Sarakalim

Opioid agonists inhibit neurogenic mucus secretion in the airways. The mechanism of the inhibition is unknown but may be via opening of potassium (K+) channels. We studied the effect on neurogenic secretion in ferret trachea in vitro of the OP1 receptor (formerly known as δ opioid receptor) agonist [D‐Pen2,5]enkephalin (DPDPE), the OP2 receptor (formely κ) agonist U‐50,488H, the OP3 receptor (formerly μ) agonist [D‐Ala2, N‐Me‐Phe, Gly‐ol5]enkephalin (DAMGO), the ATP‐sensitive K+ (KATP) channel inhibitor glibenclamide, the large conductance calcium activated K+ (BKCa) channel blocker iberiotoxin, the small conductance KCa (SKCa) channel blocker apamin, the KATP channel opener levcromakalim, a putative KATP channel opener RS 91309, and the BKCa channel opener NS 1619. Secretion was quantified by use of 35SO4 as a mucus marker.Electrical stimulation increased tracheal secretion by up to 40 fold above sham‐stimulated levels. DAMGO or DPDPE (10 μM each) significantly inhibited neurogenic secretion by 85% and 77%, respectively, effects which were reversed by naloxone. U‐50,488H had no significant inhibitory effect on neurogenic secretion, and none of the opioids had any effect on ACh‐induced or [Sar9]substance P‐induced secretion.Inhibition of neurogenic secretion by DAMGO or DPDPE was reversed by iberiotoxin (3 μM) but not by either glibenclamide or apamin (0.1 μM each). Iberiotoxin alone did not affect the neurogenic secretory response.Levcromakalim, RS 91309 or NS 1619 (3 nM–3 μM) inhibited neurogenic secretion with maximal inhibitions at 3 μM of 68%, 72% and 96%, respectively. Neither levcromakalim nor RS 91309 at any concentration tested significantly inhibited acetylcholine (ACh)‐induced secretion, whereas inhibition (60%) was achieved at the highest concentration of NS 1619, a response which was blocked by iberiotoxin.Inhibition of neurogenic secretion by levcromakalim (3 μM) or RS 91309 (30 nM) was inhibited by glibenclamide but not by iberiotoxin. In contrast, inhibition by NS 1619 (30 nM and 3 μM) was blocked by iberiotoxin but not by glibenclamide.We conclude that, in ferret trachea in vitro, OP1 or OP3 opioid receptors inhibit neurogenic mucus secretion at a prejunctional site and that the mechanism of the inhibition is via opening of BKCa channels. Direct opening of BKCa channels or KATP channels also inhibits neurogenic mucus secretion. In addition, opening of BKCa channels inhibits ACh‐evoked secretion of mucus. Drugs which open BKCa channels may have therapeutic anti‐secretory activity in bronchial diseases in which neurogenic mechanisms and mucus hypersecretion are implicated in pathophysiology, for example asthma and chronic bronchitis.British Journal of Pharmacology (1998) 123, 1631–1638; doi:10.1038/sj.bjp.0701786