title: Alkaline Phosphatase Inhibitors Attenuate Renovascular Responses to Norepinephrine.
abstract: Tissue nonspecific alkaline phosphatase (TNAP) contributes to the production of adenosine by the kidney, and A1-receptor activation enhances renovascular responses to norepinephrine. Therefore, we hypothesized that TNAP regulates renovascular responsiveness to norepinephrine. In isolated, perfused rat kidneys, the TNAP inhibitor l-p-bromotetramisole (0.1 mmol/L) decreased renal venous levels of 5'-AMP (adenosine precursor) and adenosine by 61% (P<0.0384) and 62% (P=0.0013), respectively, at 1 hour into treatment and caused a 10-fold rightward shift of the concentration-response relationship to exogenous norepinephrine (P<0.0001). Similarly, 2 other TNAP inhibitors, levamisole (1 mmol/L) and 2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide (0.02 mmol/L), also right shifted the concentration-response relationship to norepinephrine. The ability of TNAP inhibition to blunt renovascular responses to norepinephrine was mostly prevented or reversed by restoring A1-adenosinergic tone with the A1-receptor agonist 2-chloro-N6-cyclopentyladenosine (100 nmol/L). All 3 TNAP inhibitors also attenuated renovascular responses to renal sympathetic nerve stimulation, suggesting that TNAP inhibition attenuates renovascular responses to endogenous norepinephrine. In control propranolol-pretreated rats, acute infusions of norepinephrine (10 μg/kg/min) increased mean arterial blood pressure from 95±5 mm Hg to a peak of 169±4 mm Hg and renovascular resistance from 12±2 mm Hg/mL/min to a peak of 55±12 mm Hg/mL/min; however, in rats also treated with intravenous l-p-bromotetramisole (30 mg/kg), the pressor and renovascular effects of norepinephrine were significantly attenuated (blood pressure: basal and peak, 93±7 and 146±6 mm Hg, respectively; renovascular resistance: basal and peak, 13±2 and 29±5 mm Hg/mL/min, respectively). TNAP inhibitors attenuate renovascular and blood pressure responses to norepinephrine, suggesting that TNAP participates in the regulation of renal function and blood pressure.
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA. edj@pitt.edu.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA.
authors.forename: Yumeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, PA.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D007668:Kidney / Q000098:blood supply / Q000294:innervation; D007978:Levamisole / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects*; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects*; D014655:Vascular Resistance
chemical_list: D007978:Levamisole; D000469:Alkaline Phosphatase; D009638:Norepinephrine
keywords: adenosine; adenosine receptors; alkaline phosphatase; kidney; norepinephrine; vasoconstriction