TY - JOUR
T1 - Activation of prostaglandin E2 EP1 receptor increases arteriolar tone and blood pressure in mice with type 2 diabetes
AU - Rutkai, Ibolya
AU - Feher, Attila
AU - Erdei, Nora
AU - Henrion, Daniel
AU - Papp, Zoltan
AU - Edes, Istvan
AU - Koller, Akos
AU - Kaley, Gabor
AU - Bagi, Zsolt
N1 - Funding Information:
This study was supported by grants from the NIH PO1-HL-43023, HL-46813, American Heart Association, 0735540T, and by the Hungarian Ministry of Health: 449/ 2006, 454/2006 grants.
PY - 2009/7
Y1 - 2009/7
N2 - 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 m) 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 M), 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.
AB - 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 m) 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 M), 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.
KW - Arteriole
KW - Diabetes
KW - EP receptor
KW - Hypertension
KW - Prostanoid
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U2 - 10.1093/cvr/cvp098
DO - 10.1093/cvr/cvp098
M3 - Article
C2 - 19299433
AN - SCOPUS:67649327410
SN - 0008-6363
VL - 83
SP - 148
EP - 154
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 1
ER -