Nitric Oxide and Thromboxane A2–Mediated Pulmonary Microvascular Dysfunction

Abstract

To examine whether the lung releases nitric oxide (NO) in response to thromboxane A 2 and to examine the local release of NO as a protective compensatory mechanism by which the lung responds to the proinflammatory and vasoactive effects of thromboxane A 2. Design: The lungs of anesthetized Sprague-Dawley rats were perfused in vitro with Krebs-Henseleit buffer that contained an inhibitor of NO synthase (nitroglycerinenitro-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␣, 9␣-epoxymethanoprostaglandin F 2␣ (U-46 619) (7.1 ϫ 10 −8 mol/L) was added to the perfusate. Fifteen minutes later, the capillary filtration 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 (PϽ.05). The addition of sodium nitroprusside reduced the increase in capillary filtration coefficient associated with U-46 619 by 50% (PϽ.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 (PϽ.01) with a corresponding rise in total vascular resistance (PϽ.05). This effect was exacerbated by L-NAME (PϽ.05) and inhibited by sodium nitroprusside (PϽ.05). Exposure of the isolated lungs to U-46 619 caused a 4-fold increase in cyclic guanosine monophosphate levels within the perfusate. Conclusion: These data are consistent with the hypothesis that NO release may be an important protective mechanism by which the lung responds to thromboxane A 2 .

PKC-Dependent Phosphorylation of eNOS at T495 Regulates eNOS Coupling and Endothelial Barrier Function in Response to G+ -Toxins

“…The consensus view is that eNOS-derived NO and exogenous NO protects against increased endothelial permeability in response to a number of agents including thrombin [34], hyperoxia [36], oxidants [37], PMA [38] and TxA2 [39] and also has an important role in maintaining barrier function under basal conditions [10]. In contrast, reactive oxygen species have been shown to promote disruption of the endothelial barrier [40]-[42].…”

Homologous desensitization of signalling by the alpha (α) isoform of the human thromboxane A2 receptor: A specific role for nitric oxide signalling

“…Moreover, increased NO synthesis and release is known to occur in response to TXA 2 in other cell/tissue types, such as within the pulmonary microvasculature where the local release of NO acts as a compensatory mechanism in response to the proinflammatory and vasoactive effects of TXA 2 [79]. NO regulation and synthesis via activation of the Ca 2+ dependent eNOS or nNOS isozymes can occur in response to a diverse array of agonists that signal through GPCRs, including the widely documented bradykinin and muscarinic acetylcholine receptors signalling pathways, in addition to TP [70,80].…”

Role of Thromboxane in Producing Hepatic Injury During Hepatic Stress

“…In addition to vasoconstrictors, TXA 2 also causes "cross talk" with the vasodilators. 98 Up-regulation of inducible NO synthase (iNOS) and release of its product NO by Kupffer cells in the liver is markedly enhanced by LPS administration. 99 Although the production of TXB 2 is also induced by LPS, this effect is partly attenuated by NO.…”