Prospective health surveillance for COVID-19 among health care workers at a university medical center in Taiwan, January to June 2020.

BACKGROUND: Healthcare personnel (HCP) at the front line of care are exposed to occupational hazards that place them at risk for infection, which then endanger patient safety and compromise the capability of the healthcare workforce. As of March 8, 2021 more than 420,170 HCP in US had been infected with SARS CoV-2 with 1388 deaths. In two Taiwan hospitals COVID-19 outbreaks involved HCP and resulted in shutdown of service. This report describes our prospective health surveillance of the HCP and COVID-19 containment measures in a teaching hospital in Taiwan during Jan. 1 through June 30, 2020. METHODS: We prospectively monitored incidents, defined as an HCP with the predefined symptoms, reported by HCP through the web-based system. HCP were managed based on an algorithm that included SARS CoV-2 RNA PCR testing. Infection prevention and control policy/practice were reviewed. RESULTS: This hospital took care of 17 confirmed COVID-19 cases during the study period and the first Case was admitted on January 23, 2020. Among the 14,210 HCP, there were 367 incident events. Of 283 HCP tested for SARS CoV-2, 179 had predefined symptoms. These included 10 HCP who met the national case definition for COVID-19 infection and 169 based on Extended COVID-19 Community Screening program. The other 104 asymptomatic HCP were tested based on hospital policy. All of them had tested negative. CONCLUSION: We attribute our success in preventing COVID-19 infections among HCP to rapid, proactive, decisive, integrated national and institutional response in the early stages of the epidemic.

Social capital and transaction cost on co-creating IT value towards inter-organizational EMR exchange.

This study adopts social capital theory and transaction cost theory to explore the feasibility of an inter-organizational cross-hospital electronic medical records (EMR) exchange system, and the factors that affect its adoption. The concept of value co-creation is also used to assess such a system, and its influence on the performance of participating medical institutes. This research collected 330 valid paper-based questionnaires from the medical staff of various institutes. The results showed that social interaction ties and shared vision positively affected medical institutes' willingness to adopt the EMR exchange system, while asset specificity and uncertainty increased the related transaction costs. With a greater willingness to invest in relation-specific assets and to meet the related transaction costs, this behavior lead to an increase in medical IT value, as well as better results for the related medical institutes, medical staff, and patients. Therefore, this study suggests that such institutes encourage their medical staff to participate in seminars or reunions in order to develop their professional and social networks, and set up clear schedules and desire for expected effects when introducing the cross-hospital EMR exchange system.

Service quality and perceived value of technology-based service encounters: evaluation of clinical staff satisfaction in Taiwan.

Previous research has evaluated technology-based service encounters (TBSEs) in the delivery of health care by assessing patient satisfaction. This study examined service quality and perceived value of TBSEs used in health organisations from the perspective of clinical staff, with staff technology readiness as a moderator. A quantitative survey was conducted in Taiwan, across private and public healthcare organisations. Results showed that TBSEs had a direct effect on service quality and perceived value, which in turn had a direct effect on staff satisfaction in using TBSEs. However, service quality had no effect on perceived value when moderated by technology readiness. Theoretical and managerial implications of these findings are discussed.

Inhibition or deletion of soluble epoxide hydrolase prevents hyperglycemia, promotes insulin secretion, and reduces islet apoptosis.

Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of endogenous inflammatory and antiapoptotic mediators. However, the roles of sEH in diabetes and the pancreas are unknown. Our aims were to determine whether sEH is involved in the regulation of hyperglycemia in diabetic mice and to investigate the reasons for the regulation of insulin secretion by sEH deletion or inhibition in islets. We used two separate approaches, targeted disruption of Ephx2 gene [sEH knockout (KO)] and a selective inhibitor of sEH [trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid (t-AUCB)], to assess the role of sEH in glucose and insulin homeostasis in streptozotocin (STZ) mice. We also examined the effects of sEH KO or t-AUCB on glucose-stimulated insulin secretion (GSIS) and intracellular calcium levels in islets. Hyperglycemia in STZ mice was prevented by both sEH KO and t-AUCB. In addition, STZ mice with sEH KO had improved glucose tolerance. More important, when insulin levels were assessed by hyperglycemic clamp study, sEH KO was found to promote insulin secretion. In addition, sEH KO and t-AUCB treatment augmented islet GSIS. Islets with sEH KO had a greater intracellular calcium influx when challenged with high glucose or KCl in the presence of diazoxide. Moreover, sEH KO reduced islet cell apoptosis in STZ mice. These results show not only that sEH KO and its inhibition prevent hyperglycemia in diabetes, but also that sEH KO enhances islet GSIS through the amplifying pathway and decreases islet cell apoptosis in diabetes.

