Antagonism of the pulmonary vasoconstrictor response to prostaglandin F2alpha by N-dimethylamino substitution of prostaglandin F2alpha

Abstract

Efforts to develop an in vivo prostaglandin (PG) antagonist have met with limited success. In this study, N-dimethylamino analogs of PGF2alpha which have proven to be effective in vitro prostaglandin antagonists, were tested for antagonism to the PGF2alpha and arachidonic acid (AA) responses in the canine lung lobe preparation. PGF2alpha (1 microgram/kg) and AA (100 microgram/kg) increased lobar arterial pressure by 54 and 83%, respectively. Infusion of analogs did not change lobar arterial pressure. N-dimethylamine PGF2alpha (0.8-3.2 microgram/ml) antagonized the PGF2alpha response by 66 to 79%. N-dimethylamide PGF2alpha (1.6-8.0 microgram/ml) produced a dose-dependent antagonism (24-75%) with an IC50 value of 3.8 microgram/ml. Neither analog significantly attenuated the pulmonary response to AA. Thus, these N-dimethylamino analogs of PGF2alpha exhibit a potency which is superior to previous in vivo prostaglandin antagonists. In addition, they have effectively differentiated the pulmonary vascular responses of AA and PGF2alpha.