EFFECTS OF SOME K-CHANNEL INHIBITORS ON THE ELECTRICAL BEHAVIOR OF GUINEA-PIG ISOLATED TRACHEALIS AND ON ITS RESPONSES TO SPASMOGENIC DRUGS()

1 A study has been made of the effects of inhibitors selective among p lasmalemmal K+-channels on the sensitivity and responsiveness of guine a-pig trachealis muscle to carbachol, histamine and KCl. The effects o f the K+-channel inhibitors on the resting membrane potential and spon taneous electrical activity of the trachealis cells have also been exa mined. 2 In indomethacin (2.8 mu M)-treated trachealis muscle, dofetil ide (1 mu M) and glibenclamide (10 mu M) were each devoid of spasmogen ic activity. In contrast 4-aminopyridine (4-AP, 62.5 mu M-8 mM), chary bdotoxin (ChTX, 100 nM) and iberiotoxin (IbTX, 100 nM) were each spasm ogenic. Spasm evoked by 4-AP, IbTX or ChTX was reduced, though not abo lished, by atropine (1 mu M). Spasm evoked by 4-AP (1 mM), ChTX (100 n M) or IbTX (100 nM) was unaffected by tetrodotoxin (TTX; 3.1 mu M) or by tissue pretreatment with capsaicin (1 mu M for 30 min). Spasm evoke d by IbTX dr ChTX was abolished by nifedipine (1 mu M). 3 Dofetilide ( 1 mu M) and glibenclamide (10 mu M) were each without effect on the tr acheal sensitivity or responsiveness to carbachol, histamine or KCl. 4 -AP (1 mM) antagonized carbachol, potentiated histamine but did not af fect tissue sensitivity to KCl. When the effects of 4-AP were examined in the presence of atropine (1 mu M), it potentiated all the spasmoge ns including carbachol. IbTX and ChTX (each 100 nM) potentiated all th ree spasmogens. Potentiation of histamine induced by 4-AP (1 mM) or Ib TX (100 nM) was also observed in tissues treated with a combination of atropine (1 mu M) and TTX (3.1 mu M). 4 Dofetilide (1 and 10 mu M) wa s without effect on the resting membrane potential or spontaneous elec trical activity of the trachealis cells. 4-AP (1 mM) evoked depolariza tion and caused a small increase in the frequency of slow wave dischar ge. The depolarization evoked by 4-AP was abolished by atropine (1 mu M). IbTX (100 nM) and ChTX (100 nM) each evoked little or no change in resting membrane potential but converted the spontaneous slow waves i nto spike-like, regenerative action potentials. These electrophysiolog ical effects of IbTX and ChTX were unaffected by atropine (1 mu M). 5 It is concluded that the dofetilide-sensitive, cardiac, delayed rectif ier K+-channel is either not expressed in trachealis muscle or is of n o functional importance in that tissue. The ATP-sensitive K+-channel ( K-ATP) does not moderate tracheal sensitivity to spasmogens such as ca rbachol, histamine and KCl. The 4-AP-sensitive delayed rectifier K+-ch annel (K-dr) and the large Ca2+-dependent K+-channel (BKCa) each moder ate trachealis muscle sensitivity to spasmogens. Neither K-dr nor BKCa plays an important role in determining the resting membrane potential of guinea-pig trachealis cells. However, the BKCa channel is responsi ble for limiting the effects of the increase in membrane Ca2+ conducta nce associated with the depolarizing phase of slow waves. It is BKCa c hannel opening that prevents the development of a slow wave into a spi ke-like regenerative action potential.