ACTIVATION AND REACTIVATION OF THE ATP-SENSITIVE K+ CHANNEL OF THE HEART CAN BE MODIFIED BY DRUGS

Activation and reactivation of the ATP-sensitive K+ channel (I(K.ATP)) were studied with the patch-clamp technique in guinea-pig ventricular myocytes. The K+ channel openers, nicorandil and pinacidil, activated I(K.ATP) in an internal ATP-dependent manner. Both drugs increased th e open probability of I(K.ATP) without changing the channel conductanc e. They prolonged lifetimes of bursts and shortened interburst interva ls without influencing the fast gating within bursts. These effects we re the opposite of those of internal ATP. However, the interaction bet ween ATP and either nicorandil or pinacidil appeared not to be simple competition. We found that three carbonyl compounds-3,4-dihydroxybenza ldehyde, 2, 3-dihydroxybenzaldehyde, and 2,4-dihydroxyacetophenone-cou ld activate I(K.ATP) through an intracellular mechanism that was depen dent upon the presence of ADP and Mg2+. It has been suggested that the se three carbonyl compounds bind covalently to proteins to form a Schi ff base, which may be responsible for their effects upon I(K.ATP) Inte rnal application of the proteolytic enzyme trypsin prevented both the spontaneous and Ca2+-induced rundown of the K(K.ATP) channel. Tryptic digestion did not change either the channel's sensitivity to inhibitio n by ATP nor the fast gating kinetics of I(K.ATP). Internal applicatio n of an exopeptidase, carboxypeptidase A, but not leuaminopeptidase, p revented the spontaneous and Ca2+-induced rundown of the I(K/ATP) chan nel, effects similar to those of trypsin treatment. These results sugg est that the target site of trypsin digestion may be located on the ca rboxy (C)-terminal of the channel proteins or associated regulatory un its.