Inhibition of the prostaglandin E2 EP3 receptor does not affect beta adrenergic signaling in the heart
Bryson TD, Pandrangi TS, Khan SZ, Xu J, Peterson E, and Harding P. Inhibition of the prostaglandin E2 EP3 receptor does not affect beta adrenergic signaling in the heart. FASEB Journal 2018; 32(1 Suppl):675.8.
High blood pressure is a major risk factor for cardiovascular disease. Prostaglandin E2 (PGE2) is a metabolite of arachidonic acid and is known to mediate inflammation and blood pressure regulation. Previous data from our lab have shown that PGE2 reduces contractility when signaling via its EP3 receptor subtype and that EP3 expression increases in the Angiotensin II (Ang II) model of hypertension. Furthermore, we demonstrated in vivo that the hypertensive effect of Ang II could be abrogated using an EP3 inhibitor (EP3i), suggesting an interaction between the two pathways. Since stimulation of the sympathetic nervous system increases Ang II and is an important regulator of cardiovascular function, we therefore hypothesized that inhibition of EP3 would also antagonize beta adrenergic signaling. To test our hypothesis, we studied 4 groups of male 10-12 wk. old C57Bl/6 mice receiving: (1) vehicle, (2) the beta adrenergic agonist Isoproterenol, ISO 30 mg/kg/d S.C., (3) the EP3i L798,106 40 μg/kg/d, (4) ISO + L798,106 for 10 days. ISO or its vehicle were given via osmotic mini pump and L798,106 or its vehicle were administered via daily injections S.C. Systolic blood pressure (BP) was measured every 2 days via tail cuff and cardiac function was assessed by echo at the end of the study period. At baseline, there were no differences in BP between the 4 groups. As expected, ISO infusion significantly increased both BP (105 ± 3.4 mmHg vs. 130 ± 4.1 mmHg, p<0.01) and heart rate (600 ± 21 bpm vs. 749 ± 16 bpm, p<0.005) at end of study, however, there was no difference in BP between the ISO group and the ISO + EP3i group (130 ± 4.1 mmHg vs 125 ± 6.1 mmHg, respectively) nor heart rate (749 ± 16 bpm vs 729 ± 26 bpm). Consistent with the blood pressure data, myocyte cross sectional area increased with ISO infusion from 195.5 ± 9.1 μm2 to 234.0 ± 10.4 μm2, p < 0.05 and this was unchanged at 219.9 ± 13.1 μm2 in the ISO+EP3i group. Similar results were noted in the heart weight to body weight ratios. Echocardiography in conscious animals demonstrated no significant differences in either ejection fraction (EF), shortening fraction, or left ventricle dimensions between the ISO group and the ISO + EP3i group. In conclusion, our data suggest that contrary to our hypothesis, there is no interaction between the EP3 receptor signaling pathway and the beta adrenergic pathway after ten days of ISO infusion. Thus, EP3 receptor signaling appears to be uniquely linked to the angiotensin II pathway.