Cluster of parvovirus infection among hospital staff working in coronary care units.

BACKGROUND: Parvovirus B19 is associated with erythema infectiosum in children or arthralgia and arthritis in adults. The virus is relatively conserved and nucleotide identity is expected in viruses that are epidemiologically related. Here, we describe the first cluster of parvovirus infection among hospital staff documented in Taiwan. METHODS: Active surveillance was conducted in coronary care units (CCUs) at a 2200-bed teaching hospital for 1 month in 2007. A case defined clinically as occurring in a patient or staff in CCUs with new onset of fever or rash. Serum was tested for parvovirus B19 IgM and IgG by immunoblotting and DNA by nested polymerase chain reaction. When viremia was detected, nucleotide sequences were analyzed and compared with those of two clinical isolates. The attack rate was defined as the cumulative incidence of acute infection in CCU staff and patients during the study period. RESULTS: Among 57 staff and 15 patients, five nurses met the clinical case definition. Three had acute infection as demonstrated by viral DNA and IgM. The attack rate was 5.3% for the staff and zero for patients. Seroprevalence rate was lower in staff than in patients (26.3%vs. 53.3%). The isolates collected from three cases were highly similar to a community isolate, and they varied with each other by 2-6 nucleotides. The isolate collected from a nurse was identical to that from her friend 3 weeks apart and was concordant with mutual transmission. A sequence with 45 nucleotide variations was identified from a staff member with chronic infection who was negative for IgM and had only weak IgG anti-VP1 reaction with immunoblotting. We did not find any patient as the source of infection. CONCLUSION: We identified a cluster of parvovirus infection that was caused by three circulating strains which did not support the hypothesis of transmission of a single strain in CCUs.

Glomerular 20-HETE, EETs, and TGF-beta1 in diabetic nephropathy.

The early stage of diabetic nephropathy (DN) is linked to proteinuria. Transforming growth factor (TGF)-beta1 increases glomerular permeability to albumin (P(alb)), whereas 20-HETE and EETs reduce P(alb). To investigate the impact of hyperglycemia and hyperlipidemia on 20-HETE, EETs, and TGF-beta1 in the glomeruli, rats were divided into four groups: ND rats were fed a normal diet, HF rats were fed a high-fat diet, STZ rats were treated with 35 mg/kg of streptozotocin, and HF/STZ rats were fed a HF diet and treated with STZ. After 10 wk on these regimens, blood glucose, urinary albumin, serum cholesterol, serum triglyceride levels, and the kidney-to-body weight ratio were significantly elevated in STZ and HF/STZ rats compared with HF and ND rats. STZ and HF/STZ rats had histopathologic changes and abnormal renal hemodynamics. Expression of glomerular CYP4A, enzymes for 20-HETE production, was significantly decreased in STZ rats, whereas expression of glomerular CYP2C and CYP2J, enzymes for EETs production, was significantly decreased in both STZ and HF/STZ rats. Moreover, glomerular TGF-beta1 levels were significantly greater in STZ and HF/STZ rats than in HF and ND rats. Five-week treatment of STZ rats with clofibrate induced glomerular CYP4A expression and 20-HETE production, but reduced glomerular TGF-beta1 and urinary protein excretion. These results demonstrate that hyperglycemia increases TGF-beta1 but decreases 20-HETE and EETs production in the glomeruli, changes that may be important in causing glomerular damage in the early stage of DN.

Colfibrate attenuates blood pressure and sodium retention in DOCA-salt hypertension.

Clofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonist, increases renal tubular cytochrome P450 4a (Cyp4a) expression thereby increasing 20-hydroxyeicosatetraenoic acid (20-HETE) production. To determine if clofibrate affects blood pressure regulation we studied mice with DOCA-salt induced hypertension in wild-type and PPAR alpha knockout mice. Wild-type mice treated with DOCA-salt had higher mean arterial pressures and higher cumulative sodium balance, but lower renal 20-HETE production than did vehicle-treated mice. Treating DOCA-salt mice with clofibrate attenuated the increase in mean arterial pressure and cumulative sodium balance while increasing 20-HETE production and renal Cyp4a expression. In contrast the PPAR alpha knockout mice treated with clofibrate and DOCA-salt showed no attenuation in the increase of blood pressure, cumulative sodium balance, renal 20-HETE production or Cyp4a protein expression. Expression of the PPAR alpha protein was greater in proximal tubules than in renal microvessels. Our results show that PPAR alpha pathway induces renal tubular 20-HETE production which affects sodium retention and blood pressure regulation in DOCA-salt-treated mice.

An assessment of technology-based service encounters & network security on the e-health care systems of medical centers in Taiwan.

BACKGROUND: Enhancing service efficiency and quality has always been one of the most important factors to heighten competitiveness in the health care service industry. Thus, how to utilize information technology to reduce work load for staff and expeditiously improve work efficiency and healthcare service quality is presently the top priority for every healthcare institution. In this fast changing modern society, e-health care systems are currently the best possible way to achieve enhanced service efficiency and quality under the restraint of healthcare cost control. The electronic medical record system and the online appointment system are the core features in employing e-health care systems in the technology-based service encounters. METHODS: This study implemented the Service Encounters Evaluation Model, the European Customer Satisfaction Index, the Attribute Model and the Overall Affect Model for model inference. A total of 700 copies of questionnaires from two authoritative southern Taiwan medical centers providing the electronic medical record system and the online appointment system service were distributed, among which 590 valid copies were retrieved with a response rate of 84.3%. We then used SPSS 11.0 and the Linear Structural Relationship Model (LISREL 8.54) to analyze and evaluate the data. RESULTS: The findings are as follows: (1) Technology-based service encounters have a positive impact on service quality, but not patient satisfaction; (2) After experiencing technology-based service encounters, the cognition of the service quality has a positive effect on patient satisfaction; and (3) Network security contributes a positive moderating effect on service quality and patient satisfaction. CONCLUSION: It revealed that the impact of electronic workflow (online appointment system service) on service quality was greater than electronic facilities (electronic medical record systems) in technology-based service encounters. Convenience and credibility are the most important factors of service quality in technology-based service encounters that patients demand. Due to the openness of networks, patients worry that transaction information could be intercepted; also, the credibility of the hospital involved is even a bigger concern, as patients have a strong sense of distrust. Therefore, in the operation of technology-based service encounters, along with providing network security, it is essential to build an atmosphere of psychological trust.

Effects of internal marketing on nurse job satisfaction and organizational commitment: example of medical centers in Southern Taiwan.

As nurses typically represent the largest percentage of employees at medical centers, their role in medical care is exceptionally important and becoming more so over time. The quality and functions of nurses impact greatly on medical care quality. The concept of internal marketing, with origins in the field of market research, argues that enterprises should value and respect their employees by treating them as internal customers. Such a marketing concept challenges traditional marketing methods, which focus on serving external customers only. The main objective of internal marketing is to help internal customers (employees) gain greater job satisfaction, which should promote job performance and facilitate the organization accomplishing its ultimate business objectives. A question in the medical service industry is whether internal marketing can similarly increase the job satisfaction of nurses and enhance their commitment to the organization. This study aimed to explore the relational model of nurse perceptions related to internal marketing, job satisfaction, and organizational commitment by choosing nurses from two medical centers in Southern Taiwan as research subjects. Of 450 questionnaire distributed, 300 valid questionnaires were returned, giving a response rate of 66.7%. After conducting statistical analysis and estimation using structural equation modeling, findings included: (1) job satisfaction has positive effects on organizational commitment; (2) nurse perceptions of internal marketing have positive effects on job satisfaction; and (3) nurse perceptions of internal marketing have positive effects on organizational commitment.

