Impaired Release of PGI2 in Pulmonary Hypertension: Arachidonic acid is released from cell membrane phospholipids by the action of phospholipase A2 and C. In endothelial cells and platelets, these enzymes are activated by a number of stimuli, including thrombin, epinephrine, and sheer stress.
A two-step oxygenase, eyclo-oxygenase, converts arachidonic acid to prostaglandin H2 or endoperoxide. The constitutive form of cyclo-oxygenase is expressed in both endothelial cells and platelets. The prostaglandin H2 is the substrate for PGI2 synthase, normally only found in the endothelial cell, and thromboxane synthase found in both platelets and endothelium canadian health mall. Thromboxane A2, the product of thromboxane synthase, opposes the actions of PGI2 in being a potent vasoconstrictor and inducer of platelet aggregation.
In response to conditions of increased pulmonary blood flow, such as exercise, there is evidence of increased release of PGI2 and thromboxane A2. The release of these two vasoactive compounds has been studied by measuring the concentration of their hydrolytic products 6-KETO-PGFlct (PGI2) and thromboxane B2 (thromboxane A2). These measurements avoid the vascular cannula-tion required for blood samples that can stimulate release of PGI2 and thromboxane. Exercise causes a greater rise in the release of PGI2 relative to thromboxane A2. There is indirect evidence that this is, in part, a result of “activation” of the pulmonary endothelium. Patients with fibrotic lung disease, on exercise, show a relatively greater rise in thromboxane B2 than 6-KETO-PGFlct in the urine. This effect can be reversed, ie, the relative rise in PGI2 being greater than thromboxane, if the patients inhaled a higher fractional inspired oxygen to correct their exercise-induced hypoxemia.
At the cellular level, hypoxia is known to reduce the release of PGI2 from endothelial cell cultures. Indeed, the responsiveness of vascular smooth muscle to PGI2 falls with hypoxia and can be construed as evidence that hypoxia mirrors the effect of thromboxane A2 in endothelial cell cultures. Whether this association reflects part of the hypoxia sensing system remains to be elucidated.