[Show abstract][Hide abstract] ABSTRACT: Increased dietary linoleic acid has been associated with reduced blood pressure in clinical and animal studies possibly mediated by prostaglandins. Urinary linoleate and prostaglandin metabolite excretion were investigated in subjects exposed to a salt-loading/salt-depletion regimen. Twelve healthy subjects were recruited from the New Orleans population (before Hurricaine Katrina) and admitted to the Tulane-Louisiana State University-Charity Hospital General Clinical Research Center after a 5-day outpatient lead-in phase on a 160-mmol sodium diet. On inpatient day 1, the subjects were maintained on the 160-mmol sodium diet, and a 24-hour urine specimen was collected. On day 2, the subjects received 2 L of IV normal saline over 4 hours and continued on a 160-mmol Na(+) diet (total: 460 mmol of sodium). Two 12-hour urine collections were obtained. On day 3, the subjects received three 40-mg oral doses of furosemide, two 12-hour urine collections were obtained, and the subjects were given a 10-mmol sodium diet. Urinary oxidized lipids were measured by high-performance liquid chromatography-tandem quadrupole mass spectroscopy. The excretion of the urinary linoleate metabolites, dihydroxyoctadecamonoenoic acids, and trihydroxyoctadecamonoenoic acids increased significantly during intravenous salt loading as compared with day 1 and the salt-depleted periods. The urinary excretion of 6-keto- prostaglandin F1alpha was unaffected by salt loading but was dramatically increased 7- to 10-fold by salt depletion. Prostaglandin E2 excretion was positively correlated with sodium excretion. The salt-stimulated production of linoleic acid diols and triols may inhibit tubular sodium reabsorption, thereby assisting in the excretion of the sodium load.
[Show abstract][Hide abstract] ABSTRACT: Background: The ubiquitin ligase NEDD4L is a candidate gene for essential hypertension based on both physiological and genetic evidence. NEDD4L ubiquinates the distal renal tubule epithelial sodium channel (ENaC) and therefore plays an important role in regulating the trafficking of ENaC from the plasma membrane. Genetic linkage studies of hypertension have also been reported to show linkage to a region 18q which includes the NEDD4L gene. A high prevalence (30%) polymorphism in NEDD4L at G82723A has been recently identified which codes for a cryptic splice site which yields a nonfunctional protein. This polymorphism would presumably lead to an increase in the plasma membrane residence time of ENaC, enhanced distal tubule sodium and water reabsorption, and hypertension.Methods: We tested this hypothesis by determining the frequency of the NEDD4L A allele in African-Americans with hypertension using a case-control design. We studied the frequency of the NEDD4L A allele in 93 hypertensive African-Americans and 98 healthy African-Americans to determine whether there was an association of A allele with hypertension. The DNA was isolated from blood and then genotyped for the variant NEDD4L 82723 A allele using TaqMan-based allelic discrimination assays.Results: The patient demographics and NEDD4L A allele frequency is shown in the table below.Conclusions: We found no association between this cryptic splice site NEDD4L 82723 A polymorphism and hypertension in African-Americans.
No preview · Article · Jan 2006 · Clinical Pharmacology & Therapeutics
[Show abstract][Hide abstract] ABSTRACT: The cytochrome P450 (CYP) epoxygenase pathway produces arachidonic acid metabolites that are vasoactive, that affect renal sodium handling, and that have been proposed to play a mechanistic role in hypertension. Multiple single nucleotide polymorphisms (SNP) in CYP2C8, 2C9, 2J2 and soluble epoxide hydrolase (sEH) have been identified, many of which have altered functional activity in vitro. We performed a case-control study to determine the prevalence of epoxygenase-related SNP in African American individuals and to evaluate whether these SNP are associated with increased risk of hypertension.
Normotensive African American individuals (N = 107) and African American patients with hypertension (N = 108) were recruited. DNA was extracted from a venous blood sample and genotyped for CYP2C8*2,*3, CYP2C9*2-*5,*8,*11, CYP2J2 *2-*7, L50L, R49S, V113M, N124S, sEH R287Q, and sEH 403Rins variant alleles by allelic discrimination using real-time polymerase chain reaction. Genotype and allele frequencies were calculated and associations with hypertension were estimated using unconditional logistic regression, adjusting for age and sex.
No association was found between any of the variant alleles and hypertension. We did find that only the CYP2C8*3and CYP2C9*2 alleles were in strong linkage disequilibrium in both the hypertensive and healthy African American groups, a finding that was reported previously in healthy individuals of white ethnicity.
These results suggest that these epoxygenase-related SNP are not associated with increased risk of hypertension in the African American population. There was significant linkage disequilibrium between CYP2C8*3 and CYP2C9*2 alleles that was not associated with hypertension.
No preview · Article · Nov 2005 · American Journal of Hypertension
[Show abstract][Hide abstract] ABSTRACT: BackgroundCYP2C9, CYP2J2, and sEH have been shown to be involved in the formation and metabolism of vasoactive epoxides of the epoxygenase pathway which have been proposed to play a role in the pathogenesis of hypertension and progression of renal failure. The AA population with endstage renal disease (ESRD) on HD has a high prevalence of hypertension and may have altered prevalence of these polymorphismsMethods
We studied the frequency of CYP2C9*8 and *11, sEH R287Q and anR403insertion, and CYP2J2*2-*7 and the newly identified CYP2J2 polymorphisms R49S, L50L, V113M, N124S in 97 AA ESRD patients and 84 healthy AA to determine whether there is a significant difference in prevalence rates of these polymorphisms. The mean age of the ESRD patients was 53.3± 12.1 years (mean± sd) and the healthy AA was 38.6± 9.1 years. The ESRD patients and healthy subjects were 43.3% and 38.6 % female, respectively. The DNA was isolated from peripheral blood mononuclear cells and then genotyped for the variant alleles using TaqMan-based allelic discrimination assays.ResultsThe prevalence of the CYP2J2 variant alleles with the exception of CYP2J2*7 (see Table) ranged from 0 to 1.1% in the healthy and ESRD populations. Additional results are shown in the table below.Conclusions
There was no significant difference in prevalence rates of the CYP2C9, CYP2J2, and sEH alleles in AA with ESRD compared with the healthy AA population. This is similar to the results we previously reported for CYP2C9*2-5 and CYP2C8*2-*3.Clinical Pharmacology & Therapeutics (2005) 77, P57-P57; doi: 10.1016/j.clpt.2004.12.108Table 1. Prevalence of Epoxygenase SNPs In AA on HDAlleleESRD (%) N = 97Healthy (%) N = 101P Chi-SquareCYP2C9*84.63.0NSCYP2C9*112.11.0NSsEH R287Q10.88.0NSsEH R403ins02.0NSCYP212*78.511.1NS