NANC transmitters in the female pig urethra–localization and modulation of release via α2‐adrenoceptors and potassium channels

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Abstract
To investigate further the release, localization and identity of a non‐nitrergic mediator of smooth muscle relaxation in the female pig urethra, we studied the effects of drugs acting at α2‐adrenoceptors or K+ channels, the effects of capsaicin and chemical sympathectomy, and the actions of several transmitter candidates. Electrical field stimulation (EFS; frequencies above 12 Hz) of spontaneously contracted smooth muscle strips from the female pig urethra evoked long‐lasting, frequency‐dependent relaxations in the presence of prazosin, scopolamine, and NG‐nitro‐L‐arginine. Treatment with the selective α2‐adrenoceptor agonist UK‐14 304 markedly reduced the relaxations evoked by EFS at all frequencies tested (16–30 Hz). The inhibitory effect of UK‐14 304 was completely antagonized by the α2‐adrenoceptor antagonist rauwolscine. The muscarinic M1 receptor antagonist, pirenzepine, or exogenously administered carbachol, did not have any effects on the electrically evoked relaxations. Inhibition of high conductance Ca2+ activated K+ channels by iberiotoxin or charybdotoxin significantly enhanced the relaxations evoked by EFS at all frequencies. However, inhibition of voltage‐sensitive K+ channels with 4‐aminopyridine or dendrotoxin‐1, treatment with the ATP‐sensitive K+ channel blocker, glibenclamide, or treatment with the high and low conductance Ca2+ activated K+ channel blockers, tetraethylammonium chloride and apamin, had no effect on the relaxations evoked by EFS. Electrically evoked relaxations were not affected by adrenergic denervation with 6‐hydroxydopamine (6‐OHDA) at any frequency. However, treatment with 6‐OHDA abolished prazosin‐sensitive electrically induced contractions, and a long‐lasting relaxation was revealed. Treatment with capsaicin, believed to damage selectively a subpopulation of primary afferent fibres, did not affect basal tone or relaxations evoked by EFS. Exogenously applied vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase‐activating peptide (PACAP)‐27, PACAP‐38, adenosine, ATP and 5‐hydroxy‐tryptamine caused relaxations of the urethral preparations, whereas prostaglandin E2 and calcitonin gene‐related peptide had no effects. VIP 10‐28, α, β‐methylene‐ATP, reactive blue‐2, suramin or indomethacin did not reduce the electrically‐evoked relaxations at any frequency. However, the relaxations were slightly reduced by trypsin or α‐chymotrypsin. The present results suggest that the release of the unknown mediator in the female pig urethra can be modulated via α2‐adrenoceptors and high conductance Ca2+ activated K+ channels. Furthermore, the mediator does not appear to be localized to or released from adrenergic or capsaicin‐sensitive sensory nerve‐endings. The identity of the transmitter remains to be established. British Journal of Pharmacology (1997) 121, 1605–1612; doi:10.1038/sj.bjp.0701308