ACCELERATION OF STIFFNESS IN UNDERPERFUSED DIABETIC RAT HEARTS BY GLYBURIDE, A K-ATP CHANNEL BLOCKER, AND ITS PREVENTION BY LEVCROMAKALIM AND INSULIN

Object: To clarify the role of the K-ATP channels in myocardial dysfun ction during underperfusion with norepinephrine (NE) in the diabetic h eart, particularly the heart treated with sulphonylurea derivatives. M ethods: Isolated 6-week streptozotocin-diabetic rat hearts with a ball oon in the left ventricle (LV) were paced and perfused with normoxic K rebs-Henseleit solution. Agents were infused for 15-25 min before as w ell as during 60-min underperfusion (2 ml/min/g heart weight) with 10( -6) M NE. Regional myocardial flaw distribution was measured using dye microspheres. The effects of ex vivo glyburide (10(-6) M, a sulphonyl urea anti-diabetic drug and a specific K-ATP channel inhibitor) on con tractile dysfunction and abnormal regional myocardial energy metabolis m were examined during underperfusion with NE in the absence or presen ce of levcromakalim (10(-4) M, a selective KC channel opener) and insu lin (2 mU/min/g heart weight). Results: The flow rate was greater in t he LV subendocardium than the subepicardium during normal perfusion, a nd smaller at 60-min underperfusion with NE. The LV diastolic tension and pressure during underperfusion with NE increased more rapidly in t he presence of glyburide. At 60-min underperfusion with NE, the diasto lic 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-t reated heart, particularly in the LV subendocardium. Thus, ex vivo gly buride enhanced the increase in LV stiffness and abnormal myocardial e nergy metabolism during underperfusion with NE in diabetic hearts. The se changes were reduced by levcromakalim to the level during underperf usion with NE without glyburide. Insulin did not prevent the glyburide -induced earlier exacerbation of the increase in LV stiffness during u nderperfusion with NE, but reduced the detrimental effects 20 min afte r the onset of underperfusion. Conclusions: K-ATP channels in the diab etic myocardium probably open during underperfusion with NE, and it he lps delay the initiation of the increase in cardiac stiffness. Glyburi de may have harmful effects in the ischemic diabetic heart; the myocar dial K-ATP channel blockade during underperfusion with NE enhanced the increase in LV stiffness and abnormal myocardial energy metabolism. T he glyburide-induced detrimental effects in the ischemic diabetic hear t are prevented by levcromakalim and partly by insulin. (C) 1997 Elsev ier Science B.V.