Cardioprotective effects of a novel calcium antagonist related to the structure of cromakalim.
A novel pyranoquinoline analog (BMS-188107) of the ATP-sensitive potassium channel (KATP) opener cromakalim was previously shown to be devoid of KATP opening activity in nonischemic myocardium and vascular smooth muscle, but appeared to be a relatively potent calcium antagonist. This clear differentiation between channels within a structural series is a novel finding. With the idea that KATP openers are often more active in ischemic relative to nonischemic myocardium, we determined the cardioprotective effects of this agent in isolated rat hearts and whether these anti-ischemic effects are abolished by KATP blockade. Isolated rat hearts were subjected to 25 min of global ischemia and 30 min of reperfusion and the severity of ischemic/reperfusion injury was determined. BMS-188107 was given before ischemia at 0.5 to 10 microM. Pretreatment (before ischemia) with BMS-188107 caused significant cardiodepressant activity and increased coronary flow only at a concentration of 10 microM, although modest negative inotropic effects were observed at the 0.5 and 1 microM concentrations. Significant improvements in postischemic contractile function and reductions in lactate dehydrogenase release were observed with 1 to 10 microM BMS-188107, indicating significant reductions in ischemic/reperfusion injury. Neither the pre- nor the postischemic effects of 1 to 10 microM BMS-188107 were significantly altered by the KATP blockers sodium 5-hydroxydecanoate (100 microM) or glyburide (1 microM). Previous studies did not determine the effect of BMS-188107 on sodium channels and thus, the effect of this agent on maximum upstroke velocity of the action potential was determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Grover
G J
GJ
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
Sleph
P G
PG
Dzwonczyk
S
S
McCullough
J R
JR
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D019806:Cromakalim; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015221:Potassium Channels / Q000187:drug effects; D011758:Pyrroles / Q000737:chemistry; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control; D015222:Sodium Channels / Q000187:drug effects*
D001578:Benzopyrans; D002121:Calcium Channel Blockers; D015221:Potassium Channels; D011758:Pyrroles; D015363:Quinolones; D015222:Sodium Channels; D019806:Cromakalim; C083893:BMS 188107; D005905:Glyburide