© 1996 American Heart Association, Inc.
Articles |
Protein Kinase C Activates ATP-Sensitive K+ Current in Human and Rabbit Ventricular Myocytes
From the Department of Medicine and Research Center, Montreal Heart Institute (G.-R.L., S.N.), the Department of Medicine, University of Montreal (G.-R.L., S.N.), and the Department of Pharmacology and Therapeutics, McGill University (K.H., D.D., S.N.), Montreal, Quebec, Canada.
Correspondence to Dr Stanley Nattel, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8.
Abstract Mediators involved in ischemic
preconditioning, such as adenosine and
norepinephrine, can activate protein kinase C
(PKC), and a variety of observations suggest that both PKC and
ATP-sensitive K+ current (IKATP) play essential
roles in ischemic preconditioning. PKC is therefore a candidate
to link receptor binding to IKATP activation, but it has
not been shown whether and how PKC can activate
IKATP in the heart. The present study was designed to
determine whether PKC can activate IKATP in rabbit
and human ventricular myocytes. Under conditions designed
to minimize Na+ and Ca2+ currents, dialysis of
rabbit ventricular myocytes with pipette solutions
containing reduced [ATP] elicited IKATP, with a
50% effective concentration (EC50) of 260 µmol/L. In
cells that failed to show IKATP under control conditions,
superfusion with 1 µmol/L phorbol 12,13-didecanoate (PDD) elicited
IKATP in a fashion that depended on pipette [ATP], with
an [ATP] EC50 of 601 µmol/L. PDD-induced
IKATP activation was concentration dependent, with an
EC50 of 7.1 nmol/L. The highly selective PKC
inhibitor bisindolylmaleimide totally prevented
IKATP activation by PDD, and in blinded experiments, 1
µmol/L PDD elicited IKATP in eight of nine cells, whereas
its non–PKC-stimulating analogue 4
-PDD failed to elicit
IKATP in any of the five cells tested (P=.003).
Similar experiments were conducted in human ventricular
myocytes and showed that 0.1 µmol/L PDD elicited IKATP at
pipette [ATP] of 100 and 400 µmol/L (five of five cells at each
concentration) but not at 1 mmol/L [ATP] (none of five cells). We
conclude that PKC activates IKATP in rabbit and
human ventricular myocytes by reducing channel sensitivity
to intracellular ATP. This finding has potentially important
implications for understanding the mechanisms of ischemic
preconditioning.
Key Words: ischemic preconditioning • myocardial ischemia • cardioprotection • myocardial infarction • G proteins
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