Endothelium-dependency of yohimbine-induced corpus cavernosum relaxation.
Development and maintenance of penile erection requires the relaxation of the smooth muscle cells in the cavernous bodies and is essentially mediated by nitric oxide (NO). The penile flaccid state is conversely maintained by the alpha adrenergic neuroeffector system and by other vasoconstrictors, such as endothelin-1 (ET-1). In this study we examined the mechanisms involved in yohimbine-induced relaxation in human and rabbit corpora cavernosa (CC). We essentially found that yohimbine not only blocks contractions induced by adrenergic agonists, but also by non-adrenergic substances, such as ET-1. This effect was unrelated to antagonism at the level of ET receptors, because yohimbine did not affect ET-1-induced increase in intracellular calcium in isolated CC cells. Conversely, our data suggest that yohimbine counteracts ET-1-induced contractions by interfering with NO release from the endothelium. In fact, yohimbine-induced CC relaxation was inhibited by the mechanical removing of the endothelium and by blocking NO formation or signalling via guanylate cyclase and cGMP formation. Conversely, yohimbine activity was strongly increased by inhibiting cGMP degradation. In an experimental model of hypogonadism, performed on rabbits by chronic treatment with a long-lasting GnRH agonist, the relaxant yohimbine activity was also decreased, but completely restored by androgen supplementation. This effect was evident only in preparations in which the main source of NO was present (endothelium) or in which NO formation was not impaired by L-NAME. Our data indicate that the relaxant effect of yohimbine is both endothelium and androgen-dependent. This might justify the lack of efficacy of this drug in treatment of some form of organic erectile dysfunction.
Filippi
S
S
Department of Clinical Physiopathology, Andrology Unit, University of Florence, Florence, Italy.
Luconi
M
M
Granchi
S
S
Natali
A
A
Tozzi
P
P
Forti
G
G
Ledda
F
F
Maggi
M
M
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000172:deficiency; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002478:Cells, Cultured; D004727:Endothelium / Q000502:physiology; D006801:Humans; D007006:Hypogonadism / Q000139:chemically induced / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000166:cytology / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D010413:Penis / Q000166:cytology / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D017329:Triptorelin Pamoate / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D011942:Receptors, Adrenergic, alpha; D017329:Triptorelin Pamoate; D010656:Phenylephrine; D015016:Yohimbine; D009569:Nitric Oxide