Summary
The ability of the human pulmonary vascular bed to synthesize prostaglandins (PGs) in response to cholinergic stimulation was investigated in healthy male volunteers. In all of them, except controls, carbaminoylcholine (CCh) was injected subcutaneously at a dose of 5 μg/kg. In 3 subjects [1-14C]-labelled arachidonate was then infused at a constant rate into the right atrium between 10 and 15 min after the administration of the drug and the blood from the subclavian artery was sampled simultaneously. The arterial content of [14C]-labelled metabolites was extracted, separated by thinlayer chromatography and quantified using liquid scintillation spectrometry. In 8 other subjects PGI2-like activity after the administration of CCh was assayed in the arterial blood and in 1 subject in the venous blood, using a technique for continuous measurement of platelet aggregation on blood-superfused collagen strip.
The major portion of [14C]-activity in the radiochromatograms migrated in parallel with the 6-keto-PGF1α standard. No early defined peaks corresponding to any of the unlabelled PGs D2, E2, or F2α , appeared, but in one chromatogram a minor radiopeak corresponding to authentic thromboxane B2 was observed. Also in the platelet aggregation experiments, 5–15 min after the administration of CCh, a significant increase in the PGI2-like activity was observed in the arterial as well as in the peripheral venous blood, which effect of the drug was abolished by pretreatment with atropine and acetylsalicylic acid.
The results demonstrate that the human pulmonary vasculature has a considerable ability to synthesize prostacyclin and that cholinergic stimulation causes a liberation of significant amounts of this prostaglandin from the lungs into the systemic circulation.
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References
Baenziger NL, Dillender MJ, Majerus PW (1977) Cultured human skin fibroblasts and arterial cells produce a labile platelet-inhibitory prostaglandin. Biochem Biophys Res Commun 78:294–301
Burch JW, Stanford N, Majerus PW (1978a) Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest 61:314–319
Burch JW, Baenziger NL, Stanford N, Majerus PW (1978b) Sensitivity of fatty acid cyclooxygenase from human aorta to acetylation by aspirin. Proc Natl Acad Sci USA 75:5181–5184
Christ-Hazelhof E, Nugteren DH (1981) Prostacyclin is not a circulating hormone. Prostaglandins 22:739–746
FitzGerald GA, Friedman LA, Miyamori I, O'Grady J, Lewis PJ (1979) A double blind placebo controlled crossover study of prostacyclin in man. Life Sci 25:665–672
FitzGerald GA, Brash AR, Falardeau P, Oates JA (1981) Estimated rate of prostacyclin secretion into the circulation of normal man. J Clin Invest 68:1272–1276
Flower RJ, Cheung HS, Cushman DW (1973) Quantitative determination of prostaglandins and malondialdehyde formed by the arachidonate oxygenase (prostaglandin synthetase) system of bovine seminal vesicle. Prostaglandins 4:325–341
Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376
Furchgott RF, Davidson D, Lin CI (1979) Conditions which determine whether muscarinic agonists contract or relax rabbit aortic rings and strips. Blood Vessels 16:213–214
Gryglewski R, Korbut R, Ocetkiewicz A (1978b) Reversal of platelet aggregation by prostacyclin. Pharmacol Res Commun 10:185–189
Gryglewski R, Korbut R, Ocetkiewicz A, Splawinski J, Wojtaszek B, Swies J (1978c) Lungs as a generator of prostacyclin-hypothesis on physiological significance. Naunyn-Schmiedeberg's Arch Pharmacol 304:45–50
Gryglewski RJ, Korbut R, Ocetkiewicz A, Stachura J (1978d) In vivo method for quantification of anti-platelet potency of drugs. Naunyn-Schmiedeberg's Arch Pharmacol 302:25–30
Hamberg M (1972) Inhibition of prostaglandin synthesis in man. Biochem Biophys Res Commun 49:720–726
Kelton JG, Hirsh J, Carter CJ, Buchanan MR (1978) Thrombogenic effect of high-dose aspirin in rabbits. Relationship to inhibition of vessel wall synthesis of prostaglandin I2-like activity. J Clin Invest 62:892–895
