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Pentoxifylline has recently been reported to stimulate in vitro the synthesis of prostacyclin. However it is not known so far whether the drug is able to stimulate prostacyclin synthesis in man also in vivo. In the present study the effects of pentoxifylline on prostaglandin synthesis and several circulatory parameters were studied in 10 controls and 10 patients with occlusive arterial disease after acute i.v. and medium term oral treatment. Prostacyclin (as 6-keto-PGF1 alpha) and PGE2 plasma concentrations have been measured together with arterial blood flow, peripheral vascular resistance, platelet aggregation and red blood cell deformability. Pentoxifylline was found both in healthy subjects and patients to significantly increase prostacyclin plasma concentration after i.v. treatment. In medium term oral treatment prostacyclin concentration was found to increase only two hours after administration and not 8 hours after. No significant variations in PGE2 plasma concentration were found at any time in both groups. Pentoxifylline significantly enhanced resting and post-ischemic blood flow of the lower limbs and simultaneously decreased peripheral vascular resistance both in healthy subjects and patients. Different grades of delayed platelet aggregation and increased red blood cell deformability were also observed. In conclusion results of the present placebo controlled study show that pentoxifylline increases arterial blood flow in patients with occlusive arterial disease. Moreover pentoxifylline induces a temporary stimulation of prostacyclin synthesis which can be suggested to contribute to the clinical activity of the drug as far as an antithrombotic effect in terms of inhibition of platelet aggregation is concerned.

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To investigate the role of prostaglandins 12 and E2 in modulating the vasoconstrictor response to sympathetic stimulation, repeated and proximate cold pressor tests were performed in 23 healthy young volunteers. Limb vascular resistance (blood flow measured by venous occlusion plethysmography), prostaglandin 12 (as 6-ketoprostaglandin FJa) and prostaglandin E2 plasma levels (detected by radioimmunoassay), and plasma catecholamines (detected by highperformance liquid chromatography and electrochemical detection) were measured. A progressive increase in the duration of the vasoconstrictor response was observed with repetition of cold applications (p<0.001, by analysis of variance for trends). This increase was associated with a progressive decrease in cold-induced elevation of 6-ketoprostaglandin F,a and prostaglandin E2 plasma levels until, after five stimulations, neither prostaglandin was detectable.The maximum detected concentration of norepinephrine did not significantly change, but its area under the curve in time showed a trend toward an increase. Epinephrine levels did not significantly change. The increase of vascular resistance was significantly correlated with the decrease of both prostaglandins (r= 0.93, p<0.05 for prostaglandin E2 and r= 0.89,p<0.05 for 6-ketoprostaglandin F1j), whereas no significant correlations were found between variations of vascular resistance and catecholamines. Prostaglandin blockade induced by diclofenac sodium administration caused, from the first cold application, a pattern of the vasoconstrictor response and plasma prostaglandin and norepinephrine changes similar to that observed at the fifth cold application in untreated subjects, when prostaglandins are no longer detectable in plasma. We conclude that an increased vasoconstrictor response to sympathetic stimulation in humans may result from a diminished inhibitory influence of prostaglandins on adrenergic transmission. (Circulation Research 1990;67:580-588) In animal experiments, both exogenous catecholamines and nerve stimulation have been reported to induce prostaglandin release from different organs such as the spleen' and the kidneys2 as well as from isolated blood vessels.3-6 In tissue fragments and isolated perfused organs, prostaglandin 12 (PGI2) and prostaglandin E2 (PGE2) have been found to modulate the effects of sympathetic stim-