The process of assisting behavior modification in a child with attention-deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a common psychological disease among children. The purpose of this study was to describe the process of assisting with behavior modification in a child with ADHD. The patient had undergone medical treatment for a year with no obvious effect. With the guidance of other professional people, the child's teachers and nursing instructors, the researchers proceeded with behavioral modification in conjunction with medication for another year. The medication treatment followed doctors' prescriptions, and, as regards the behavioral treatment, doctors and experts drafted and decided the content of the behavioral contract. The main basic techniques were skillful reinforcement and punishment. Then, via interviews with his parents and teachers, information was obtained that provided an understanding of the patient's condition and progress. It was found that the improvements were very significant. On the basis of the research results, the researchers submit that: (1) drug treatment combined with behavioral treatment apparently improves the daily behaviors of hyperactive children; (2) good communication with parents and psychological preparation are the most critical keys to the success of substantial behavioral improvement among hyperactive children; (3) establishment and integration of social resources, including provision of transitional parenting education solutions, and cooperation and sound interaction from school teachers, which fosters consolidated team work, are the critical factors to behavioral improvement among hyperactive children.

Epoxyeicosatrienoic Acid inhibition alters renal hemodynamics during pregnancy.

In this study we examined the expression of cytochrome P450 (CYP) 2C and CYP2J isoforms in renal proximal tubules and microvessels isolated from rats at different stages of pregnancy. We also selectively inhibited epoxyeicosatrienoic acid (EET) production by the administration of N-methanesulfonyl-6-(2-proparyloxyphenyl)hexanamide (MSPPOH 20 mg/kg/day iv) to rats during Days 14-17 of gestation and to age-matched virgin rats and determined the consequent effects on renal function. Western blot analysis showed that CYP2C11, CYP2C23, and CYP2J2 expression was significantly increased in the renal microvessels of pregnant rats on Day 12 of gestation. In the proximal tubules, CYP2C23 expression was significantly increased throughout pregnancy, while the expression of CYP2C11 was increased in early and late pregnancy and the expression of CYP2J2 was increased in middle and late pregnancy. MSPPOH treatment significantly increased pregnant rats' mean arterial pressure, renal vascular resistance, and sodium balance but significantly decreased renal blood flow, glomerular filtration rate, and urinary sodium excretion, as well as fetal pups' body weight and length. In contrast, MSPPOH treatment had no effect on renal hemodynamics or urinary sodium excretion in age-matched virgin rats. In pregnant rats, MSPPOH treatment also caused selective inhibition of renal cortical EET production and significantly decreased the expression of CYP2C11, CYP2C23, and CYP2J2 in the renal cortex, renal microvessels, and proximal tubules. These results suggest that upregulation of renal vascular and tubular EETs contributes to the control of blood pressure and renal function during pregnancy.

Customer satisfaction in medical service encounters -- a comparison between obstetrics and gynecology patients and general medical patients.

This study is concerned with the "service encounter", and seeks to describe, by use of the Service Encounter Evaluation Model, how the processes involved in the service encounter affect customer satisfaction. Its findings have implications for management practice and research directions, and recommendations are made. With the implementation of a national health insurance scheme, an ever-prospering economy and continually improving educational levels in Taiwan, demand among citizens for good health and medical care is ever increasing. Obstetrics and gynecology patients often differ greatly from general patients, in terms of their moods and emotions. This research involved an empirical study, whose subjects were 590 customers of general clinics and 339 customers of gynecology clinics, in various medical centers in southern Taiwan. By factor analysis, the study established four influencing factors, which were "Medical professionals", "Nursing professionals", "Service personnel" and "Space and facilities". Using the Linear Structural Relation Model (LISREL), it found that medical professionals, nursing professionals, service personnel and space and facilities were effective predictors of medical treatment satisfaction. We also found that the greatest positive impact on overall medical treatment satisfaction resulted from rises in satisfaction with medical professionals, but that the least impact was achieved in relation to service personnel in the general and gynecology clinics.

