve and from the endothelium to induce relaxation of the corpora cavernosa and helicinal arteries increasing intracavernosal pressure. To evoke such relaxation, NO activates the soluble guanylyl cyclase (sGC), which catalyzes cyclic guanosine monophosphate (cGMP) production from guanosine triphosphate. NO activates the soluble guanylyl cyclase (sGC), which catalyzes cyclic guanosine monophosphate (cGMP) production from guanosine triphosphate. cGMP acts on intracellular effectors leading to reduced intracellular calcium levels, dissociation of actin and myosin fibers, and smooth muscle relaxation.[8]
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