scholarly journals Stimulation of diuresis and natriuresis by renomedullary infusion of a dual inhibitor of fatty acid amide hydrolase and monoacylglycerol lipase

2017 ◽  
Vol 313 (5) ◽  
pp. F1068-F1076 ◽  
Author(s):  
Ashfaq Ahmad ◽  
Zdravka Daneva ◽  
Guangbi Li ◽  
Sara K. Dempsey ◽  
Ningjun Li ◽  
...  
Keyword(s):  
Blood Flow ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Renal Medulla ◽  
Dependent Manner ◽  
Medullary Blood Flow ◽  
Cox 2 ◽  
Amide Hydrolase ◽  
Cox 1 ◽  
Fatty Acid Amide

The renal medulla, considered critical for the regulation of salt and water balance and long-term blood pressure control, is enriched in anandamide and two of its major metabolizing enzymes, cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH). Infusion of anandamide (15, 30, and 60 nmol·min−1·kg−1) into the renal medulla of C57BL/6J mice stimulated diuresis and salt excretion in a COX-2- but not COX-1-dependent manner. To determine whether endogenous endocannabinoids in the renal medulla can elicit similar effects, the effects of intramedullary isopropyl dodecyl fluorophosphate (IDFP), which inhibits the two major endocannabinoid hydrolases, were studied. IDFP treatment increased the urine formation rate and sodium excretion in a COX-2- but not COX-1-dependent manner. Neither anandamide nor IDFP affected the glomerular filtration rate. Neither systemic (0.625 mg·kg−1·30 min−1 iv) nor intramedullary (15 nmol·min−1·kg−1·30 min−1) IDFP pretreatment before intramedullary anandamide (15–30 nmol·min−1·kg−1) strictly blocked effects of anandamide, suggesting that hydrolysis of anandamide was not necessary for its diuretic effect. Intramedullary IDFP had no effect on renal blood flow but stimulated renal medullary blood flow. The effects of IDFP on urine flow rate and medullary blood flow were FAAH-dependent as demonstrated using FAAH knockout mice. Analysis of mouse urinary PGE2 concentrations by HPLC-electrospray ionization tandem mass spectrometry showed that IDFP treatment decreased urinary PGE2. These data are consistent with a role of FAAH and endogenous anandamide acting through a COX-2-dependent metabolite to regulate diuresis and salt excretion in the mouse kidney.

scholarly journals Modulation of mean arterial pressure and diuresis by renomedullary infusion of a selective inhibitor of fatty acid amide hydrolase

2018 ◽  
Vol 315 (4) ◽  
pp. F967-F976 ◽  
Author(s):  
Ashfaq Ahmad ◽  
Sara K. Dempsey ◽  
Zdravka Daneva ◽  
Ningjun Li ◽  
Justin L. Poklis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mean Arterial Pressure ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Kidney Tissue ◽  
Renal Medulla ◽  
Selective Inhibitor ◽  
Amide Hydrolase ◽  
Arachidonoyl Glycerol ◽  
Fatty Acid Amide

The kidneys contribute to the control of body fluid and electrolytes and the long-term regulation of blood pressure through various systems, including the endocannabinoid system. Previously, we showed that inhibition of the two major endocannabinoid-hydrolyzing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, in the renal medulla increased the rate of urine excretion (UV) and salt excretion without affecting mean arterial pressure (MAP). The present study evaluated the effects of a selective FAAH inhibitor, N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidine carboxamide (PF-3845) on MAP and renal functions. Infusion of PF-3845 into the renal medulla of C57BL/6J mice reduced MAP during the posttreatment phases and increased UV at 15 and 30 nmol/min per gram kidney weight (g kwt), relative to the pretreatment control phase. Intravenous PF-3845 administration reduced MAP at the 7.5, 15, and 30 doses and increased UV at the 15 and 30 nmol⋅min−1⋅g−1 kwt doses. PF-3845 treatment elevated sodium and potassium urinary excretion and medullary blood flow. Homozygous FAAH knockout mice were refractory to intramedullary PF-3845-induced changes in MAP, but UV was increased. Both MAP and UV responses to intramedullary PF-3845 in C57BL/6J mice were diminished by pretreatment with the cannabinoid type 1 receptor-selective antagonist, rimonabant (3 mg/kg, ip) but not the cyclooxygenase 2-selective inhibitor, celecoxib (15 mg/kg, iv). Liquid chromatography-tandem mass spectrometry analyses showed increased anandamide in kidney tissue and 2-arachidonoyl glycerol in plasma after intramedullary PF-3845. These data suggest that inhibition of FAAH in the renal medulla leads to both a diuretic and blood pressure-lowering response mediated by elevated anandamide in kidney tissue or 2-arachidonoyl glycerol in plasma.

scholarly journals COX-2 and fatty acid amide hydrolase can regulate the time course of depolarization-induced suppression of excitation

2011 ◽  
Vol 164 (6) ◽  
pp. 1672-1683 ◽  
Author(s):  
A Straiker ◽  
J Wager-Miller ◽  
SS Hu ◽  
JL Blankman ◽  
BF Cravatt ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Time Course ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Cox 2 ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets

2007 ◽  
Vol 52 (4) ◽  
pp. 1095-1105 ◽  
Author(s):  
Di Zhang ◽  
Anita Saraf ◽  
Teodozyi Kolasa ◽  
Pramila Bhatia ◽  
Guo Zhu Zheng ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Exacerbation of Background Nuclear Cataracts in Sprague-Dawley Rats in Embryo-Fetal Development Studies With JNJ-42165279, a Fatty Acid Amide Hydrolase Inhibitor

2021 ◽  
pp. 019262332110104
Author(s):  
Marjolein van Heerden ◽  
Wendy Roosen ◽  
Sophie Lachau-Durand ◽  
Graham Bailey ◽  
Anthony Ndifor
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
In Utero ◽  
Histological Evaluation ◽  
High Dose ◽  
Lens Fiber ◽  
Sprague Dawley ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Fetal examinations in embryo-fetal developmental (EFD) studies are based on macroscopic and dissecting microscopic evaluations, and histopathology is rarely performed other than to confirm macroscopic findings. Fetal lens examination is therefore generally limited to the presence, size, shape, and color of any abnormality. In a Sprague-Dawley rat EFD study with the fatty acid amide hydrolase (FAAH) inhibitor JNJ-42165279, an unusually high incidence of macroscopic granular foci was noted within the lens of gestation day 21 fetuses across all groups including controls, with higher incidence in the high-dose group. On histological evaluation of the lenses from fetuses with/without gross findings, primary lens fiber hypertrophy (swelling) and degeneration were observed across vehicle- and JNJ-42165279-exposed fetuses. In a follow-up study to investigate the progression or resolution of the fetal lens changes, animals exposed to suprapharmacological doses of JNJ-42165279 in utero had higher incidence of nuclear cataracts as detected via slit-lamp ophthalmic examinations on postnatal days 18 to 21 and 35 to 41. No histologic correlates for these cataracts were identified. We conclude that fetal primary lens fiber hypertrophy and nuclear cataracts at ophthalmology, are common background changes in this rat strain that are exacerbated by in utero exposure to the FAAH inhibitor JNJ-42165279.

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