Mechanisms of Vasoconstriction Induced by 9,ll-Epithio-ll,12-methano-thromboxane A2 in the Rabbit Coronary Artery

The vasoconstrictor effects of 9,ll-epithio-ll,12-methano-thromboxane A2 (STA2) on smooth muscle strips of the rabbit coronary artery have been investigated in vitro. Right coronary artery (RCA) was more responsive to STA2 than either the left anterior descending or the circumflex coronary artery. On endothelium-denuded RCA strips, the sensitivity and responsiveness to STA2 were greater than observed on intact muscle strips. A thromboxane(Tx)-antagonist, (9,11), (ll,12)-dideoxa-9a, lla-dimethylmethano-ll,12-methano-13,14-dihydro-13-aza-14-oxo-15-cyclopenthyl-16,17,18,19,20pethanoI-15-epi-TxA 2 (ONO-3708), inhibited the STA2-induced contraction, whereas atropine or prazosin had no effect. Nifedipine partly inhibited the STA2-induced contraction, one half of which was still evoked in Ca-free solution. When acetylcholine was applied prior to the application of STA2 in Ca-free solution, the STA2-vasoconstriction disappeared. In saponin-treated chemically skinned muscle strips, STA2 itself had no effect on either the pCa-tension relation or on the release of Ca 2+ from intracellular stores. However, inositol 1,4,5-trisphosphate released Ca from such stores, and 12-o-tetradecanoyl phorbol-13-acetate (TPA) and 1,2-diolein, activators of protein kinase C, enhanced the contraction induced by 0.3 fiM Ca. It is concluded that STA2 acts on the TxA2 receptor and produces contraction due to an increase in both voltageand agonist(receptor)-dependent Ca influx. STA2 also releases Ca 2+ from AChand caffeine-sensitive storage sites. (Circulation Research 1987;60:402-409)