Pharmacological profiling of neuropeptides on rabbit vaginal wall and vaginal artery smooth muscle in vitro

Abstract

Background and purpose: Hypothalamic neuropeptides centrally modulate sexual arousal. However, the role of neuropeptides in peripheral arousal has been ignored. Vascular and non-vascular smooth muscle relaxation in the vagina is important for female sexual arousal. To date, in vitro studies have focused on vaginal strips with no studies on vaginal arteries. The aim of this study was to compare the effects of sexual hypothalamic neuropeptides on rabbit vaginal wall strips and arteries.

Experimental approach: Tissue bath and wire myography techniques were used to measure isometric tension from strips and arteries, respectively.

Key results: Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) relaxed both preparations, effects that were only antagonized by the VIP/PACAP antagonist VIP6-28 (10 nM) and the PAC(1) antagonist PACAP 6-38 (1 microM). The melanocortin agonist alpha-melanocortin-stimulating hormone (1 microM), but not bremelanotide (1 microM), also relaxed both preparations. Oxytocin and vasopressin contracted vaginal preparations, which could be antagonized by the V(1A) antagonist SR 49059. Neuropeptide Y (NPY) and the NPY Y(1) agonist Leu(31), Pro(34) NPY only contracted arteries, which was antagonized by the NPY Y(1) receptor antagonist BIBP 3226. Melanin-concentrating hormone (MCH; 1 microM) contracted arteries.

Conclusion and implications: Hypothalamic neuropeptides can exert contractile and relaxant effects on vaginal strips and arteries. NPY Y(1), V(1A), MCH(1) antagonists as well as VIP/PAC(1) agonists may have therapeutic potential in both central and peripheral female sexual arousal. Differences in effect of neuropeptides between preparations raise the question of which preparation is important for female sexual arousal.

Figure 1

Effect of oxytocin (OT) and vasopressin (AVP) on rabbit vaginal strips and arteries in vitro. Panel (a) shows an experimental trace of increasing concentrations of AVP on (i) vaginal strips and (ii) vaginal arteries. Panel (a) iii is the average concentration response curve to AVP in both tissues. Panel (b) is the same as (a), but in the presence of oxytocin.

Figure 2

Effect of pituitary adenylate cyclase-activating polypeptide (PACAP 1–27) and vasoactive intestinal peptide (VIP) on rabbit vaginal strips and arteries in vitro. Panel (a) shows an experimental trace of increasing concentrations of PACAP 1–27 on (i) vaginal strips and (ii) vaginal arteries, pre-contracted with phenylephrine (PE). Panel (a) iii shows the average concentration response curve to PACAP 1–27 in both tissues. Panel (b) is the same as (a), but in the presence of VIP.

Figure 3

Effect of OT and AVP in the presence of L-368899 and SR 49059 in vagina strips and arteries. The left hand column shows the effect of both OT and AVP in the presence of either the OT antagonist L-368899 (a and b) or the V1A antagonist SR 49059 (c and d) on vagina strips. Graphs in the right hand column are the same as the left hand column but on vagina arteries.

Figure 4

Characterization of neuropeptide Y (NPY) Y₁ receptors in vaginal arteries. Panel (a) is the concentration response curve to the NPY Y₁ agonist Leu³¹, Pro³⁴ NPY, in vaginal arteries. Panel (b) shows the effect of the peptide NPY Y₁ antagonist BIBP 3226 (3 μM) on the concentration response curve to NPY.

Figure 5

Inhibition of vasoactive intestinal peptide (VIP)-induced relaxations with VIP6–28 and pituitary adenylate cyclase-activating polypeptide (PACAP 6–38) in vaginal arteries. Panel (a) shows the effect of the VIP/PACAP antagonist VIP6–28 (10 nM) on the concentration response curve to VIP in vaginal arteries pre-contracted with phenylephrine (PE). Panel (b) is the same as (a), but in the presence of the PAC₁ antagonist PACAP 6–38 (1 μM).