Effects of a thromboxane A2 analogue and prostacyclin on lung fluid balance in newborn lambs.

Abstract

We have previously shown that the pulmonary venoconstriction produced by a stable thromboxane A 2 analogue (STAJ is attenuated by prostacyclin (PGIi), but PGI, increases the STA 2 -induced edema. The present study was designed to determine the effects of STA 2 and PGI 2 on the fluid balance in isolated blood-perfused newborn lamb lungs. Vascular permeability was evaluated by use of the fluid filtration coefficient (Kf) and the osmotic reflection coefficient for total proteins (cr, hematocrit-protein double indicator technique), and pulmonary capillary pressure (Pc) was estimated by the double occlusion technique. All lungs had a period of hydrostatic stress induced by elevation of the left atriai pressure from 5 to 20 mm Hg to promote fluid filtration, and the rate of lung weight gain (AW/AT) during this period was determined. Studies were made in four groups; before the hydrostatic stress, lungs were given 1) STA 2 (50 /*g, n=6), 2) PGI 2 (0.4 /ig/kg/min, n = 6), 3) both PGI 2 and STA 2 (n=6), or 4) vehicles (control, n=5). Measurements of Kf were made at the baseline period and after the hydrostatic stress. T hromboxane A 2 (TxA 2 ) is a potent pulmonary vasoconstrictor that may be involved in the early phase of endotoxin-induced pulmonary hypertension and edema. This pulmonary hypertensive response has been suggested to be the result of TxA 2 -mediated pulmonary venoconstriction since the protein-poor lung lymph flow is increased in this early phase.12 By use of the arterial and venous occlusion technique in isolated newborn lamb lungs, we have recently demonstrated that a stable TxA 2 analogue, 9,11-epithioll,12-methano-TxA 2 (STA 2 ), produced pulmonary hypertension primarily by causing pulmonary Received March 27, 1989; accepted June 16, 1989. venoconstriction. 3 Although exogenous prostacyclin (PGI 2 ) attenuated this response to STA 2 by decreasing the pulmonary venoconstriction, PGI 2 administration significantly increased the STA 2 -induced pulmonary edema.3 These observations were interpreted as being consistent with an increase in microvascular permeability by PGI 2 that potentiated the STA 2 -induced pulmonary edema, despite the attenuation of the elevation of the pulmonary microvascular pressure by PGI 2 . However, the possibility that PGI 2 increased lung vascular surface area rather than permeability was not completely excluded in this study because vascular permeability was not directly evaluated.Pulmonary microvascular membrane permeability may be estimated by changes in filtration coefficient (Kf) in isolated perfused lungs. 4 However, when changes in the number of perfused microvessels occur, as with microvascular embolism, vasodilation, or vasoconstriction, Kf may not be a reliable parameter of changes in permeability because Kf depends on membrane surface area.

Prostaglandins potentiate U-46619-induced pulmonary microvascular dysfunction

“…This is clearly different from the experience reported in the present study [as well as that reported by other investigators (12,21)] in which PGI 2 alone had no effect on K f . Even in the presence of U-46619, the increase in K f associated with PGI 2 exposure was much more modest than that suggested by Yoshimura et al (38). The reason for this difference is unclear, although fundamental differences in the experimental models are likely to be important [e.g., a sanguineous perfusate was utilized in the Yoshimura study (38), whereas an asanguineous buffer was used in the present study].…”

“…Even in the presence of U-46619, the increase in K f associated with PGI 2 exposure was much more modest than that suggested by Yoshimura et al (38). The reason for this difference is unclear, although fundamental differences in the experimental models are likely to be important [e.g., a sanguineous perfusate was utilized in the Yoshimura study (38), whereas an asanguineous buffer was used in the present study]. Furthermore, the total amount of PGI 2 administered in the Yoshimura study was more than 100 times greater than that of the present study (about 300 µg over 180 min in the Yoshimura study vs. 2.6 µg in the present study).…”

“…U-46619 (7.1 ϫ 10 Ϫ8 M) was then added to perfusate, and 15 min later Ppa, Ppv, and Pc were measured, and K f and RT were calculated. 5,37,38). This concentration has been previously shown to inhibit the release of TxA 2 , PGF 2␣ , and PGI 2 in an experimental model similar to that employed in these experiments (3,5).…”

“…In the latter two reports (37,38), the investigators, utilizing an ex vivo newborn lamb lung model, found that the K f of lungs exposed to PGI 2 and a TxA 2 -receptor agonist (9,11-epithio-11,12-methanoTxA 2 ) was significantly greater than that of lungs exposed to either PGI 2 or TxA 2 -receptor activation alone. This increase in fluid filtration was accompanied by a reduction in vascular hydrostatic pressure, suggesting that, in addition to a direct effect on microvascular permeability, PGI 2 may have increased pulmonary K f by increasing vascular surface area (37,38). These results are similar to those of the present study in that the K f of lungs exposed to PGI 2 and U-46619 was nearly 70% greater than that of lungs exposed to U-46619 alone (P Ͻ 0.02).…”

“…To the authors' knowledge, there are no studies examining the effect of PGE 2 and PGF 2␣ on TxA 2 -mediated changes in pulmonary microvascular permeability and only two studies examining the effect of PGI 2 (37,38). In the latter two reports (37,38), the investigators, utilizing an ex vivo newborn lamb lung model, found that the K f of lungs exposed to PGI 2 and a TxA 2 -receptor agonist (9,11-epithio-11,12-methanoTxA 2 ) was significantly greater than that of lungs exposed to either PGI 2 or TxA 2 -receptor activation alone.…”