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.