Effects of A23187, exogenous phospholipase A2 and exogenous arachidonic acid on pulmonary vascular resistance in isolated rabbit lung.

The authors gave infusions of exogenous arachidonic acid (AA), exogenous phospholipase A2 (PLA2) or A23187 into the pulmonary circulation of isolated salt-perfused rabbit lungs. Exogenous PLA2 and A23187 are agents that release the AA that is usually in the lung (i.e., endogenous pulmonary AA). The exogenous AA or A23187 led to pulmonary cyclooxygenase enzyme conversion of exogenous and endogenous AA to thromboxane A2 (TXA2), as TXB2, and prostacyclin, as 6-keto-prostaglandin-F1 alpha, as well as to elevations in pulmonary vascular resistance (PVR). The elevations in PVR as well as the elevations in TXB2 and 6-keto-prostaglandin-F1 alpha were prevented by indomethacin, a cyclooxygenase enzyme inhibitor, and the elevations in TXB2 and PVR but not the elevations in 6-keto-prostaglandin-F1 alpha were prevented by 1-benzylimidazole, a selective inhibitor of thromboxane synthesis. Maximum elevations in PVR occurred from conversion of AA to less than maximum levels of TXA2. Exogenous PLA2 led to release of endogenous AA with conversion to prostacyclin. However, such release of endogenous AA by exogenous PLA2 did not lead to conversion to TXA2 or to elevations in PVR. The authors conclude that elevations in PVR that depend on conversion of AA to TXA2 are limited by factors other than the amount of TXA2 or the amount of AA that is potentially available for such conversion.(ABSTRACT TRUNCATED AT 250 WORDS)

cAMP levels from endogenous and exogenous arachidonic acid in isolated dog lung.

We infused exogenous arachidonic acid (AA) into salt-perfused isolated dog lungs. This led to elevations in adenosine 3',5'-cyclic monophosphate (cAMP) which were from conversion of the AA to cyclooxygenase products. The maximal levels of cAMP occurred at far less than maximal levels of cyclooxygenase products. Next, we infused A 23187 to release endogenous pulmonary AA. This led to elevations in cAMP that were from conversion of this endogenous AA to cyclooxygenase products. The level of these products was far less than maximal levels from exogenous AA. However, maximal levels of cAMP from conversion of endogenous AA were similar to maximal levels of cAMP from conversion of exogenous AA. We conclude that maximal levels of pulmonary cAMP from endogenous or exogenous AA are from conversion of the AA to far less than maximal levels of pulmonary cyclooxygenase products. This indicates that levels of cAMP rather than levels of cyclooxygenase products are a potential rate-limiting step in cAMP-linked pulmonary actions of such products from pulmonary conversion of endogenous or exogenous AA.

Distribution of cyclooxygenase products with cyclooxygenase inhibition in isolated dog lung.

Arachidonic acid metabolism can lead to synthesis of cyclooxygenase products in the lung as indicated by measurement of such products in the perfusate of isolated lungs perfused with a salt solution. However, a reduction in levels of cyclooxygenase products in the perfusate may not accurately reflect the inhibition of levels of such products as measured in lung parenchyma. We infused sodium arachidonate into the pulmonary circulation of isolated dog lungs perfused with a salt solution and measured parenchymal, as well as perfusate, levels of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), prostaglandin F2 alpha (PGF2 alpha), prostaglandin E2 (PGE2), and thromboxane B2 (TxB2). These studies were repeated with indomethacin (a cyclooxygenase enzyme inhibitor) in the perfusate. We found that indomethacin leads to a marked reduction in perfusate levels of PGF2 alpha, PGE2, 6-keto-PGF1 alpha, and TxB2, as well as a marked reduction in parenchymal levels of 6-keto-PGF1 alpha and TxB2 when parenchymal levels of PGF2 alpha and PGE2 are not reduced. We conclude that, with some cyclooxygenase products, a reduction in levels of these products in the perfusate of isolated lungs may not indicate inhibition of levels of these products in the lung parenchyma and that a reduction in one parenchymal product may not predict the reduction of other parenchymal products. It can be speculated that some of the physiological actions of indomethacin in isolated lungs may result from incomplete or selective inhibition of synthesis of pulmonary cyclooxygenase products.

Effect of oral administration of arachidonic acid on prostaglandin and zinc metabolism in plasma and small intestine of the rat.

