Pinacidil-induced opening, like glibenclamide-induced closure of cardiac KATP channels, protects cardiac function against ischemia in isolated, working, erythrocyte perfused rat hearts.
Glibenclamide-induced closure of ATP-dependent potassium (KATP) channels decreases coronary blood flow during normoxic and post-ischemic conditions. We have found that post-ischemic cardiac function is improved after glibenclamide treatment. Our theory was that this is a result of higher intracellular calcium concentrations due to reduction in ischemia-mediated hyperpolarization of the myocardial cell membrane. We hypothesized therefore that opening KATP channels would reduce post-ischemic function in our isolated, erythrocyte perfused, working rat heart model. During treatment with 1 or 12 mumol.L-1 pinacidil (protein unbound concentration) both before and after 12 minutes global ischemia coronary blood flow increased 2-3 fold compared with vehicle, while cardiac functional recovery post-ischemically was improved with both concentrations. Because closing and opening cardiac KATP channels both improve post-ischemic function, our calcium theory above can be discounted. The protective effect of glibenclamide may possibly be ascribed to metabolic effects such as preservation of ATP levels during ischemia.
Legtenberg
Roger J
RJ
Department of Physiology 237, University of Nijmegen, The Netherlands.
Houston
Ralph J
RJ
Smits
Paul
P
Oeseburg
Berend
B
D000818:Animals; D005905:Glyburide / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D017202:Myocardial Ischemia / Q000517:prevention & control*; D020110:Pinacidil / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D015221:Potassium Channels; D020110:Pinacidil; D005905:Glyburide