The kidney cytochrome P-450 2C23 arachidonic acid epoxygenase is upregulated during dietary salt loading

We have previously shown that salt excess has adverse cardiac effects in spontaneously hypertensive rats (SHR), independent of its increased arterial pressure; however, the renal effects have not been reported. In the present study we evaluated the role of three levels of salt loading in SHR on renal function, systemic and renal hemodynamics, and glomerular dynamics. At 8 wk of age, rats were given a 4% ( n = 11), 6% ( n = 9), or 8% ( n = 11) salt-load diet for the ensuing 8 wk; control rats ( n = 11) received standard chow (0.6% NaCl). Rats had weekly 24-h proteinuria and albuminuria quantified. At the end of salt loading, all rats had systemic and renal hemodynamics measured; glomerular dynamics were specially studied by renal micropuncture in the control, 4% and 6% salt-loaded rats. Proteinuria and albuminuria progressively increased by the second week of salt loading in the 6% and 8% salt-loaded rats. Mean arterial pressure increased minimally, and glomerular filtration rate decreased in all salt-loaded rats. The 6% and 8% salt-loaded rats demonstrated decreased renal plasma flow and increased renal vascular resistance and serum creatinine concentration. Furthermore, 4% and 6% salt-loaded rats had diminished single-nephron plasma flow and increased afferent and efferent arteriolar resistances; glomerular hydrostatic pressure also increased in the 6% salt-loaded rats. In conclusion, dietary salt loading as low as 4% dramatically deteriorated renal function, renal hemodynamics, and glomerular dynamics in SHR independent of a minimal further increase in arterial pressure. These findings support the concept of a strong independent causal relationship between salt excess and cardiovascular and renal injury.

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Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.2.h327 ◽

1993 ◽

Vol 264 (2) ◽

pp. H327-H335 ◽

Cited By ~ 36

Author(s):

M. Rosolowsky ◽

W. B. Campbell

Keyword(s):

Arachidonic Acid ◽

Coronary Arteries ◽

Vascular Tone ◽

Epoxyeicosatrienoic Acids ◽

Lipoxygenase Inhibitor ◽

Physiological Processes ◽

Coronary Vascular Tone ◽

Cytochrome P 450 ◽

Endothelium Dependent Relaxation

Metabolites of arachidonic acid regulate several physiological processes, including vascular tone. The purpose of this study was to determine which metabolites of arachidonic acid are produced by bovine coronary arteries and which may regulate coronary vascular tone. Arachidonic acid induced a concentration-related, endothelium-dependent relaxation [one-half maximum effective concentration (EC50) of 2 x 10(-7) M and a maximal relaxation of 91 +/- 2% at 10(-5) M] of bovine coronary arteries that were contracted with U-46619, a thromboxane mimetic. The concentration of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a metabolite of prostaglandin I2 (PGI2), increased from 82 +/- 6 to 328 +/- 24 pg/ml with arachidonic acid (10(-5) M). Treatment with the cyclooxygenase inhibitor indomethacin attenuated arachidonic acid-induced relaxations by approximately 50% and blocked the synthesis of 6-keto-PGF1 alpha. PGI2 caused a concentration-related relaxation (EC50 of 10(-8) M and a maximal relaxation of 125 +/- 11% at 10(-7) M). BW755C, a cyclooxygenase and lipoxygenase inhibitor, inhibited arachidonic acid-induced relaxation to the same extent as indomethacin. When vessels were treated with both indomethacin and BW755C, the inhibition of relaxation was the same as either inhibitor alone. SKF 525a, a cytochrome P-450 inhibitor, reduced arachidonic acid-induced relaxation by approximately 50%. When SKF 525a was given in combination with indomethacin, the relaxation by arachidonic acid was almost completely inhibited. SKF 525a inhibited the synthesis of epoxyeicosatrienoic acids (EETs).(ABSTRACT TRUNCATED AT 250 WORDS)

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High-salt diet depresses acetylcholine reactivity proximal to NOS activation in cerebral arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00127.2002 ◽

