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  • The biological actions of ET are mediated via

    2020-05-21

    The biological actions of ET‐1 are mediated via two distinct receptor subtypes, the endothelin A and endothelin B receptors (ETA/ETB). While activation of ETA is assumed to mediate contraction of smooth muscle cells, the activity of ETB is related to transient vasodilation [22]. In human corpus cavernosum smooth muscle, the expression of both ETA and ETB has been shown; however, the contraction of cavernous vascular and nonvascular tissue brought about by ETA seems to be predominant with regard to the control of erectile smooth muscle [23]. In cultured vaginal myofibroblast Afuresertib isolated from the posterior vaginal wall, the expression of mRNA encoding for ETA and ETB has also been demonstrated. On the mRNA level, a predominant expression of ETB over ETA was registered. In contrast to the situation in penile corpus cavernosum, it seems that in human vaginal myofibroblasts the binding of ET‐1 is almost exclusively mediated by the ETB receptor [24]. Aside from the endothelin system, the renin‐angiotensin system (RAS) has also been suggested to mediate the contraction of the vagina. Ang II is a potent vasoconstrictor produced from Ang I by the metalloendopeptidase angiotensin‐converting enzyme (ACE). In our experiments, Ang II failed to induce a pronounced contraction of human vaginal smooth muscle, hence not supporting the hypothesis of a role of the RAS system in mediating contractile responses of the human vagina. It has been demonstrated earlier that VIP, CNP, and BK exerted only minor reversions of the tension of human vaginal smooth muscle brought about by ET‐1 [15]. This has been explained in terms of a rapid biological degradation of these peptides by the activity of metalloendopeptidases, such as ACE/kininase II, NEP, carboxypeptidase N = CPN, and carboxypeptidase M. This study presents, for the first time, evidence that the relaxation response of the vaginal strip preparations (contracted by ET‐1) to the cumulative addition of BK, CNP, or VIP is significantly enhanced in the presence of the endopeptidase inhibitor KC 12615. This observation is in agreement with findings from a number of in vitro and in vivo protocols: in isolated porcine coronary arteries, phosphoramidon or thiorphan increased the relaxation response of the tissue to CNP or BK [25]. In the female rabbit, the inhibition of NEP resulted in a significant enhancement of both the amplitude and duration of rabbit vaginal blood flow induced by pelvic nerve stimulation or the administration of VIP [26]. In male rats, the injection of the NEP inhibitor UK 77.568 increased the plasma level of VIP [8]. The bronchodilation of rabbit trachea brought about by VIP was enhanced in the presence of the metalloendopeptidase inhibitor phosphoramidon [27]. A study conducted in a cohort of hypertensive patients revealed that the inhibition of NEP resulted in an increase in VIP concentrations in the heart, thereby exerting protective effect on the myocardium [28]. In human forearm vessels, the vasodilation induced by CNP was increased with the co‐infusion of tiorphan [29]. The combined application of BK and the ACE inhibitor lisinopril produced hypotension in rats; this effect was further enhanced when the NEP inhibitor candoxatril was added to the drug mixture [30]. Our experiments demonstrated that KC 12615 enhanced the reversion exerted by VIP, CNP, and BK of the tonic contraction of human vaginal tissue induced by ET‐1; however, the endopeptidase inhibitor, when added alone, failed to produce significant relaxation. This might be due to the fact that NEP catalyzes not only the degradation of vasodilator peptides (such as VIP, CNP, and BK) but also the vasoconstrictor peptides including ET‐1 [31]. In healthy volunteers, infusion of the NEP inhibitor candoxatrilat to a brachial artery caused a slowly progressive vasoconstriction. The combination of the NEP inhibitor and BQ‐123, known as endothelin receptor antagonist, resulted in vasodilation similar to that registered after the administration of BQ‐123 alone [32]. In normotensive patients, inhibition of NEP increased circulating levels of atrial natriuretic peptide (ANP) and induced natriuresis; however, it did not lower or increase blood pressure [33]. Given these observations, it has been suggested that the net effect of NEP inhibition on smooth muscle tone is related to more than one peptide. The question is also raised as to whether the predominant target peptides act mainly as vasodilators or as vasoconstrictors [31]. Efforts are actually being made to identify selective NEP inhibitors as potential new drug candidates for the treatment of FSAD. In the female rabbit, administration of R13 and UK‐414.495 resulted in an increase in vaginal blood flow and vaginal engorgement induced by the stimulation of the pelvic nerve. No effects of the compounds on blood pressure or other cardiovascular parameters were noted 34, 35. When looking at the results from the tissue bath studies described in the present manuscript, the following should be taken into consideration: