Cardiovascular Research Advance Access first published online on March 19, 2009
This version [Corrected Proof] published online on April 8, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp098
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Activation of prostaglandin E2 EP1 receptor increases arteriolar tone and blood pressure in mice with type 2 diabetes
1 Division of Clinical Physiology, Institute of Cardiology, University of Debrecen, Debrecen, Hungary
2 University of Angers, CNRS UMR 6214, INSERM U771, Angers 49045, France
3 Department of Physiology, New York Medical College, Valhalla, NY 10595, USA
4 Department of Pathophysiology and Gerontology, University of Pecs, Pecs, Hungary
* Corresponding author. Tel: +1 914 594 4085; Fax: +1 914 594 4018. E-mail address: zsolt_bagi{at}nymc.edu
Aims: Type 2 diabetes mellitus is frequently associated with hypertension, but the underlying mechanisms are not completely understood. We tested the hypothesis that activation of type 1 prostaglandin E2 (PGE2) receptor (EP1) increases skeletal muscle arteriolar tone and blood pressure in mice with type 2 diabetes.
Methods and results: In 12-week-old, male db/db mice (with homozygote mutation in leptin receptor), systolic blood pressure was significantly elevated, compared with control heterozygotes. Isolated, pressurized gracilis muscle arterioles (
90 µm) of db/db mice exhibited an enhanced pressure- and angiotensin II (0.1–10 nM)-induced tone, which was reduced by the selective EP1 receptor antagonist, AH6809 (10 µM), to the level observed in arterioles of control mice. Exogenous application of PGE2 (10 pM–100 nM) or the selective agonist of the EP1 receptor, 17-phenyl-trinor-PGE2 (10 pM–100 nM), elicited arteriolar constrictions that were significantly enhanced in db/db mice (max: 31 ± 4 and 29 ± 5%), compared with controls (max: 20 ± 2 and 14 ± 3%, respectively). In the aorta of db/db mice, an increased protein expression of EP1, but not EP4, receptor was also detected by western immunoblotting. Moreover, we found that oral administration of the EP1 receptor antagonist, AH6809 (10 mg/kg/day, for 4 days), significantly reduced the systolic blood pressure in db/db, but not in control mice.
Conclusion: Activation of EP1 receptors increases arteriolar tone, which could contribute to the development of hypertension in the db/db mice.
KEYWORDS Diabetes; Hypertension; Arteriole; Prostanoid; EP receptor
Time for primary review: 31 days