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  • It is without doubt that the vagina plays

    2021-01-11

    It is without doubt that the vagina plays a significant role in the perception of coital stimulation leading to sexual arousal and, finally, orgasm. In response to sensory stimulation, relaxation of vaginal vascular and nonvascular smooth muscle occurs, resulting in an increase in local blood flow and lubrication. The diameter of the vaginal lumen also increases, thus allowing penetration of the male penis during sexual intercourse. Nevertheless, the mediators and mechanisms contributing to this process are still poorly understood 1, 2. It has been suggested that vasoactive peptides, such as the vasoactive intestinal polypeptide (VIP), natriuretic peptides (NPs), and bradykinin (BK), are among those non‐adrenergic, non‐cholinergic, and non‐nitrinergic endogenous compounds presumably mediating the physiological responses during sexual activity 3, 4, 5. These peptides act through the binding to specific receptors, thereby triggering the production of intracellular cyclic nucleotides cyclic adenosine monophosphate (AMP) and/or cyclic guanosine monophosphate. This, in turn, leads to the relaxation of genital vascular and nonvascular smooth muscle. It has been proposed that the normal female arousal process is dependent on the balance between the activity of vasodilator peptides, such as VIP, C‐type NP (CNP) and BK, and vasoconstrictor peptides, such as endothelin‐1 (ET‐1), angiotensin II (Ang II) and neuropeptide Y. The metabolism of those peptides is under the control of an enzyme known as neutral endopeptidase (NEP). NEP, which is located on the cell surface, is dependent on the presence of Zn2+ and catalyzes the degradation of several endogenous peptides, including CNP, BK, VIP, substance P, and Ang II, via an endoproteolytic action toward hydrophobic amino acids. The enzyme shares a structural similarity with the so‐called endothelin‐converting enzyme (ECE) and was initially isolated from renal epithelial Domiphen Bromide sale cells. However, it is also expressed in vascular endothelial and smooth muscle cells 6, 7, 8, 9, 10. In addition to the degradation of vasoactive peptides, NEP also catalyzes the conversion of big endothelin‐1 (Big ET‐1) into ET‐1, a potent vasoconstrictor peptide [11]. Extensive knowledge of the function of endopeptidases and the mechanisms regulating their activity has made identification of novel inhibitors of these enzymes and their application to clinical treatment a focal interest. Inhibition of endopeptidases may increase the concentration of peptides in various vascular and nonvascular tissues, thereby exerting specific clinical effects [12]. Clinical studies have provided evidence that an increase in the physiological levels of vasodilator peptides, such as BK, CNP, VIP, and a decrease of vasoconstrictor peptides (such as Ang II, ET‐1), mediated via the inhibition of their degradation/production, are sufficient to bring about therapeutic effects. In humans, NEP inhibitors are actually being considered a treatment for hypertension and cardiovascular diseases [13]. Although the role of endogenous peptides in the control of genital smooth muscle tone has been investigated mainly in human male penile erectile tissue (corpus cavernosum penis), to date only a few studies have been conducted to investigate the role of endogenous peptides in the control of the vagina. Up until today, no study has considered the potential role of endopeptidase inhibition to influence human vaginal smooth muscle tone. In order to elucidate further the significance of endopeptidases inhibitor and endogenous vasoactive peptides in the control of vaginal smooth muscle tone, tissue bath experiments were carried out to evaluate the effects of the endopeptidase inhibitor KC 12615 on the reversion of tension induced by ET‐1 of isolated human vaginal smooth muscle tissue in response to BK, CNP, or VIP. The effects were also investigated of KC 12615 on the contraction of vaginal smooth musculature mediated by Big ET‐1, a precursor of ET‐1.