Koesis JJ, Hernandovich J, Silver MJ, Smith JB, Ingerman C (1973) Duration of inhibition of platelet prostaglandin formation and aggregation by ingested aspirins or indomethacin. Prostaglandins 3:141–144
Masotti G, Galanti G, Poggesi L, Abbate R, Neri Serneri GG (1979) Differential inhibition of prostacyclin production and platelet aggregation by aspirin. Lancet II:1213–1216
Mitchell MD, Brunt JD, Webb R (1981) Instability of 6-ketoprostaglandin F1α when subjected to normal extraction procedures. Prostaglandins Med 6:437–440
Moncada S, Higgs EA, Vane JR (1977) Human arterial and venous tissues generate prostacyclin (prostaglandin X) a potent inhibitor of platelet aggregation. Lancet I:18–21
Moncada S, Korbut R, Bunting S, Vane JR (1978) Prostacyclin is a circulating hormone. Nature 273:767–768
Myatt L, Jogee M, Lewis PJ, Elder MG (1981) The metabolism of prostacyclin and 6-oxo-PGF1α in man. In: Lewis PJ, O'Grady J (eds) The clinical pharmacology of prostacyclin. Raven Press, London New York, pp 30–42
Nowak J, Wennmalm A (1979) Human forearm and kidney conversion of arachidonic acid to prostaglandins. Acta Physiol Scand 106:307–312
Nowak J, Radomski M, Kaijser L, Gryglewski RJ (1981a) Conversion of exogenous arachidonic acid to prostaglandins in the pulmonary circulation in vivo. A human and animal study. Acta Physiol Scand 112:405–411
Nowak J, Bohman SO, Berlin T, Sonnenfeld T (1981b) Prostaglandin synthesis in human skeletal muscle and kidney microsomes: formation of substantial amounts of an unknown, polar compound. Acta Physiol Scand 113:557–559
Orchard MA, Robinson C (1981) Stability of prostacyclin in human plasma and whole blood: studies on the protective effect of albumin. Thromb Haemost 46:645–647
van der Ouderaa FJ, Buytenhek M, Nugteren DH, van Dorp DA (1980) Acetylation of prostaglandin endoperoxide synthetase with acetylsalicylic acid. Eur J Biochem 109:1–8
Pace-Asciak CR, Carrara MC, Levine L, Nicolaou KC (1980) PGI2-specific antibodies administered in vivo suggest against a role for endogenous PGI2 as a circulating vasodepressor hormone in the normotensive and spontaneously hypertensive rat. Prostaglandins 20:1053–1060
van Praag D, Farber SJ (1980) Prostaglandin biosynthesis in normal and ureteral obstructed rabbit kidney; Formations of a novel metabolite. In: Samuelsson B, Ramwell PW, Paoletti R (eds) Advances in prostaglandin and thromboxane research, vol 7. Raven Press, New York, pp 1181–1183
Radomski M, Swies J, Korbut R, Ocetkiewicz A, Gryglewski RJ (1980) Regulation of PGI2 release by mediators of autonomic nervous system. In: Abstracts of presentations. Seventh Congress of the Polish Pharmacological Society, p 195
Roth GJ, Stanford N, Majerus PW (1975) Acetylation of prostaglandin synthase by aspirins. Proc Natl Acad Sci USA 72:3073–3076
Roth GJ, Siok CJ (1978) Acetylation of the NH2-terminal serine of prostaglandin synthetase by aspirin. J Biol Chem 253:3782–3784
Smith JB, Ogletree ML, Lefer AL (1978) Antibodies which antagonise the effects of prostacyclin. Nature 274:64–65
Steer ML, MacIntyre DE, Levine L, Salzman EW (1980) Is prostacyclin a physiologically important circulating anti-platelet agent. Nature 283:194–195
Sun FF, Taylor BM, McGuire JC, Wong PY-K, Malik KU, McGiff JC (1979) Metabolic disposition of prostacyclin. In: Vane JR, Bergström S (eds) Prostacyclin. Raven Press, New York, pp 119–131
Szczeklik A, Gryglewski RJ, Nizankowski R, Musial J, Pieton R, Mruk J (1978) Circulatory and anti-platelet effects of intravenous prostacyclin in healthy men. Pharmacol Res Commun 10:545–556
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Brandt, R., Dembińska-Kiéc, A., Gryglewski, R.J. et al. Release of prostacyclin from the human pulmonary vascular bed in response to cholinergic stimulation. Naunyn-Schmiedeberg's Arch. Pharmacol. 325, 69–75 (1984). https://doi.org/10.1007/BF00507056
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DOI: https://doi.org/10.1007/BF00507056