Glibenclamide attenuates ischemia-induced acidosis and loss of
cardiac function in rats
Roger J. Legtenberg
, Ralph J.F. Houston
, Arend Heerschap
, Paul Smits
Department of Physiology 237, University Medical Center Nijmegen, P.O. Box 9101, NL-6500 HB, Nijmegen, The Netherlands
Department of Anesthesiology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands
Department of Radiology, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Pharmacology-Toxicology, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Department of Internal Medicine, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
Received 21 June 2001; received in revised form 3 September 2001; accepted 23 October 2001
Previous research has shown that the sulfonylurea derivative glibenclamide may improve post-ischemic cardiac functional recovery.
channel blockade is a possible explanation for this observation, alternative mechanisms exist. Therefore, we simultaneously
recorded cardiac function and the intracellular concentration of ATP, phosphocreatine, Pi and pH before and after ischemia in the presence of
glibenclamide or vehicle.
Phophorus magnetic resonance (MS) spectroscopy on erythrocyte-perfused, isolated working rat hearts was
performed. Glibenclamide 4 mmol l
or vehicle alone was tested (both n = 5). The following protocol was used: 8 min performance
assessment, 10 min drug treatment, 12 min global ischemia, 20 min reperfusion with drug treatment and 8 min functional recovery
assessment. Compared with vehicle, glibenclamide significantly decreased coronary blood flow (59.5 F7.0% vs. 94.3 F 1.3%, P = 0.008),
ischemia-induced cardiac functional loss (7.4F1.3% vs. 18.8 F3.3%; P = 0.019) as well as the ichemia-induced intracellular acidosis
(6.75 F0.01 vs. 6.43F0.03 for vehicle, P = 0.03).
In conclusion, glibenclamide is able to reduce the myocardial functional loss after ischemia while preserving pH but not ATP levels during
ischemia. This suggests that the beneficial response to glibenclamide is probably not the result of myocardial K
channel blockade, but
may be explained by inhibition of glycolysis. D 2002 Published by Elsevier Science B.V.
Phosphorus magnetic resonance spectroscopy; Heart, isolated, working; Ischemia; Metabolism; Diabetes, type 2; Glibenclamide; K
Sulfonylurea derivatives, e.g. glibenclamide, are still the
corner stone in the treatment of type 2 diabetes mellitus. The
blood glucose lowering effect of these drugs is achieved by
closing the so-called ATP-sensitive K
) channels in
the pancreatic b cells. This subsequently results in depola-
rization of the membrane and opening of voltage-gated Ca
channels. The resulting Ca
influx ultimately leads to
insulin secretion by the pancreatic b cells (Gerich, 1989;
Groop, 1992). Interestingly, K
channels have also been
discovered in the myocardium, and it has been shown that
sulfonylurea derivatives are able to interact with these K
channels (Noma, 1983). During ischemia, myocardial K
channels open due to a decrease of the ATP/ADP ratio,
resulting in K
efflux which in turn results in hyperpolari-
zation of the myocardial membrane. The subsequent short-
ening of the action potential preserves energy utilization and
in this way the opening of myocardial K
channels acts as
an endogenous protective mechanism of the heart (Coetzee,
1992; Nichols et al., 1991; Noma, 1983).
Based on this endogenous role of myocardial K
channels during ischemia, it is logical that blocking these
channels with sulfonylurea derivatives does have an influ-
ence on the outcome of an ischemic insult, which has also
been shown in several experimental models of ischemia.
Glibenclamide may increase the post-ischemic infarct size
0014-2999/02/$ - see front matter D 2002 Published by Elsevier Science B.V.
PII: S 0014-2999(01)01483-2
Corresponding author. Tel.: +31-24-3613674; fax: +31-24-3540535.
E-mail address: P.Smits@farm.kun.nl (P. Smits).
Berend Oeseburg sadly died on December 30, 2000.
European Journal of Pharmacology 434 (2002) 35 – 42