E. W. Spannhake

Bronchoactive metabolites of arachidonic acid and their role in airway function

Abstract The purpose of this brief review is to summarize some of the information currently available regarding the potential involvement of prostanoids and leukotrienes in bronchopulmonary function. A considerable amount of work in this area has been completed in recent years, in some cases confirming earlier concepts and in other cases, providing new interpretations and insights. Earlier reviews of the actions of prostaglandins in the lung include those of Rosenthale, et al. (1), Smith (2), Puglisi and Maggi (3) and Hedqvist and Mathe (4).

Metabolism of prostaglandin endoperoxide by microsomes from cat lung.

It has been reported that the prostaglandin (PG) precursor, arachidonic acid, produces divergent hemodynamic responses in the feline pulmonary vascular bed. However, the pattern of arachidonic acid products formed in the lung of this species is unknown. In order to determine the type and activity of terminal enzymes in the lung, prostaglandin biosynthesis by microsomes from cat lung was studied using the prostaglandin endoperoxide, PGH2, as a substrate. The major products of incubations of PGH2 with microsomes were thromboxane (TX) B2 (the major metabolite of TXA2), 6-keto-PGF1 alpha (the breakdown product of PGI2) and 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT). Formation of TXB2 was markedly reduced by imidazole. Tranylcypromine decreased the formation of TXB2 and HHT and inhibited the formation of 6-keto-PGF1 alpha. At low PGH2 concentrations, equal production of TXB2 and 6-keto-PGF1 alpha was observed. However, as PGH2 concentration increased, 6-keto-PGF1 alpha production approached early saturation while TXB2 production increased in a linear fashion. These results suggest that enzymatic formation of TXA2 and PGI2 is a function of substrate availability in the lung. These findings provide a possible explanation for the divergent hemodynamic responses to arachidonic acid infusions at high and low concentrations in the feline pulmonary vascular bed.

6-keto-PGE1 exhibits more potent bronchodilatory activity in the cat than its precursor, PGI2.

In anesthetized, vagotomized an mechanically ventilated cats, we investigated the bronchodilatory activity of the PGI2 metabolite, 6-keto-PGE1, relative to PGI2 and PGE2. In a range of doses from 0.3-10.0 microgram, i.v. injection of 6-keto-PGE1 produced a dose-related decrease in central airway resistance (RL) in animals bronchoconstricted by 5-HT. This effect on RL was 3-10 times greater than that produced by i.v. PGI2. At the lower doses, 6-keto-PGE1 was also more potent than PGI2 in increasing dynamic lung compliance; their effects upon semi-static compliance were not significantly different. Comparison of the bronchopulmonary effects of the two prostanoids did not show any consistent difference in their temporal patterns. In contrast to PGI2 or PGE2, 6-keto-PGE1 had minimal pulmonary vasomotor activity. Inhibition of the cyclooxygenase pathway with sodium meclofenamate had no effect on the bronchopulmonary actions of 6-keto-PGE1 or on its duration of action. These data indicate that 6-keto-PGE1 is a more potent bronchodilator than PGI2 in the cat. They further suggest that conversion of PGI2 to 6-keto-PGE1, if it occurs to an appreciable extent in the lung in vivo, could enhance bronchodilatory activity.

Cyclooxygenase mediated airway response to leukotriene D4 in the cat

The effects of leukotriene D4 (LTD4) on pulmonary mechanics were investigated in anesthetized, paralyzed cats under conditions of controlled ventilation. Intravenous injections of LTD4 in doses of 3, 10, and 30 micrograms caused significant increases in transpulmonary pressure (PTP) and lung resistance (RL) while decreasing dynamic compliance (Cdyn). LTD4 also increased systemic arterial pressure (PAo). The changes in PTP, RL, and Cdyn in response to LTD4 were blocked by sodium meclofenamate, a cyclooxygenase inhibitor. However, there was no significant change in the increase in PAo following cyclooxygenase blockade. U 46619, a thromboxane mimic, was 30 to 100 times more potent than LTD4 in increasing PTP, RL and decreasing Cdyn in the cat. These data show that LTD4 has significant smooth muscle constrictor activity in central airways as well as peripheral portions of the feline lung. In addition, these data suggest that in the cat the actions of intravenously administered LTD4 on lung mechanics are mediated by release of cyclooxygenase products while the systemic pressor effects are not dependent upon the integrity of the cyclooxygenase pathway.

Partial Inhibition of Hypoxia-lnduced Erythropoietin Production by Cholinergic Blockade in the Dog

Summary Anesthetized dogs exposed to hypoxic hypoxia showed elevated plasma erythropoietic activity by 6 hr. This activity was significantly decreased by atropine pre-treatment. Methylatropine, a peripheral-acting analog of atropine, was equally effective in reducing the erythropoietic response. Neither atropine nor methylatropine, at the doses employed, appeared to exert their effect through blockade at the autonomic ganglia. These studies suggest that the erythropoietic response to short-term hypoxia in the dog involves a peripheral, cholinergic-ally mediated event, perhaps within the kidney itself. We are very grateful to Mr. Rene Stiaes and Mr. Jesse Brookins for their excellent technical assistance.

In vivo metabolism of dihomo-γ-linolenic acid to bronchoactive products in the canine lung

Abstract We investigated the effects of dihomo-γ-linolenic acid (DGLA), the fatty acid precursor to the monoenoic prostaglandins, on pulmonary mechanics in the intact chest, artificially ventilated dog. Under conditions of normal airway tone, intravenously administered DGLA produced a modest, dose-related increase in lung resistance and decrease in dynamic lung compliance. These responses were approximately 30–100 times less than those produced by arachidonic acid. The bronchoconstrictive responses to DGLA were abolished by prior inhibition of the cyclooxygenase with indomethacin. PGD1 was equal in activity to PGF1α in causing constriction of central and peripheral airways of the dog. PGE1 was without significant airway effects in these animals under conditions of resting airway tone. We conclude that DGLA is a moderately good substrate for the cyclooxygenase pathway enzymes of the canine lung, producing products having a predominantly bronchoconstrictive effect. This bronchoconstriction is most likely due to the synthesis of PGD1 and PGF1α and is not due to the synthesis of lipoxygenase pathway products.