ANTIHYPERTENSIVE EFFECTS OF AJ-2615, A NEW CALCIUM-ANTAGONIST WITH ALPHA-1-ADRENERGIC BLOCKING ACTIVITY IN EXPERIMENTAL HYPERTENSIVE ANIMALS

The antihypertensive effect of AJ-2615 [(+/-)-N-(6,11-dihydrodibenzo[b , 11-yl)-4-(4-fluoro--phenyl)-1-piperazinebutanamide maleate], a novel calcium (Ca) antagonist having alpha1-adrenergic blocking activity as well, was compared with that of the existing Ca antagonists (diltiaze m, nifedipine, and nicardipine) in various hypertensive models of dogs and rats. When given orally to renal hypertensive dogs (RHDs) and spo ntaneously hypertensive rats (SHRs), AJ-2615 (RHDs, ED25 mm Hg = 6-0 m g/kg; SHRs, ED25 mm Hg = 24.9 mg/kg) was approximately as effective as diltiazem (RHDs, ED25 mm Hg = 6.3 mg/kg; SHRs, ED25 mm Hg = 54.7 mg/k g) in lowering the blood pressure. This antihypertensive effect was sl ower in onset and longer in duration (RHDs, greater-than-or-equal-to 9 h; SHRs, greater-than-or-equal-to 20 h) compared with any of the othe r reference drugs. AJ-2615 (10 mg/kg p.o.) given to RHDs once daily fo r 29 days significantly reduced the blood pressure measured 24 h after each dose and caused a stable antihypertensive effect without major d iurnal variations. When given in single oral doses to RHDs and SHRs, A J-2615 had no large effect on the heart rate while the reference drugs induced a large increase or decrease in heart rate in response to a b lood pressure fall. These results suggested that AJ-2615 has potential as a long-acting (once daily dosage regimen) antihypertensive drug wi thout causing a steep blood pressure fall and tachycardia.