Neuroregulation of mucus secretion by opioid receptors and KATP and BKCa channels in ferret trachea in vitro

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Abstract
1. 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 delta opioid receptor) agonist [D-Pen2,5]enkephalin (DPDPE), the OP2 receptor (formely kappa) agonist U-50,488H, the OP3 receptor (formerly micro) agonist [D-Ala2, N-Me-Phe, Gly-ol5]enkephalin (DAMGO), the ATP-sensitive K+ (K(ATP)) channel inhibitor glibenclamide, the large conductance calcium activated K+ (BK(Ca)) channel blocker iberiotoxin, the small conductance K(Ca) (SK(Ca)) channel blocker apamin, the K(ATP) channel opener levcromakalim, a putative K(ATP) channel opener RS 91309, and the BK(Ca) channel opener NS 1619. Secretion was quantified by use of 35SO4 as a mucus marker. 2. Electrical stimulation increased tracheal secretion by up to 40 fold above sham-stimulated levels. DAMGO or DPDPE (10 microm 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. 3. Inhibition of neurogenic secretion by DAMGO or DPDPE was reversed by iberiotoxin (3 microM) but not by either glibenclamide or apamin (0.1 microM each). Iberiotoxin alone did not affect the neurogenic secretory response. 4. Levcromakalim, RS 91309 or NS 1619 (3 nM-3 microM) inhibited neurogenic secretion with maximal inhibitions at 3 microM 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. 5. Inhibition of neurogenic secretion by levcromakalim (3 microM) or RS 91309 (30 nM) was inhibited by glibenclamide but not by iberiotoxin. In contrast, inhibition by NS 1619 (30 nM and 3 microM) was blocked by iberiotoxin but not by glibenclamide. 6. 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 BK(Ca) channels. Direct opening of BK(Ca) channels or K(ATP) channels also inhibits neurogenic mucus secretion. In addition, opening of BK(Ca) channels inhibits ACh-evoked secretion of mucus. Drugs which open BK(Ca) 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.