Nitric oxide and thromboxane A(2)-mediated pulmonary microvascular dysfunction

Objectives: To examine whether the lung releases nitric oxide (NO) in respo nse to thromboxane A(2) and to examine the local release of NO as a protect ive compensatory mechanism by which the lung responds to the proinflammator y and vasoactive effects of thromboxane A(2). Design: The lungs of anesthetized Sprague-Dawley rats were perfused in vitr o with Krebs-Henseleit buffer that contained an inhibitor of NO synthase (n itroglycerine-nitro-L-arginine methyl ester [L-NAME]) (10(-4) mol/L), an NO donor (sodium nitroprusside) (10(-8) mol/L), or perfusate alone. Following equilibration, the thromboxane A(2) receptor agonist 9,11-dideoxy-11 alpha , 9 alpha-epoxymethanoprostaglandin F-2 alpha (U-46 619) (7.1 X 10(-8) mol/ L) was added to the perfusate. Fifteen minutes later, the capillary filtrat ion coefficient, pulmonary arterial pressure, and vascular resistance were measured. Pulmonary NO release was assessed by quantitating the release of cyclic guanosine monophosphate into the perfusate. Results: The capillary filtration coefficient of lungs exposed to U-46 619 was 3.5 times greater than that of lungs perfused with buffer alone (P<.05) . The addition of sodium nitroprusside reduced the increase in capillary fi ltration coefficient associated with U-46 619 by 50% (P<.05) whereas L-NAME had no effect. The addition of U-46 619 to the perfused lung caused a 3.0 +/- 0.4 mm Hg increase in pulmonary artery pressure (P<.01) with a correspo nding rise in total vascular resistance (P<.05). This effect was exacerbate d by L-NAME (P<.05) and inhibited by sodium nitroprusside (P<.05). Exposure of the isolated lungs to U-46 619 caused a 4-fold increase in cyclic guano sine monophosphate levels within the perfusate. Conclusion: These data are consistent with the hypothesis that NO release m ay be an important protective mechanism by which the lung responds to throm boxane A(2).