Synergism between prostanoids and other vasoactive agents.
BACKGROUND
Prostaglandin E2 is usually considered to be a vasodilator, but some vascular beds respond with weak vasoconstriction mediated by prostanoid EP3-receptors. We have used the guinea pig isolated thoracic aorta to examine the nature of the synergism between the EP3 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 Ca2+ 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 Ca2+-activated K+ channels (BKCa), 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 (alpha1-adrenoceptor agonist), U-46619 (TP agonist), cyclopiazonic acid (sarcoplasmic Ca2+ pump inhibitor), and 4-aminopyridine (4-AP, Kv channel blocker). Nifedipine had no effect on enhancements of threshold sulprostone responses, and partially inhibited the enhancements of larger responses.


CONCLUSIONS
BKCa channel activation appears to increase progressively as sulprostone-induced contraction increases. CTX removes this "BKCa brake," thereby providing an "L-type channel" Ca2+ flux to prime the EP3-receptor-driven Ca2+-sensitization mechanism (via Rhokinase activation, unpublished observations). In contrast, the other agents, including 4-AP, direct a non-L-type channel source of Ca2+ to the calmodulin-myosin light chain arm.
Jones
Robert L
RL
Department of Pharmacology, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. rljones@cuhk.edu.hk
Shum
Winnie W C
WW
Gurney
Alison M
AM
D000818:Animals; D001013:Aorta, Thoracic; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D003196:Computer Graphics; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004357:Drug Synergism; D006168:Guinea Pigs; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D010455:Peptides; D014662:Vasoconstrictor Agents; D018999:Charybdotoxin; D010656:Phenylephrine; C016767:sulprostone; D009543:Nifedipine; D015232:Dinoprostone