Synergism Between Prostanoids and Other Vasoactive Agents

A bstract   Background : Prostaglandin E 2 is usually considered to be a vasodilator, but some vascular beds respond with weak vasoconstriction mediated by prostanoid EP 3 ‐receptors. We have used the guinea pig isolated thoracic aorta to examine the nature of the synergism between the EP 3 agonist sulprostone and other vasoactive agents. Methods : Muscle tension was recorded from endothelium‐denuded rings of aorta suspended in conventional organ baths. Indomethacin and the TP‐receptor antagonist GR 32191 were usually present. Results : Sulprostone (0.1–300 nM) showed two profiles: low‐responder preparations (maximum response = 15–35% of 100 nM U‐46619 response) were insensitive to the L‐type Ca 2+ blocker nifedipine, whereas high‐responders (maximum = 35–70%) showed a nifedipine‐sensitive component at higher sulprostone concentrations only. Charybdotoxin (CTX), a blocker of large‐conductance Ca 2+ ‐activated K + channels (BK Ca ), slightly enhanced threshold sulprostone responses and markedly enhanced larger responses; the enhancements were abolished by nifedipine. In contrast, threshold sulprostone responses were dramatically enhanced in the presence of established small contractions to phenylephrine (α 1 ‐adrenoceptor agonist), U‐46619 (TP agonist), cyclopiazonic acid (sarcoplasmic Ca 2+ pump inhibitor), and 4‐aminopyridine (4‐AP, K v channel blocker). Nifedipine had no effect on enhancements of threshold sulprostone responses, and partially inhibited the enhancements of larger responses. Conclusions : BK Ca channel activation appears to increase progressively as sulprostone‐induced contraction increases. CTX removes this “BK Ca brake,” thereby providing an “L‐type channel” Ca 2+ flux to prime the EP 3 ‐receptor‐driven Ca 2+ ‐sensitization mechanism (via Rhokinase activation, unpublished observations). In contrast, the other agents, including 4‐AP, direct a non‐L‐type channel source of Ca 2+ to the calmodulin‐myosin light chain arm.