Abstract P143: The Angiotensin AT2 Receptor Agonist Compound 21 Is a Low Affinity Thromboxane A2 Receptor Antagonist
Objective: The purpose of this study was to investigate potential vasorelaxant effects of angiotensin AT2-receptor stimulation by the specific AT2-receptor agonist C21 in pericardial resistance arteries from cardiovascular disease patients.
Methods: Parietal pericardium was obtained during coronary artery bypass-grafting and/or valve replacement in patients. Pericardial arteries from pigs and mesenteric arteries from C57BL-6J and AT2R deficient (AT2R-/y) mice were used for comparison.
Isolated arteries were mounted onto wire myographs, pre-contracted with either K+, phenylephrine, endothelin-1 (ET-1) or the thromboxane agonist U46619, and the relaxing effect of C21 (0.1nM - 10μM) was investigated in the absence or presence of 3nM valsartan (AT1R antagonist), 10μM PD123319 or 10μM M132 (AT2R antagonists).
Results: C21 significantly relaxed ET-1 contracted porcine arteries (Emax -37 ± 6 %; -0.87 vs -0.45 N/m relaxation; N=6; P<0.05, two-way ANOVA) and phenylephrine contracted mouse mesenteric arteries (Emax -52 ± 10 %; -0.26 vs -0.09 N/m relaxation; N=6; P<0.01, two-way ANOVA), and this was inhibited by PD123319 or M132 and absent in arteries from AT2R-/y. C21 significantly induced vasorelaxation in U46619 contracted vessels from all species and vascular beds (e.g. in human pericardial arteries: Emax -78 ± 10 %; -0.67 vs -0.07 N/m relaxation; N=17; P<0.01, two-way ANOVA), and this effect was not blocked by AT2R antagonists and still present in AT2R-/y. C21 further inhibited U46619 induced platelet aggregation. An Arrestin Biosensor Assay revealed that C21 binds to the TXA2 receptor with a Ki of 3.74 μM.
Conclusion: Depended on species, vascular bed and contractile stimulus, C21 relaxes resistance-sized arteries by AT2R stimulation or by TXA2 antagonism. These data together with the low affinity binding of C21 to the TXA2 receptor and its effect on platelet aggregation strongly suggest that C21 is not only a high affinity, selective AT2R agonist, but also a low affinity TXA2 receptor antagonist.
Author Disclosures: U.M. Steckelings: C. Other Research Support (includes receipt of drugs, supplies, equipment or other in-kind support); Modest; Free drug supply (Compound 21) by Vicore Pharma. M. Fredgart: None. T. Leurgans: None. M. Stenelo: None. M. Nybo: None. L.M. Rasmussen: None. J.G.R. De Mey: None.
- © 2015 by American Heart Association, Inc.