Human internal mammary artery contraction by isoprostaglandin F-2 alpha type-III (8-iso-prostaglandin F-2 alpha)

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 a ssociated 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 evaluat e the effects of isoprostaglandin F-2 alpha type-III on isolated human inte rnal mammary arteries, and to characterise the signalling underlying mechan isms. in organ baths, concentration-dependent contractions of human interna l 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, th is effect was associated with a decreased maximal contraction. AH 6809 (6-i sopropoxy-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 i nhibitor indomethacin (10(-5) M) (E-max: 147 +/- 20% vs. 213 +/- 19% in con trol group, P < 0.05). Isoprostaglandin F-2 alpha type-III stimulated throm boxane 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-li poxygenase inhibitor (10(-5) M) did not affect isoprostaglandin F-2 alpha t ype-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 contraction s induced by isoprostaglandin F-2 alpha type-III are mediated by TP recepto r but not EP1-DP-receptor activation, (3) thromboxane A(2) but not cysteiny l leukotrienes production is involved in the vascular effects of isoprostag landin 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 m ammary artery spasm in situations of oxidant stress such as coronary bypass surgery. (C) 2000 Elsevier Science B.V. All rights reserved.