The effect of different doses of arachidonic acid (AA) on the intestinal zinc transport rate and on the plasma and intestinal PGE2, PGF2 alpha and 6-keto-PGF1 alpha levels in rats were measured to determine whether the metabolism of AA is involved in the zinc transport mechanism. Twenty-four rats were divided into 4 groups of 6 rats. Each rat received either 1.0 ml of distilled water, 0.5 mg, 1.0 mg or 1.5 mg/ml of AA intraduodenally at 24 and 4 hours before sacrifice. One hour before sacrifice, each rat also received 10 micrograms of 65Zn intraduodenally. The zinc transport rate decreased in comparison to controls when 0.5 mg of AA was given to the rats, but increased when 1.0 mg or 1.5 mg of AA was given. The levels of PGE2, PGF2 alpha and 6-keto-PGF1 alpha (PGI2 metabolite) in the intestinal mucosa all decreased in proportion to the amount of AA given. However, in the plasma, only PGF2 alpha levels decreased while PGE2 and 6-keto-PGF1 alpha levels showed no change compared to controls. When rats were given 1.5 mg of AA without oral administration of 65Zn, plasma PGE2 levels increased while PGF2 alpha levels decreased. The results suggest that AA metabolism influences the zinc transport mechanism by modulating the relative levels of PGE2, PGF2 alpha and PGI2 in plasma and small intestine.

Inhibition of cyclooxygenase production does not prevent arachidonate from increasing extravascular lung water and albumin in an isolated dog lung.

We examined the hypothesis that arachidonic acid can lead to pulmonary edema, increased pulmonary vascular permeability, and increased pulmonary vascular resistance (PVR) in an isolated dog lung. The lung was perfused with a dextran-salt solution to remove blood elements. Compared to controls, 20 mg/min sodium arachidonate into the pulmonary circulation led to edema and to an increase in a permeability and surface area index (PSI%), PVR, and cyclooxygenase (i.e. prostaglandin) production as measured by 6-keto-PGF1 alpha, TXB2 and PGF2 alpha. With 20 mg/min arachidonate, indomethacin inhibited the increase in cyclooxygenase production, reduced the increase in PVR and increased the edema and PSI%. Indomethacin, alone, did not produce edema or an increase in PSI% or PVR. Lower doses of arachidonate (0.1 to 5 mg/min) led to increasing cyclooxygenase production without obvious edema or an increase in PSI% or PVR. We conclude: 1) arachidonate can lead to pulmonary edema and an increase in PVR, and may lead to an increase in pulmonary vascular permeability; these effects of arachidonate do not require normal numbers of circulating blood elements; 2) arachidonate appears to contribute to pulmonary edema and increased PSI% by a noncyclooxygenase effect since inhibition of cyclooxygenase production did not prevent, and lower doses of cyclooxygenase production did not produce edema or an increase in PSI%; 3) the increase in PVR appeared to have a cyclooxygenase component since inhibition of cyclooxygenase production reduced the increase, and 4) indomethacin can increase the magnitude of edema and PSI% from arachidonate by an undefined mechanism.

The effects of arachidonic acid, PGI2, and 6-keto-PGF1 alpha on cyclic nucleotide concentrations in a ventilated and artificially perfused isolated dog lung.

In 35 isolated dog lung preparations, the pulmonary circulation of the right lung was completely separated from that of the left so that 1 lung of each preparation could serve as a control. The lungs were ventilated with 14% O2, 6% CO2 and 80% N2 and the pulmonary circulations were perfused with a dextran-salt-bicarbonate solution containing theophylline. Samples of perfusate were assayed for cyclic AMP and cyclic GMP (radioimmunoassay). Infusions of arachidonic acid (n=6) and PGI2 (n=4) but not 6-keto-PGF1 alpha (n=3) into the pulmonary circulation led to increases in cyclic AMP compared to control. Cyclic GMP levels were unchanged by the various infusions. Indomethacin (n=4) and acetylsalicylic acid (n=4) (prostaglandin (PG) synthesis inhibitors), and tranylcypromine (n=4) (a PGI2 synthetase inhibitor), prevented the cyclic AMP increases from arachidonic acid. This prevention was not the result of interference with the ability of cells to produce or release cyclic AMP since indomethacin (n=3), acetylsalicylic acid (n=3), and tranylcypromine (n=4) did not prevent cyclic AMP increases from PGI2. We conclude that infusion of arachidonic acid into the canine lung elevated pulmonary cyclic AMP but not cyclic GMP; that part or all of this increase most likely resulted from conversion of arachidonic acid to products of PG synthesis, particularly PGI2; that infusion of PGI2 mimicked arachidonic acid in that pulmonary cyclic AMP but not cyclic GMP was elevated, and that 6-keto-PGF1 alpha, a metabolite of PGI2, is unlikely to account for the cyclic AMP increases in this study.