title: Inhibition of the adenosine2A receptor-epoxyeicosatrienoic acid pathway renders Dahl salt-resistant rats hypertensive.
abstract: Adenosine-induced renovasodilation in Dahl rats is mediated via activation of adenosine(2A) receptors (A(2A)Rs) and stimulation of epoxyeicosatrienoic acid (EET) synthesis. Unlike Dahl salt-resistant rats, salt-sensitive rats exhibit an inability to upregulate the A(2A)R-EET pathway with salt loading; therefore, we examined the effect of in vivo inhibition of the A(2A)R-EET pathway on blood pressure and the natriuretic response to salt-loading in Dahl salt-resistant rats. N-Methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 20 mg/kg per day), an epoxygenase inhibitor, or ZM241385 (ZM; 5 mg/kg per day), an A(2A)R antagonist, was given daily as an IV bolus dose for 3 days before and after placing rats on high salt intake (2% saline). After 3 days of high salt, systolic blood pressure per 24 hours increased from 108+/-2 mm Hg to 136+/-5 mm Hg and 140+/-4 mm Hg when treated with MS-PPOH or ZM, respectively (P<0.001). Plasma levels of EETs and dihydroxyeicosatrienoic acids during salt loading and MS-PPOH (29.3+/-1.8 ng/mL) or ZM treatment (9.8+/-0.5 ng/mL) did not increase to the same extent as in vehicle-treated rats (59.4+/-1.7 ng/mL; P<0.001), and renal levels of EETs+dihydroxyeicosatrienoic acids were 2-fold lower with MS-PPOH or ZM treatment. On day 3 of the high salt intake, MS-PPOH- and ZM-treated rats exhibited a positive Na(+) balance, and plasma Na(+) levels were significantly increased (163.3+/-1.2 and 158.1+/-4.5 mEq/L, respectively) compared with vehicle-treated rats (142.1+/-1 mEq/L), reflecting a diminished natriuretic capacity. These data support a role for the A(2A)R-EET pathway in the adaptive natriuretic response to modulate blood pressure during salt loading.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Elvira L
authors.initials: EL
authors.lastname: Liclican
authors.forename: Anabel B
authors.initials: AB
authors.lastname: Doumad
authors.forename: Jianjin
authors.initials: J
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Charles T
authors.initials: CT
authors.lastname: Stier
authors.forename: Mairéad A
authors.initials: MA
authors.lastname: Carroll
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004326:Drinking / Q000502:physiology; D015777:Eicosanoids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D006977:Hypertension, Renal / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000577:Amides; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D018341:Receptors, Adrenergic, alpha-2; D017673:Sodium Chloride, Dietary; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D010088:Oxidoreductases