Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 19, 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, New York 10595, USA
4 Department of Pathophysiology and Gerontology, University of Pecs, Pecs, Hungary
Correspondence: Zsolt Bagi MD, Ph.D., Department of Physiology, New York Medical College, Valhalla, NY 10595, USA, Phone: 914-594-4085, Fax: 914-594-4018, E-Mail: 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 to 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 to 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 systolic blood pressure in db/db, but not in control mice.
Conclusions: Activation of EP1 receptors increases arteriolar tone, which could contribute to the development of hypertension in the db/db mice.
Time for primary review: 31 Days