Increased Prostacyclin Biosynthesis in Patients with Severe Atherosclerosis and Platelet Activation

• Published in: The New England journal of medicine Vol. 310; no. 17; pp. 1065 - 1068
• Main Authors: FitzGerald, Garret A, Smith, Bruce, Pedersen, Anders K, Brash, Alan R
• Format: Journal Article
• Language: English
• Published: Boston, MA Massachusetts Medical Society 26.04.1984
• Subjects: 6-Ketoprostaglandin F1 alpha - analogs & derivatives; 6-Ketoprostaglandin F1 alpha - urine; Adolescent; Adult; Aged; Arteriosclerosis; Arteriosclerosis - blood; Arteriosclerosis - metabolism; Arteriosclerosis - urine; Atherosclerosis; Atherosclerosis (general aspects, experimental research); beta-Thromboglobulin - analysis; Biological and medical sciences; Biosynthesis; Blood and lymphatic vessels; Blood platelets; Blood Platelets - physiology; Cardiology. Vascular system; Chromatography; Coronary vessels; Creatinine; Endothelium; Epoprostenol - biosynthesis; Excretion; Humans; Male; Mass spectrometry; Medical sciences; Metabolites; Middle Aged; Platelet Aggregation; Platelets; Pregnancy; Prostacyclin; Scientific imaging; Urine; Biosynthesis; Prostaglandin I2; Atherosclerosis; Platelet function
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJM198404263101701

Prostacyclin is a potent vasodilator and platelet inhibitor produced by vascular endothelium. Endogenous production of prostacyclin under physiologic conditions is extremely low, far below the capacity of vascular tissue to generate this substance in response to stimulation in vitro. This may reflect a low frequency or intensity of stimulation of prostacyclin production. We postulated that if prostacyclin does act as an endogenous platelet-inhibitory agent, it should be produced in greater amounts in a clinical setting in which platelet–vascular interactions are likely to be increased. To test this hypothesis, we examined prostacyclin biosynthesis in patients with severe atherosclerosis and evidence of platelet activation in vivo. Excretion of 2,3-dinor-6-keto-prostaglandin F 1α , a major urinary prostacyclin metabolite, was significantly higher in 9 patients with severe atherosclerosis and evidence of platelet activation (251 to 1859 pg per milligram of creatinine) than in 54 healthy volunteers (45 to 219 pg per milligram of creatinine; P<0.001). This difference represented an alteration in biosynthesis rather than in metabolism, since the fractional conversion of infused prostacyclin to the dinor metabolite was identical in both groups. Prostacyclin production may be low in healthy persons because there is almost no stimulus for its production but enhanced in patients with severe atherosclerosis as a consequence of platelet interactions with endothelium or other vascular insults. These observations are compatible with a role for prostacyclin as a local regulator of platelet–vascular interactions. (N Engl J Med 1984; 310:1065–8.) PROSTACYCLIN is a vasodilator compound that potently inhibits platelet function and is the principal metabolite of arachidonic acid formed by vascular endothelial cells. 1 , 2 Attempts to measure prostacyclin biosynthesis in vivo have focused on metabolites because of the evanescent nature of the parent compound. A major urinary metabolite of systemically administered prostacyclin in human beings is 2,3-dinor-6-keto-prostaglandin F 1α (PGI-M), 3 and measurement of this metabolite by gas chromatography–mass spectrometry is a sensitive and specific approach to the noninvasive assessment of endogenous prostacyclin biosynthesis. 4 Despite the potent actions of prostacyclin in vitro, we have previously demonstrated that in human beings the rate . . .