Anti-ischemic and vasorelaxant effects of the new benzazepine calcium channel blocker SQ 31,765.
The anti-ischemic effects of SQ 31,765 or its relatively inactive enantiomer SQ 32,189 (to test for effects not related to calcium channel blockade) were determined in a model of stable angina. Anesthetized dogs were given saline (n = 6), SQ 31,765 (n = 6; 0.2 mg/kg) or SQ 32,189 (n = 6; 0.2 mg/kg) i.v. 10 min before ischemia. The effect on pacing-induced ST-segment elevation (pacing + left anterior descending coronary artery stenosis) and myocardial blood flow were determined. SQ 31,765 reduced ST-elevation (P less than .05) compared to saline at 10, 40 and 70 min after infusion (5.9 +/- 1.4 and 12.0 +/- 1.4 mV, respectively, at 70 min). SQ 32,189, which is a 10-fold less potent calcium channel blocker in coronary arteries, did not affect ST-elevation (11.8 +/- 2.1 mV). Left anterior descending coronary artery stenosis during atrial pacing resulted in a significant reduction in subendocardial flow in all groups before drug infusion (41 +/- 7, 44 +/- 7 and 35 +/- 9 ml/min/100 g for saline, SQ 31,765 and SQ 32,189, respectively) and treatment with SQ 31,765 did not affect this flow. SQ 32,189 further reduced subendocardial blood flow such that it was significantly lower compared to saline. To test for any partial agonist activity, Bay k 8644 and SQ 32,189 were tested as constrictors of porcine coronary strips in vitro. Bay k 8644 induced appreciable force whereas SQ 32,189 did not. However, the vasorelaxant potency of SQ 32,189 was decreased under hypoxic conditions. Thus, SQ 31,765 can reduce the severity of ischemia in a manner which is independent of changes in myocardial blood flow or hemodynamic alterations.
Grover
G J
GJ
Squibb Institute for Medical Research, Department of Pharmacology, Princeton, New Jersey.
Parham
C S
CS
Sleph
P G
PG
Moreland
S
S
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000188:drug therapy* / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
D001552:Benzazepines; D002121:Calcium Channel Blockers; D014665:Vasodilator Agents; C062147:SQ 31765; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D004110:Diltiazem