Effects of a Prostaglandin I₂ Analog Iloprost on Cytoplasmic Ca²⁺ Levels and Muscle Contraction in Isolated Guinea Pig Aorta

Abstract

In the isolated guinea pig aorta, the prostaglandin 12 analog iloprost (0.01-10 μM) inhibited the contractions induced by the thromboxane A₂ analog U46619 (9, 11-dideoxy-llα, 9α-epoxymethanoprostaglandin F_2α; 30 nM) and prostaglandin F_2α (PGF_2α, 1 μM) in a concentration-dependent manner. In contrast, iloprost only partially inhibited the high K⁺ (65.4 mM)-induced contraction. In the muscle stimulated with high K⁺, verapamil (0.3 and 10 μM)inhibited [Ca²⁺]_i and muscle tension in parallel, whereas iloprost (1 μM) inhibited muscle tension with only a small decrease in [Ca²⁺]_i. In the muscle stimulated with U46619 (30 nM), verapamil and iloprost decreased both [Ca²⁺]_i and muscle tension. However, as compared with the effect of verapamil, iloprost more strongly inhibited muscle tension than [Ca²⁺]_i. The iloprost (0.1—1 μM)-induced relaxation was accompanied by a concentration-dependent increase in cAMP content. It was further demonstrated that inhibition of the U46619-contractions was augmented in the presence of cycloxygenase inhibitors, such as indomethacin (10 μM), ibuprofen (10 μM) and aspirin (10 μM). In contrast, the inhibition of PGF_2α-induced contraction was not affected by indomethacin. Similarly, the inhibitory effect of forskolin on U46619-induced contractions, but not on PGF_2α-induced contraction, was enhanced by indomethacin. These results suggest that iloprost inhibits vascular smooth muscle contraction by decreasing [Ca²⁺]_i and the Ca²⁺ sensitivity of contractile elements through a cAMP-dependent mechanism. The results also suggest that in U46619-stimulated muscle, vasoactive prostaglandins that counterbalance the relaxing action of cAMP may be generated.