Unusual pulmonary vasodilator activity of 13,14-dehydroprostacyclin methyl ester: comparison with endoperoxides and other prostanoids.

Abstract

Medical SciencesUnusual pulmonary vasodilator activity of 13,14-dehydroprostacyclin methyl ester: Comparison with endoperoxides and other prostanoids ( Contributed by Josef Fried, September 12,1977 ABSTRACT Microsomes from stomach fundus and blood vessels transform the endoperoxide, PGH2, into a newly discovered unstable substance, PGI2, that relaxes arterial stri4s and inhibits platelet aggregation. 13,14-Dehydro-PGI2 methyl ester, a newly synthesized, stable PGI2 analog, was found to have potent vasodilator activity in the feline and simian pulmonary vascular bed. The PGI2 analog decreased lobar arterial perfusion pressure in the intact cat and monkey. Because pulmonary blood flow was held constant and left atrial pressure was unchanged, the decrease in perfusion pressure reflects a decrease in pulmonary vascular resistance. The dilator response was unusual in that it persisted for 10-12 min, whereas the response to PGEI, the only other vasodilator prostaglandin in the mature animal, persisted for only 1-2 min. The dilator response to the PGI2 analog was enhanced when pulmonary vascular resistance was increased. This substance had less effect on cardiac output and aortic pressure than PGEI, whereas it was a more potent pulmonary vasodilator. These data demonstrate that prostacyclin-like substances possess novel vasodilator activity in the pulmonary circulation and suggest a therapeutic use in the treatment of pulmonary hypertensive diseases.

Prostaglandins Evoke a Whole Variety of Responses in the Lung

“…The pulmonary vasodilator effects of PGI2 were modest under resting conditions but were greatly enhanced when pulmonary vascular resistance was increased actively by infusion of a vasoconstrictor substance (23). Although PGI2 had vasodilator activity, arachidonic acid when administered as a bolus, consistently increased pulmonary vascular resistance in the intact dog and cat and in the isolated dog lung (10,12,13,21,22). These results suggest that under physiologic conditions in the intact state, the predominant products formed in the lungs when arachidonate is injected as a bolus are vasoconstrictor in nature.…”

“…Inasmuch as pulmo- (10,(12)(13)(14)(15)(16)(17)22). Arachidonic acid also increased transpulmonary pressure when the lung was ventilated at constant volume with a positive pressure ventilator (12).…”

“…The distribution and activity of terminal enzymes determine the pattern of products formed from endoperoxide intermediates in an organ (9)(10)(11). Many reports indicate that the endoperoxide intermediate, endoperoxide analogs, PGE2, PGF2a, and PGD2 all increase pulmonary vascular resistance in a variety of species (10,(12)(13)(14)(15)(16)(17). In contrast, PGE2 has dilator activity in the pulmonary circulation of fetal and neonatal animals (18).…”

“…The endoperoxide intermediates (PGG2 and PGH2) are then converted by terminal enzymes into primary prostaglandins (PG), thromboxane A2 (TXA2) or prostacyclin, PG12 (2)(3)(4)(5)(6)(7)(8)(9). The distribution and activity of terminal enzymes determine the pattern of products formed from endoperoxide intermediates in an organ (9)(10)(11). Many reports indicate that the endoperoxide intermediate, endoperoxide analogs, PGE2, PGF2a, and PGD2 all increase pulmonary vascular resistance in a variety of species (10,(12)(13)(14)(15)(16)(17).…”

“…Arachidonic acid has been shown to increase pulmonary vascular resistance in a number of species when injected as a bolus and to contract isolated segments of pulmonary artery (10,12,13,(20)(21)(22). These responses are blocked by indomethacin suggesting that in the lung arachidonate, when administered as a bolus is converted to substances that have pulmonary vasoconstrictor and bronchoconstrictor activity (10,12,13,21,22). It has, however, recently been reported that arachidonic acid has depressor activity in the pulmonary circulation when the prostaglandin precursor is infused (12).…”