PHARMACOLOGICAL PROFILE OF THE DIHYDROPYRIMIDINE CALCIUM-CHANNEL BLOCKERS SQ-32,547 AND SQ-32,946

SQ 32,926 and SQ 32,547, two dihydropyrimidine calcium channel blocker s, were characterized as potent inhibitors of depolarization-induced c ontractions of isolated smooth muscle preparations, In rat aorta, the IC,, values were 5.5 nM for SQ 32,547 and 8.1 nM for SQ 32,926, values which compare favorably with that of 2.9 nM for nifedipine. The dihyd ropyrimidines were also tested in a model of stable angina: pacing-ind uced ischemia in dogs. Both SQ 32,547 and SQ 32,926 reduced the ST-seg ment elevation observed in vehicle-treated animals. No significant cha nges in hemodynamic status were detected, suggesting that a reduction in cardiac work secondary to afterload reduction was probably not a ma jor contributor to the protective effects. Neither was increased coron ary blood flow important for the antiischemic outcome because no signi ficant effects of the dihydropyrimidines were observed on ischemic reg ional blood flow. SQ 32,547 was also studied in globally ischemic, iso lated rat hearts. In this model, SQ 32,547 was protective because it s ignificantly reduced contracture formation and lactate dehydrogenase ( LDH) release. Washing out the effect of SQ 32,547 in isolated hearts a nd smooth muscles was difficult, presumably due to its lipophilicity. In the smooth muscle preparations, the effects of both nifedipine and SQ 32,926 were much more easily washed out. As with other calcium chan nel blockers, increasing the antiischemic effects of SQ 32,547 was ass ociated with a higher cost in terms of cardiac function. In summary, t he two novel dihydropyrimidines, SQ 32,547 and SQ 32,926, showed antii schemic properties in animal models.