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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.

SUBMITTER: Aughton KL

PROVIDER: S-EPMC2538698 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

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Project description:The chronic phase of pulmonary arterial hypertension (PAH) is associated with vascular remodeling, especially thickening of the smooth muscle layer of large pulmonary arteries and muscularization of small pulmonary vessels, which normally have no associated smooth muscle. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to induce proliferation and hypertrophy of pulmonary artery smooth muscle cells (PASMC), and may be important for in vivo pulmonary vascular remodeling. Here, we show that 5-HT stimulates migration of pulmonary artery PASMC. Treatment with 5-HT for 16h increased migration of PASMC up to four-fold as monitored in a modified Boyden chamber assay. Increased migratory responses were associated with cellular morphological changes and reorganization of the actin cytoskeleton. 5-HT-induced alterations in morphology were previously shown in our laboratory to require cAMP [Lee SL, Fanburg BL. Serotonin produces a configurational change of cultured smooth muscle cells that is associated with elevation of intracellular cAMP. J Cell Phys 1992;150(2):396-405], and the 5-HT4 receptor was pharmacologically determined to be the primary activator of cAMP in bovine PASMC [Becker BN, Gettys TW, Middleton JP, Olsen CL, Albers FJ, Lee SL, et al. 8-Hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. Mol Pharmacol 1992;42(5):817-25]. We examined the role of the 5-HT4 receptor and cAMP in 5-HT-induced bovine PASMC migration. PASMC express 5-HT4 receptor mRNA, and a 5-HT4 receptor antagonist and a cAMP antagonist completely blocked 5-HT-induced cellular migration. Consistent with our previous report that a cAMP-dependent Cl(-) channel is required for 5-HT-induced morphological changes in PASMC, phenylanthranilic acid, a Cl(-) channel blocker, inhibited actin cytoskeletal reorganization and migration produced by 5-HT. We conclude that 5-HT stimulates PASMC migration and associated cytoskeletal reorganization through the 5-HT4 receptor and cAMP activation of a chloride channel.

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

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