Effect of potassium channel blockade on the anti-ischemic actions of mechanistically diverse agents.
The ATP-sensitive potassium channel opener, cromakalim, protects ischemic hearts and its effect can be reversed by glyburide. It is presently unknown if glyburide can abolish the anti-ischemic effects of mechanistically different agents or if blockers of other potassium channels can abolish the protective effects of cromakalim. Thus, the effect of glyburide on previously reported cardioprotective agents was tested in globally ischemic/reperfused isolated rat hearts. Calcium antagonists, sodium channel blockers and calmodulin antagonists were found to significantly improve postischemic contractile function and reduce lactate-dehydrogenase release after 25 min of global ischemia and 30 min of reperfusion. Glyburide did not reverse their cardioprotective effects. 5-(N,N-dimethyl)amiloride, an inhibitor of Na+/H+ exchange, significantly reduced lactatedehydrogenase release without improving postischemic contractile function, and glyburide did not reverse this. The potassium channel opener, cromakalim, protected ischemic rat hearts (improved recovery of contractile function and reduced enzyme release) and this was abolished by glyburide. Charybdotoxin blocks both calcium-activated potassium channels and voltage-gated potassium channels and E-4031 the delayed rectifier potassium channels. Neither was found to effect the action of the potassium channel opener, cromakalim. These data indicate that glyburide is selective in that it only blocks the anti-ischemic effects of potassium channel openers and not other cardioprotective compounds. In addition, cromakalim is unaffected by blockers of other potassium channels, further indicating selectivity of glyburide for ATP-sensitive potassium channels.
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Pharmacology, Princeton, New Jersey.
C A
CA
Sargent
M A
MA
Smith
S
S
Dzwonczyk
P G
PG
Sleph
G J
GJ
Grover
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D003327:Coronary Disease / Q000188:drug therapy*; D019806:Cromakalim; D005905:Glyburide / Q000494:pharmacology*; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D001578:Benzopyrans; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D019806:Cromakalim; C063968:E 4031; D008012:Lidocaine; D005905:Glyburide