2002 ◽

Vol 283 (1) ◽

pp. H353-H363 ◽

Cited By ~ 16

Author(s):

Francis A. Sylvester ◽

David W. Stepp ◽

Jefferson C. Frisbee ◽

Julian H. Lombard

Keyword(s):

Salt Intake ◽

Cerebral Arteries ◽

High Salt ◽

Receptor Expression ◽

Dietary Salt ◽

No Donor ◽

Dietary Salt Intake ◽

No Release ◽

Type 3 ◽

Cytochrome P 450

Rats were fed a low-salt (LS; 0.4% NaCl) or high-salt (HS; 4.0% NaCl) diet for 3 days, and the responses of isolated cerebral arteries to acetylcholine (ACh), the nitric oxide (NO)-dependent dilator bradykinin, and the NO donor 6-(2-hydroxy-1-methyl-2-nitrosohydrazino)- N-methyl-1-hex-anamine (NOC-9) were determined. ACh-induced vasodilation and NO release, assessed with the fluorescent NO indicator 4,5-diaminofluorescein (DAF-2) diacetate, were eliminated with the HS diet. Inhibition of cyclooxygenase, cytochrome P-450 epoxygenase, and acetylcholinesterase did not alter ACh responses. Bradykinin and NOC-9 caused a similar dilation in cerebral arteries of all groups. Arteries from animals on LS or HS diets exhibited similar levels of basal superoxide (O[Formula: see text]) production, assessed by dihydroethidine fluorescence, and ACh responses were unaffected by O[Formula: see text] scavengers. Muscarinic type 3 receptor expression was unaffected by dietary salt intake. These results indicate that 1) a HS diet attenuates ACh reactivity in cerebral arteries by inhibiting NO release, 2) this attenuation is not due to production of a cyclooxygenase-derived vasoconstrictor or elevated O[Formula: see text] levels, and 3) alteration(s) in ACh signaling are located upstream from NO synthase.

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Mediation of Arachidonic Acid Metabolite(s) Produced by Endothelial Cytochrome P-450 3A4 in Monkey Arterial Relaxation.

Hypertension Research ◽

10.1291/hypres.26.237 ◽

2003 ◽

Vol 26 (3) ◽

pp. 237-243 ◽

Cited By ~ 18

Author(s):

Kazuhide AYAJIKI ◽

Hideyuki FUJIOKA ◽

Noboru TODA ◽

Shigeru OKADA ◽

Yukiko MINAMIYAMA ◽

...

Keyword(s):

Arachidonic Acid ◽

Arachidonic Acid Metabolite ◽

Acid Metabolite ◽

Arterial Relaxation ◽

Cytochrome P 450

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ω- and (ω − 1) -hydroxylation of arachidonic acid, lauric acid and prostaglandin A1 by multiple forms of cytochrome P-450 purified from rat hepatic microsomes

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism ◽

10.1016/0005-2760(90)90293-7 ◽

1990 ◽

Vol 1043 (2) ◽

pp. 177-181 ◽

Cited By ~ 32

Author(s):

Shigeto Tanaka ◽

Susumu Imaoka ◽

Emi Kusunose ◽

Masamichi Kusunose ◽

Masanobu Maekawa ◽

...

Keyword(s):

Arachidonic Acid ◽

Lauric Acid ◽

Multiple Forms ◽

Hepatic Microsomes ◽

Prostaglandin A1 ◽

Cytochrome P 450

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Dilation of cerebral arterioles by cytochrome P-450 metabolites of arachidonic acid

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1990.259.4.h1171 ◽

1990 ◽

Vol 259 (4) ◽

pp. H1171-H1177 ◽

Cited By ~ 31

Author(s):

E. F. Ellis ◽

R. J. Police ◽

L. Yancey ◽

J. S. McKinney ◽

S. C. Amruthesh

Keyword(s):

