Cardiovascular depressant effects of N-methyl- and N-isobutyl-1,2-diphenyl ethanolamines: elucidation of the mechanisms of action.

The cardiovascular effects of N-methyl-1,2-diphenyl ethanolamine (compound M) and N-isobutyl-1,2-diphenyl ethanolamine (compound E) were examined in anaesthetized rats and their effects were compared with those of verapamil and diltiazem. Administration of compound M (10-80 mumole/kg), compound E (2-16 mumole/kg), diltiazem (1.5-24 mumole/kg) or verapamil (1.25-10 mumole/kg) induced dose-dependent decreases in arterial blood pressure and heart rate. The induced cardiovascular changes were not antagonized by chlorpheniramine, cimetidine or imidazole. Indomethacin antagonized the diltiazem-induced hypotension without any effect on that of compounds M and E. The effects of all compounds tested were antagonized by pretreatment of the rats with CaCl2 (1.2-2.4 mmole/kg). Furthermore, methylene blue significantly antagonized the compound E- and diltiazem-induced hypotension. Treatment of the animals with propranolol enhanced the compound M- and E-induced hypotension. Compounds M and E antagonized the NA-induced increase in arterial blood pressure in a competitive manner. Compounds M and E seem to exert their cardiovascular effects via interference with the influx of extracellular Ca2+. Furthermore, compound E and diltiazem may act partially via activation of guanylyl cyclase.

Antiaggregatory activity of N-methyl- and N-isobutyl-1,2-diphenyl ethanolamines in rat platelets.

The ability of N-methyl-1,2-diphenyl ethanolamine (compound M), N-isobutyl-1,2-diphenyl ethanolamine (compound E), diltiazem and verapamil to inhibit in vitro ADP-induced platelet aggregation was examined in rat platelet-rich plasma. Pretreatment of the platelets with the compounds (0.1-3 mM) for 3 min at 37 degrees C, inhibited an ADP-induced aggregation in a concentration-dependent manner. The maximum percentage inhibitions induced by compounds M, E, diltiazem and verapamil were: 95.5 +/- 6.5, 98.4 +/- 7.5, 100 and 95.9 +/- 8.3% at concentrations of 3, 0.64, 0.96 and 0.4 mM, respectively (n = 8 - 12). The inhibitory dose 50 (ID50) values for compounds M, E, diltiazem and verapamil were 1.3 +/- 0.13, 0.29 +/- 0.01, 0.44 +/- 0.03 and 0.2 +/- 0.01 mM, respectively. The antiaggregatory effects were not antagonized by methylene blue (50-200 microM), but were completely antagonized (greater than 95%) by elevation of the Ca2+ level in the platelet-rich plasma by 0.2-0.7 mM. Co-administration of (-)propranolol (17 microM) with anyone of the compounds enhanced the antiaggregatory effects. The compounds (0.1-0.2 mM) enhanced the prostacyclin (0.01 nM)-induced antiaggregatory activity. The antiaggregatory effects of the compounds are likely to be due to an inhibition of influx of Ca2+ into the platelets.