ACETYLCHOLINE-SENSITIVE MUSCARINIC K+ CHANNELS IN MAMMALIAN VENTRICULAR MYOCYTES

Acetylcholine (ACh) is known to increase K+ conductance in the atrium and in pacemaker tissues in the heart. This effect has not been well defined in mammalian ventricular tissues. We have identified and characterized the ACh-sensitive muscarinic K+ channel [I-K(ACh)] activity in isolated human, cat, and guinea pig ventricular myocytes using the patch-clamp technique. Application ofACh increased whole cell membrane current in human ventricular myocytes. Current-voltage relationship of the ACh-induced current in ventricle exhibited inward-rectification whose slope conductance was smaller than that in atrium. In single-channel recording from cell-attached patches, I-K(ACh) activity was observed when ACh was included in the solution. The channel exhibited a slope conductance of 43 +/- 2 pS. Open times were distributed according to a single exponential function with mean open lifetime of 1.8 +/- 0.3 ms. The channel had conductance and kinetic characteristics similar to human atrial I-K(ACh), which had a slope conductance of 43 +/- 3 pS and mean open lifetime of 1.6 +/- 0.3 ms. However, concentration of ACh at half-maximal stimulation (K-D) of the channel in ventricle was greater (K-D = 0.13 mu M) than that in atrium (K-D = 0.03 mu M). Adenosine caused activation of the same K+ channel. After formation of an excised inside-out patch, channel activity disappeared. Application of GTP (100 mu M) or GTP gamma S (100 mu M) to the solution caused reactivation of the channel. When myocytes were preincubated with pertussis toxin (PTX), ACh failed to activate these channels, indicating that the PTX-sensitive G protein, G(i), is essential for activation of I-K(ACh). I-K(ACh) channel activity was also found in cat and guinea pig ventricular myocytes. We conclude that ACh directly activates the I-K(ACh) in mammalian ventricular myocytes via Gi in a fashion almost identical to atrial myocytes.