Anti-ischemic activity of the novel benzazepine calcium antagonist SQ 31,486.
We tested the benzazepine, SQ 31,486 for its ability to selectively block the voltage-dependent calcium channel and to protect the ischemic myocardium. SQ 31,486 was found to be a selective calcium antagonist in vascular tissue with an IC50 value of 1.5 microM in KCl-contracted rabbit aorta. SQ 31,486 decreased contractile function and increased coronary flow in nonischemic isolated rat hearts in a concentration-dependent manner. SQ 31,486 also significantly reduced postischemic lactate dehydrogenase (LDH) release and end-diastolic pressure (EDP) compared to vehicle. Reperfusion double product [heart rate (HR) x left ventricular developed pressure (LVDP)] was also significantly improved by SQ 31,486. Diltiazem was a less potent anti-ischemic agent and was significantly more cardiodepressant relative to its anti-ischemic efficacy than was SQ 31,486. Thus, SQ 31,486 should have a larger therapeutic index. In a model of pacing-induced myocardial ischemia in anesthetized, open chest dogs, SQ 31,486 reduced pacing-induced ST-segment elevation approximately 50% at 10, 40, and 70 min after drug administration. This protective effect occurred despite a lack of effect of SQ 31,486 on ischemic regional blood flow and peripheral hemodynamic status.
Grover
G J
GJ
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Sleph
P G
PG
Parham
C S
CS
Brittain
R J
RJ
Krapcho
J
J
Moreland
S
S
D000818:Animals; D001552:Benzazepines / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D003327:Coronary Disease / Q000188:drug therapy* / Q000503:physiopathology; D004110:Diltiazem / Q000494:pharmacology; D004285:Dogs; D004558:Electric Stimulation; D004562:Electrocardiography; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008238:Lysergic Acid Diethylamide / Q000097:blood; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D011817:Rabbits; D051381:Rats
D001552:Benzazepines; D002121:Calcium Channel Blockers; D002317:Cardiovascular Agents; C065543:SQ 31486; D008238:Lysergic Acid Diethylamide; D004110:Diltiazem