Arachidonic Acid ◽

Oxygen Radicals ◽

Cyclooxygenase Inhibitors ◽

Epoxyeicosatrienoic Acid ◽

Cranial Window ◽

Window Technique ◽

Cerebral Arterioles ◽

Pg E2 ◽

Cytochrome P 450

We have recently shown that brain tissue can synthesize cytochrome P-450 monooxygenase metabolites of arachidonic acid (AA), including 5,6-epoxyeicosatrienoic acid (5,6-EET), and 14,15-EET. The purpose of this investigation was to determine the vasoactivity of EETs and AA on the cerebral microcirculation. Pial arteriolar diameter was measured in rabbits and cats using in vivo microscopy and the closed cranial window technique. Prostaglandin (PG) E2 and 6-keto-PGF1 alpha formed by the brain cortex during application of these fatty acids was measured in cerebrospinal fluid by use of radioimmunoassay. A transient dose-dependent dilation was produced by 5,6-EET (1-15 micrograms/ml), with the maximum being 23% of control in both species. Other EETs had little or no activity, and AA-induced dilation was greater in rabbits than in cats. Indomethacin or superoxide dismutase plus catalase prevented dilation by 5,6-EET and AA, indicating that both produce dilation via cyclooxygenase-dependent oxygen radicals. PGE2 and 6-keto-PGF1 alpha levels were increased by AA but not by EETs, implying that EETs do not directly activate AA metabolism. Since 5,6-EET, but not other EETs, is known to be a substrate for cyclooxygenase, our data are consistent with brain cyclooxygenase metabolism of 5,6-EET with concomitant generation of dilator oxygen radicals. An implication of these results is that many previous studies of the cerebral circulation which based conclusions on results with cyclooxygenase inhibitors may need to be additionally interpreted.

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Elevating dietary salt exacerbates hyperpnea-induced airway obstruction in guinea pigs

Journal of Applied Physiology ◽

10.1152/jappl.2001.91.3.1061 ◽

2001 ◽

Vol 91 (3) ◽

pp. 1061-1066 ◽

Cited By ~ 11

Author(s):

Timothy D. Mickleborough ◽

Robert W. Gotshall ◽

Jann Rhodes ◽

Alan Tucker ◽

Loren Cordain

Keyword(s):

Airway Obstruction ◽

Guinea Pigs ◽

Nordihydroguaiaretic Acid ◽

Baseline Period ◽

Dietary Salt ◽

Salt Loading ◽

Salt Diet ◽

Treatment Groups ◽

Salt Consumption ◽

Exercise Induced

Previous studies have indicated that increased dietary salt consumption worsens postexercise pulmonary function in humans with exercise-induced asthma (EIA). It has been suggested that EIA and hyperpnea-induced airway obstruction (HIAO) in guinea pigs (an animal model of EIA) are mediated by similar mechanisms. Therefore, the purpose of this study was to determine whether altering dietary salt consumption also exacerbated HIAO in guinea pigs. Furthermore, the potential pathway of action of dietary salt was investigated by blocking leukotriene (LT) production during HIAO in guinea pigs. Thirty-two male Hartley strain guinea pigs were split into two groups. One group ( n = 16) of animals ingested a normal-salt diet (NSD) for 2 wk; the other group ( n = 16) ingested a high-salt diet (HSD) for 2 wk. Thereafter, animals were anesthetized, cannulated, tracheotomized, and mechanically ventilated during a baseline period and during two dry gas hyperpnea challenges. After the first challenge, the animals were administered either saline or nordihydroguaiaretic acid, a LT inhibitor. Bladder urine was analyzed for electrolyte concentrations and urinary LTE4. The HSD elicited higher airway inspiratory pressures (Ptr) than the NSD ( P < 0.001) postchallenge. However, after infusion of the LT inhibitor and a second hyperpnea challenge, HIAO was blocked in both diet groups ( P < 0.001). Nonetheless, the HSD group continued to demonstrate slightly higher Ptr than the NSD group ( P < 0.05). Urinary LTE4 excretion significantly increased in the HSD group compared with the NSD group within treatment groups. This study has demonstrated that dietary salt loading exacerbated the development of HIAO in guinea pigs and that LT release was involved in HIAO and may be moderated by changes in dietary salt loading.

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