IN-VIVO DOWN-REGULATION OF M-2 RECEPTORS REVEALED BY MEASUREMENT OF MUSCARINIC K-PIG ATRIAL MYOCYTES( CURRENT IN CULTURED GUINEA)

1. Muscarinic K+ current (I-K(ACh)) elicited by acetylcholine (ACh) wa s measured in guinea-pig atrial myocytes, which were either freshly is olated or cultured for up to 8 days. 2. The half-time of activation of inward I-K(ACh) by a saturating concentration (10 mu M) of ACh decrea sed from similar to 400 ms (in freshly isolated cells) to 250 ms after 6 days in culture. This was paralleled by an increase in the fast des ensitizing component of I-K(ACh). The density of steady-state currents was not changed. Downregulation of M-2 receptors by long-term treatme nt of isolated myocytes with carbachol in vitro had opposite effects. 3. The EC50 of ACh for the activation of steady-state I-K(ACh) was red uced from 5 x 10(-7) M (day 0) to 8 x 10(-8) M (day 6). The shift in E C50 occurred with a half-time of about 2 days, similar to the recovery from downregulation induced by treating atrial myocytes with carbacho l in vitro. 4. The increase in sensitivity to ACh can be accounted for by an similar to 6-fold increase in the density of M-2 receptors. 5. It is concluded that sensitization in culture reflects recovery from d ownregulation of M-2 receptors due to the tonic vagal input to the hea rt in the intact animal.