Acceleration of stiffness in underperfused diabetic rat hearts by glyburide, a KATP channel blocker, and its prevention by levcromakalim and insulin.
OBJECTIVE
To clarify the role of the KATP channels in myocardial dysfunction during underperfusion with norepinephrine (NE) in the diabetic heart, particularly the heart treated with sulphonylurea derivatives.


METHODS
Isolated 6-week streptozotocin-diabetic rat hearts with a balloon in the left ventricle (LV) were paced and perfused with normoxic Krebs-Henseleit solution. Agents were infused for 15-25 min before as well as during 60-min underperfusion (2 ml/min/g heart weight) with 10(-6) M NE. Regional myocardial flow distribution was measured using dye microspheres. The effects of ex vivo glyburide (10(-6) M, a sulphonylurea anti-diabetic drug and a specific KATP channel inhibitor) on contractile dysfunction and abnormal regional myocardial energy metabolism were examined during underperfusion with NE in the absence of presence of levcromakalim (10(-4) M, a selective K+ channel opener) and insulin (2 mU/min/g heart weight).


RESULTS
The flow rate was greater in the LV subendocardium than the subepicardium during normal perfusion, and smaller at 60-min underperfusion with NE. The LV diastolic tension and pressure during underperfusion with NE increased more rapidly in the presence of glyburide. At 60-min underperfusion with NE, the diastolic pressure elevation was still higher in the glyburide-treated heart, and decreases in tissue ATP, creatine phosphate (CP), energy charge, phosphorylation potential and CP/inorganic phosphate (P(i)) ratio, and increases in AMP, P(i) and lactate were more marked in the glyburide-treated heart, particularly in the LV subendocardium. Thus, ex vivo glyburide enhanced the increase in LV stiffness and abnormal myocardial energy metabolism during underperfusion with NE in diabetic hearts. These changes were reduced by levcromakalim to the level during underperfusion with NE without glyburide. Insulin did not prevent the glyburide-induced earlier exacerbation of the increase in LV stiffness during underperfusion with NE, but reduced the detrimental effects 20 min after the onset of underperfusion.


CONCLUSIONS
KATP channels in the diabetic myocardium probably open during underperfusion with NE, and it helps delay the initiation of the increase in cardiac stiffness. Glyburide may have harmful effects in the ischemic diabetic heart; the myocardial KATP channel blockade during underperfusion with NE enhanced the increase in LV stiffness and abnormal myocardial energy metabolism. The glyburide-induced detrimental effects in the ischemic diabetic heart are prevented by levcromakalim and partly by insulin.
Higuchi
M
M
Department of Pharmacology, School of Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan. tomo@med.u-ryukyu.ac.jp
Miyagi
K
K
Kayo
S
S
Sakanashi
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D019806:Cromakalim / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010477:Perfusion; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019806:Cromakalim; D005905:Glyburide; D009638:Norepinephrine