Activation of ATP-sensitive potassium channels in hypoxic cardiac failure is not mediated by adenosine-1 receptors in the isolated rat heart.
BACKGROUND
Hypoxic cardiac failure is accompanied by action potential shortening, which in part might be a consequence of opening of cardiac ATP-sensitive potassium channels (K(ATP) channels). Coupling of the adenosine-1 receptor (A-1 receptor) to these channels has been described; however, the interaction of A-1-receptors and K(ATP) channels in different models of ischemia is still under debate. The hypothesis as to whether A-1 receptors are involved in hypoxic K(ATP) channel-activation in the saline-perfused rat heart was tested.


RESULTS
Pharmacologic modulation of the K(ATP) channel by Glibenclamide (inhibitor) and Rimalkalim (activator) and of the A-1 receptor by R(-)-N6-(1-methyl-2-phenylethyl)-adenosine (R(-)-PIA, agonist) and 1,3-diethyl-3,7-dihydro-8-phenyl-purine-2,6-dione (DPX, antagonist) at different oxygen tensions (95% O2 and 20% O2) was performed in isolated Langendorff-rat hearts. Peak systolic pressure (PSP, intraventricular balloon), duration of monophasic action potential (epicardial suction electrode, time to 67% of repolarization: MAP(67%)), coronary flow, and heart rate (HR) were registered. Hypoxic perfusion resulted in a significant reduction of PSP (from 106 +/-11 to 56 +/-8 mmHg, P < 0.005) and shortening of MAP(67%) (from 37 +/-3 to 25 +/-4 ms, P < 0.005). With application of 1 microM Glibenclamide, MAP(67%) returned to normoxic values and PSP increased to 78 +/-9 mmHg (P < 0.005 vs hypoxia). In normoxia, 2 microM Rimalkalin resulted in reduction of MAP(67%) and PSP, which was reversed by Glibenclamide. Application of 0.1 microM R(-)-PIA in normoxia resulted in a decrease of HR (from 235 +/-36/min to 75 +/-41/min, P < 0.005), which was accompanied by an increase of PSP from 96 +/-7 to 126 +/-9 mmHg (P < 0.05) without changes in MAP(67%). These effects were reversible by 1 microM DPX and remained unaffected by application of 1 microM Glibenclamide. Application of 1 microM DPX in hypoxia had no effect on the measured parameters.


CONCLUSIONS
In isolated rat hearts, the K(ATP) channel-system is activated in hypoxic cardiac failure and contributes to action potential shortening and reduced contractile performance. These effects seem to be independent of the A-1 receptor in this model.
Reffelmann
T
T
Medical Clinic I, University Hospital, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.
Skobel
E C
EC
Kammermeier
H
H
Hanrath
P
P
Schwarz
E R
ER
D000200:Action Potentials; D000818:Animals; D001794:Blood Pressure; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006339:Heart Rate; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D015221:Potassium Channels; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism*
D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D015221:Potassium Channels; D018047:Receptors, Purinergic P1; C117780:mitochondrial K(ATP) channel; D005905:Glyburide