Cholinergic short-term conditioning and activation of ATP-sensitive K+ current in cat atrial myocytes

In atrial myocytes, an initial exposure to acetylcholine (ACh(1)) exerts a short-term conditioning effect such that a second ACh exposure (ACh(2)) activates ATP-sensitive K- current (IK,ATP). The purpose of the present study was to determine the mechanism underlying the short-term conditioning induced by ACh that results in subsequent ACh-induced activation of I-K,I-ATP. Cat atrial myocytes were studied using a nystatin-perforated patch whole cell recording method. Changes in L-type Ca2+ current (I-Ca,I-L) amplitude were used as an index of relative changes in cyclic AMP (cAMP). The results show that when atrial myocytes are treated with two consecutive exposures to 10 mu M ACh. separated by a recovery interval, ACh(2) activates a larger increase in potassium conductance (gK(-)) than ACh(1). The additional ACh(2)-induced increase in gK(+) is selectively blocked by 10 mu M glibenclamide, indentifying the current as I-K,I-ATP. Moreover, I-Ca,I-L activated immediately after the withdrawal of ACh(1) exhibited a transient increase in amplitude above control (+76%) consistent with rebound stimulation of cAMP. Rp-cAMPs (50 mu M), a selective antagonist of cAMP-dependent protein kinase A, blocked the rebound stimulation of I-Ca,I-L and abolished ACh(2)-induced activation of I-K,I-ATP. Thapsigargin (5 mu M), an inhibitor of Ca2- ATPase in the sarcoplasmic reticulum (SR), abolished ACh(2)-induced activation of I-K,I-ATP without decreasing rebound stimulation of I-Ca,I-L. Rebound stimulation of I-Ca,I-L and ACh(2)-induced activation of I-K,I-ATP both varied as a function of ACh(1) duration. We conclude that withdrawal of an initial ACh exposure elicits a rebound cAMP-mediated stimulation of SR Ca2- uptake. This mechanism induces a short-term conditioning in atrial myocytes such that a subsequent ACh exposure activates I-K,I-ATP. The present results demonstrate novel cholinergic signaling mechanisms in the regulation of I-K,I-ATP. (C) 1997 Academic Press Limited.