Blood-vessel wall arachidonate metabolism and its pharmacological modification in a new in vitro assay system

Abstract

Prostacyclin and thromboxane production was measured in human umbilical cord arteries bathed in clotting human blood and compared with arteries bathed in Krebs buffer or clotting blood without vessels. In comparison with the combined system, vessels in buffer generated only minute amounts of immunoreactive thromboxane B2 while blood alone generated only minute amounts of immunoreactive 6-oxo-PGF1 alpha. Incubation of vessels in blood was associated with an enhanced 6-oxo-PGF1 alpha formation at 1-2 h of incubation, demonstrating an active prostacyclin synthetase and a transfer of the platelet endoperoxide precursor to this enzyme. This new combined system was used to reevaluate the selectivity of cyclooxygenase inhibitors for vascular and platelet derived eicosanoid formation. With respect to 6-oxo-PGF1 alpha accumulation, the IC50 value [mumoles/l] for tiaprofenic acid (8.5 +/- 3.0) was significantly higher than that for diclofenac (0.14 +/- 0.03) (P less than 0.05) while acetylsalicylic acid (18.0 +/- 7.0) was less potent than diclofenac and indomethacin (2.4 +/- 1.0) (P less than 0.05). With respect to thromboxane B2 formation, the IC50 values for diclofenac (0.26 +/- 0.04), indomethacin (IC50 0.30 +/- 0.05) and tiaprofenic acid (IC50 0.71 +/- 0.08) were not significantly different from each other. Acetylsalicylic acid (7.7 +/- 1.8) was less potent than either of the other compounds (P less than 0.01). While these IC50 values might suggest different potencies for inhibition of vascular and platelet cyclooxygenases by tiaprofenic acid and, possibly, indomethacin, statistical analysis was not possible because of different slopes of the dose-response curves.(ABSTRACT TRUNCATED AT 250 WORDS)