Human internal mammary artery contraction by isoprostaglandin F2α type-III (8-iso-prostaglandin F2α)

Isoprostaglandin F-2 alpha type-III (formerly known as 8-iso-prostaglandin F-2 alpha) is produced in large quantities in vivo in clinical situations associated with oxidant stress such as atherosclerosis, hypercholesterolemia, and myocardial reperfusion. Isoprostaglandin F-2 alpha type-III may alter smooth muscle and platelet functions. The aim of this study was to evaluate the effects of isoprostaglandin F-2 alpha type-III on isolated human internal mammary arteries, and to characterise the signalling underlying mechanisms. in organ baths, concentration-dependent contractions of human internal mammary arteries were obtained in response to isoprostaglandin F-2 alpha type-III stimulation. The responses to isoprostaglandin F-2 alpha type-III were inhibited in a concentration-dependent manner by the thromboxane A(2) receptor antagonist, GR 32191 ([1R-[1 alpha(Z), 2 beta,3 beta,5 alpha(+)-7-[[1, 1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclo pentyl]-4-4heptanoic acid], hydrochloride), 3 X 10(-9) to 3 X 10(-7) M). However, this effect was associated with a decreased maximal contraction. AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid, 10(-6) to 3 X 10(-5) M), an EP1-DP receptor antagonist had no effect on isoprostaglandin F-2 alpha type-III-induced contractions. The maximal responses to isoprostaglandin F-2 alpha type-III were significantly reduced in the presence of the cyclooxygenase inhibitor indomethacin (10(-5) M) (E-max: 147 +/- 20% vs. 213 +/- 19% in control group, P < 0.05). Isoprostaglandin F-2 alpha type-III stimulated thromboxane B-2 release (5.7-fold increase) from human internal mammary arteries. Baicaleine, a non-specific lipoxygenase inhibitor, (10(-4) M) and AA 861 (2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4 benzoquinone), a 5-lipoxygenase inhibitor (10(-5) M) did not affect isoprostaglandin F-2 alpha type-III response. In conclusion, this study shows that (1) isoprostaglandin F-2 alpha type-III is a vasoconstrictor in human internal mammary arteries, with a potency equivalent to prostaglandin F-2 alpha, (2) the contractions induced by isoprostaglandin F-2 alpha type-III are mediated by TP receptor but not EP1-DP-receptor activation, (3) thromboxane A(2) but not cysteinyl leukotrienes production is involved in the vascular effects of isoprostaglandin F-2 alpha type-III. Isoprostaglandin F-2 alpha type-III, produced at sites of free radical generation, may play an important role in internal mammary artery spasm in situations of oxidant stress such as coronary bypass surgery. (C) 2000 Elsevier Science B.V. All rights reserved.