We previously demonstrated that
ATP-sensitive K+
channels (KATP) protect the guinea pig myocardium against
ischemia-reperfusion injury (Cole et al., Circ. Res. 69: 571-581, 1991), but the cellular alterations leading to ischemic injury affected by KATP remain to be defined. This study investigates the relationship between activation of KATP and preservation of high-energy
phosphates during global no-flow
ischemia in arterially perfused guinea pig right ventricular walls. Electrical and mechanical activity were recorded via intracellular
microelectrodes and a force transducer.
Glibenclamide (10 and 50 microM) and
pinacidil (10 microM) were used to modulate KATP.
ATP and
creatine phosphate (CP) levels were determined at the end of no-flow
ischemia by enzymatic analysis. Preparations were subjected to 1) 20 min no-flow +/-
glibenclamide (10 or 50 microM), 2) 30 min no-flow +/-
pinacidil (10 microM) or
pinacidil (10 microM) and
glibenclamide (50 microM), or 3) 40 or 50 min of control perfusion before rapid freezing in liquid
nitrogen.
Pinacidil (10 microM) enhanced ischemic shortening of action potential duration (APD) and early contractile failure, prevented
ischemic contracture, and inhibited high-energy
phosphate depletion during
ischemia.
Glibenclamide (50 microM) inhibited the effects of
pinacidil (10 microM) on electromechanical function and preservation of
ATP and CP.
Glibenclamide (10 microM) alone inhibited the early decline in APD and produced earlier
ischemic contracture but did not enhance
ATP or CP depletion compared with untreated tissues during 20 min of no-flow.
Glibenclamide (50 microM) produced a greater inhibition of APD shortening in early
ischemia, further decreased the latency to
ischemic contracture, and caused enhanced ischemic depletion of
ATP. The data indicate the changes in electrical activity induced by KATP indirectly preserve high-energy
phosphates and reduce injury associated with
ischemia. However, the data also suggest the possible presence of additional mechanisms for cardioprotection by KATP.