Hiroshi Ozaki (1), Asaki Abe (2), Yusuke Uehigashi (2), Masayoshi Kinoshita (1), Masatoshi Hori (1), Minori Mitsui-Saito (1) and Hideaki Karaki (1)
(1) Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113, Japan (2) Department of Animal Science and Technology, Faculty of Agriculture, Okayama University, Okayama 700, Japan
Abstract: In the isolated guinea pig aorta, the prostaglandin I2 analog iloprost (0.01-10 microM) inhibited the contractions induced by the thromboxane A2 analog U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethano- prostaglandin F2alpha; 30 nM) and prostaglandin F2alpha (PGF2alpha, 1 microM) 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 microM) inhibited [Ca2+]i and muscle tension in parallel, whereas iloprost (1 microM) 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 microM)-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 microM), ibuprofen (10 microM) and aspirin (10 microM). In contrast, the inhibition of PGF2alpha-induced contraction was not affected by indomethacin. Similarly, the inhibitory effect of forskolin on U46619-induced contractions, but not on PGF2alpha- 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.
Keywords:
Iloprost, Aorta (guinea pig), cAMP, Relaxation