title: The role of myocardial KATP-channel blockade in the protective effects of glibenclamide against ischaemia in the rat heart.
abstract: Glibenclamide preserves postischaemic myocardial function in the isolated, erythrocyte perfused, working rat heart model. This study addresses the possible involvement of KATP channels in this beneficial action of glibenclamide. We hypothesized that if glibenclamide improved postischaemic cardiac function by blocking of KATP channels, opening of these KATP channels should result in the opposite, namely detrimental effects on postischaemic heart function. Postischaemic functional loss and coronary blood flow were recorded during treatment with glibenclamide (4 micromol x l(-1); n = 5), the KATP channel openers pinacidil (1 micromol x (l-1); n = 5) and diazoxide (30 micromol x l(-1); n = 5), the combination of glibenclamide with pinacidil (n = 5) and glibenclamide with diazoxide (n = 5), and vehicle (n = 8). Both pinacidil and diazoxide significantly increased coronary blood flow 2-3 times, which was abolished by glibenclamide pre- and postischaemically. This confirms that under both flow conditions glibenclamide significantly blocks KATP channels in the coronary vasculature. The 12 min. global ischaemic incident resulted in a cardiac functional loss of 22.2 +/- 2.9% during vehicle. Glibenclamide reduced the cardiac functional loss to 4.3 +/- 1.2% (P < 0.01). Interestingly, both pinacidil and diazoxide reduced the cardiac functional loss to 4.0 +/- 1.5% (P < 0.01) and 2.9 +/- 1.4% (P < 0.001), respectively. The combination pinacidil+glibenclamide resulted in additional protection compared with the individual components (0.6 +/- 0.1 versus 4.0 +/- 1.5%, P < 0.05). Thus, in contrast to its effect on coronary vascular tone, the glibenclamide-induced improvement of postischaemic cardiac function may not be mediated through blockade of the KATP channel. Alternative mechanisms may be operative, such as uncoupling of the mitochondrial respiratory chain, thereby preconditioning the hearts against stunning.
authors.affiliation: Department of Physiology, University Medical Center Nijmegen, The Netherlands.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Legtenberg
authors.forename: Gerard A
authors.initials: GA
authors.lastname: Rongen
authors.forename: Ralph J E
authors.initials: RJ
authors.lastname: Houston
authors.forename: Berend
authors.initials: B
authors.lastname: Oeseburg
authors.forename: Paul
authors.initials: P
authors.lastname: Smits
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology; D004347:Drug Interactions; D005905:Glyburide / Q000627:therapeutic use*; D008297:Male; D017202:Myocardial Ischemia / Q000517:prevention & control*; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015221:Potassium Channels; D020110:Pinacidil; D003981:Diazoxide; D005905:Glyburide