HEMODYNAMIC-EFFECTS OF ISOPROSTANES (8-ISO-PROSTAGLANDIN F2-ALPHA ANDE-2) IN ISOLATED GUINEA-PIG HEARTS

Isoprostanes are a family of prostaglandin-related compounds formed fr om arachidonic acid in a cyclooxygenase-independent manner as products of free radical-initiated lipid peroxidation. To elucidate the biolog ical activity of the F-2-and E-2-isoprostanes, 8-iso-prostaglandin F-2 alpha (8-iso-PGF(2 alpha)) and 8-iso-prostaglandin E-2 (8-iso-PGE(2)) . We measured hemodynamic effects in isolated perfused guinea pig hear ts after cumulative administration (3 x 10(-9)-10(-5) M) of these comp ounds into the coronary system. Coronary flow (CF), left ventricular p ressure (LVP), maximal rate of pressure development (dP/dt(max)), and heart rate were determined continuously. Furthermore, net release of l actate into the coronary venous effluent and myocardial pyruvate consu mption were measured. Comparative studies were performed with the know n potent vasoconstrictor endothelin-1 (6 x 10(-12)-2 x 10(-9) M). Both 8-iso-PGF(2 alpha) and 8-iso-PGE(2) induced concentration-dependent d ecreases in CF, which declined maximally to similar to 50% of the base line level. The potencies of the two compounds were almost identical. Alterations in CF were associated in both groups with parallel reducti ons of LVP and dP/dt(max); heart rate was not influenced. Furthermore, the diminished CF caused enhanced lactate release and a reduced pyruv ate consumption. All isoprostane-induced hemodynamic changes were prev ented by coapplication of the thromboxane A(2)-receptor antagonist SQ 29548 (1 mu M). 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-PGF(2 alpha) and 8-iso-PGE(2 ) are potent vasoconstrictors. The action appears to be mediated by SQ 29548-responsive thromboxane receptors. The accompanying loss of cont ractility is a secondary phenomenon, elicited by infringed oxygen supp ly.