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Isoprostanes are a family of prostaglandin-related compounds formed from arachidonic acid in a cyclooxygenase-independent manner as products of free radical-initiated lipid peroxidation. To elucidate the biological activity of the F2-and E2-isoprostanes, 8-iso-prostaglandin F2α (8-iso-PGF2α) and 8-iso-prostaglandin E2 (8-iso-PGE2), we measured hemodynamic effects in isolated perfused guinea pig hearts after cumulative administration (3 × 10−9-10−5M) of these compounds into the coronary system. Coronary flow (CF), left ventricular pressure (LVP), maximal rate of pressure development (dP/dtmax), and heart rate were determined continuously. Furthermore, net release of lactate into the coronary venous effluent and myocardial pyruvate consumption were measured. Comparative studies were performed with the known potent vasoconstrictor endothelin-1 (6 × 10−12-2 × 10−9M). Both 8-iso-PGF2α and 8-iso-PGE2 induced concentration-dependent decreases in CF, which declined maximally to ∼50% of the baseline level. The potencies of the two compounds were almost identical. Alterations in CF were associated in both groups with parallel reductions of LVP and dP/dtmax; heart rate was not influenced. Furthermore, the diminished CF caused enhanced lactate release and a reduced pyruvate consumption. All isoprostane-induced hemodynamic changes were prevented by coapplication of the thromboxane A2-receptor antagonist SQ 29548 (1 μM). Endothelin-1 caused CF reductions associated with loss of myocardial contractility, just like the isoprostanes. We conclude that in isolated guinea pig hearts, 8-iso-PGF2α and 8-iso-PGE2 are potent vasoconstrictors. The action appears to be mediated by SQ 29548-responsive thromboxane receptors. The accompanying loss of contractility is a secondary phenomenon, elicited by infringed oxygen supply.