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Synergism between prostanoids and other vasoactive agents.
Robert L Jones1, Winnie W C Shum, Alison M Gurney
1Department of Pharmacology, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. rljones@cuhk.edu.hk
Journal of Cardiac Surgery
|March 13, 2003
Summary
Prostaglandin E2 (EP3 receptor agonist) causes vasoconstriction via synergistic mechanisms. Different calcium channel blockers reveal distinct pathways for EP3 receptor-mediated smooth muscle contraction.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Molecular Biology
Background:
- Prostaglandin E2 (PGE2) is typically a vasodilator, but can cause vasoconstriction in specific vascular beds via prostanoid EP3-receptors.
- This study investigates the synergistic interactions between the EP3 receptor agonist sulprostone and other vasoactive agents in the guinea pig thoracic aorta.
Purpose of the Study:
- To elucidate the mechanisms underlying sulprostone-induced vasoconstriction in guinea pig aorta.
- To differentiate the roles of various calcium channels and signaling pathways in EP3 receptor-mediated vascular responses.
Main Methods:
- Isometric tension recordings from endothelium-denuded aortic rings.
- Application of sulprostone, phenylephrine, U-46619, and channel modulators (nifedipine, charybdotoxin, 4-aminopyridine).
- Inclusion of indomethacin and a TP-receptor antagonist in most experiments.
Main Results:
- Sulprostone induced concentration-dependent contractions with varying sensitivity to nifedipine (L-type Ca2+ channel blocker) in different preparations.
- Charybdotoxin (BKCa channel blocker) enhanced sulprostone responses, an effect abolished by nifedipine.
- Phenylephrine, U-46619, cyclopiazonic acid, and 4-aminopyridine potentiated submaximal sulprostone contractions via non-L-type calcium channels.
Conclusions:
- Large-conductance Ca2+-activated K+ (BKCa) channel activation acts as a brake on EP3 receptor-mediated contraction, which can be overcome by L-type calcium channel flux.
- Other vasoactive agents, including 4-aminopyridine, recruit non-L-type calcium channels to enhance EP3 receptor signaling through the calmodulin-myosin light chain pathway.