Pacrinolol

L-3,4-(3-3,4-Dimethoxyphene-ethylamino-2-hydroxypropoxy)-phenyl-++ +crotonic acid nitrile X HCl (Hoe 224) has beta 1-blocking action. In the isolated left atrium of the guinea pig, the ED50 necessary to counteract the positive inotropic action of 2 ng/ml isoprenaline (isoproterenol) was determined as 10.3 ng/ml in comparison to the ED50 of propranolol 2.7 ng/ml. On the isolated right atrium of the same animal, the ED50 for inhibition of increased heart rate brought about by 2 ng/ml isoprenaline was 29.5 ng/ml in comparison to the ED50 of propranolol 13.5 ng/ml. On the isolated tracheal chain of the guinea pig 40 micrograms Hoe 224/ml also inhibited relaxation induced by 50 ng isoprenaline/ml only by 31%. The ED50 for propranolol in this experiment was 1.2 ng/ml. Therefore, Hoe 224 is a very specific beta 1-blocker. In the dog anaesthetized with pentobarbital the ED50 of Hoe 224 for depression of dp/dt increase by 0.1 mg isoprenaline/kg i.v. was determined as 85 micrograms/kg i.v. Under the same conditions, the ED50 for propranolol was 10 micrograms/kg i.v., for atenolol 17 micrograms/kg i.v., for practolol 56 micrograms/kg i.v. In the conscious dog, 1.6 mg Hoe 224/kg orally depressed the increase of dp/dt brought about by 0.1 microgram isoprenaline/kg i.v. by 50%. The beta 2-blocking effect of Hoe 224 intraarterially against vasodilating effect of 0.01 microgram isoprenaline/kg given intraarterially in the A. femoralis of anaesthetized dogs was very weak. 100 micrograms Hoe 224/kg reduced the effect of isoprenaline only by 23%, but 2 micrograms propranolol/kg intraarterially reduced this effect by 61%.(ABSTRACT TRUNCATED AT 250 WORDS)

Hoe 224 (I) [65655-59-6] has β₁-blocking actions.In the isolated left atrium of the guinea pig, the ED₅₀ necessary to counteract the pos. inotropic action of 2 ng isoprenaline/mL was 10.3 mg I/mL in comparison to the ED₅₀ of 2.7 ng propranolol/mL.On the isolated right atrium of the same animal, the ED₅₀ for inhibition of increased heart rate brought about by 2 ng isoprenaline/mL was 29.5 ng I/mL in comparison to the ED₅₀ of 13.5 ng propranolol/mL.On the isolated tracheal chain of the guinea pig, 40 μg I/mL inhibited relaxation induced by 50 ng isoprenaline/mL by only 31%.The ED₅₀ for propranolol in this experiment was 1.2 ng/mL.Therefore, I is a very specific β₁-blocker.In the dog anesthetized with pentobarbital, the ED₅₀ of I for depression of the dp/dt increase by 0.1 mg isoprenaline/kg i.v. was 85 μg/kg, i.v.Under the same conditions, the ED₅₀ for propranolol was 10 μg/kg, i.v. for atenolol 17 μg/kg, i.v., and for practolol 56 μg/kg, i.v.In the conscious dog, 1.6 mg I/kg, orally, depressed the increase of dp/dt brought about by 0.1 mg isoprenaline/kg, i.v., by 50%.The β_-blocking effect of I intraarterially against the vasodilating effect of 0.01 μg isoprenaline/kg given intraarterially in the femoral artery of anesthetized dogs was very weak.A dose of 100 μg I/kg reduced the effect of isoprenaline by only 23%, but 2 μg propranolol/kg intraarterially reduced this effect by 61%.In the dog anesthetized with pentobarbital, there was an acute dose-dependent decrease in blood pressure after administration of 0.5-2 mg I/kg, i.v., which lasted for 1 h after injection.The heart rate was depressed by 40 beats/min with 0.5 mg I/kg, i.v.In spontaneously or renal hypertensive rats, an oral dose of 50 mg I/kg depressed blood pressure.The blood pressure of spontaneously hypertensive rats was also reduced by injection of 1 mg I/kg intraventricularly.