Induction of renal 20-hydroxyeicosatetraenoic acid by clofibrate attenuates high-fat diet-induced hypertension in rats.

This study compared renal hemodynamics, the expression of CYP4A isoforms [the enzymes for 20-hydroxyeicosatetraenoic acid (20-HETE) production], and tubular sodium transporters in male rats fed a high-fat (HF) or control diet for 10 weeks. We also studied the effect of treatment with clofibrate, a CYP4A inducer, on sodium retention and renal function and on CYP4A expression in HF rats. HF rats had higher blood pressure (BP), renal plasma flow, and glomerular filtration rate (GFR), but no significant change in renal vascular resistance. Reverse transcription-polymerase chain reaction analysis showed that CYP4A1 and CYP4A8 expression was significantly decreased in the renal cortex of HF rats. Western blot analysis showed up-regulation of expression of the alpha-subunit of the epithelial sodium channel (alpha-ENaC), the beta-subunit of the epithelial sodium channel (beta-ENaC), sodium/hydrogen exchanger (NHE)-3, and the renal outer medulla K(+) channel (ROMK) in HF rats, whereas expression of the gamma-subunit of the epithelial sodium channel and the alpha1-subunit of Na(+)-K(+)-ATPase remained unchanged. Thus, HF treatment caused the reduction of renal CYP4A1 and CYP4A8 expression, whereas the increases in alpha-ENaC, beta-ENaC, NHE-3, and ROMK expression in renal tubules may have contributed sodium retention and hypertension in HF rats. Furthermore, clofibrate treatment (240 mg/kg/day) caused the decrease of BP and GFR and the attenuation of cumulative sodium balance in HF rats. The attenuation of sodium retention by clofibrate treatment is linked to decreased expression of NHE-3 in renal cortex. Clofibrate induction of CYP4A expression occurred in proximal tubules and in the thick ascending limb of the loop of Henle but not in renal microvessels. This induction correlated with the expression of peroxisome proliferator-activated receptor (PPARalpha) in renal tubules. Therefore, these results suggest that the effects of clofibrate on sodium retention and blood pressure regulation in HF rats may be due to the induction of renal tubular 20-HETE production through the PPARalpha pathway.

Renal 20-HETE inhibition attenuates changes in renal hemodynamics induced by L-NAME treatment in pregnant rats.

We previously reported that inhibition of nitric oxide (NO) synthesis by N-nitro-L-arginine methyl ester (L-NAME) during late pregnancy leads to increased production of renal vascular 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 (CYP) 4A-derived vasoconstrictor, in pregnant rats. However, the effect of upregulation of vascular 20-HETE production on renal function after NO inhibition is not known. To test the hypothesis that increased gestational vascular 20-HETE synthesis after NO inhibition is involved in mediating blood pressure and renal functional changes, we first determined the IC(50) value of the effect of nitroprusside (SNP), a NO donor, on renal 20-HETE production in cortical microsomes. We then divided pregnant rats and age-matched virgin rats into a vehicle control group, an L-NAME treatment group (0.25 mg/ml in drinking water), and a group treated with L-NAME plus N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; CYP4A-selective inhibitor, 10 mg.kg(-1).day(-1) iv). After 4 days of treatment, we measured blood pressure, renal blood flow (RBF), renal vascular resistance (RVR), and glomerular filtration rate (GFR) in each group. The addition of SNP (IC(50) = 22 microM) decreased renal cortical 20-HETE production. In pregnant rats, L-NAME treatment led to significantly higher mean arterial pressure (MAP) and RVR, and lower RBF and GFR. Combined treatment with DDMS and L-NAME significantly attenuated the increases in MAP and RVR and the decrease in GFR, but not the reduction in RBF induced by L-NAME treatment. L-NAME and L-NAME plus DDMS had no significant impact on renal hemodynamics in virgin rats. In addition, chronic treatment with DDMS selectively inhibited cortical 20-HETE production without a significant effect on CYP4A expression in L-NAME-treated pregnant rats. In conclusion, NO effectively inhibits renal cortical microsomal 20-HETE production in female rats. In pregnant rats, the augmentation of renal 20-HETE production after NO inhibition is associated with increased MAP and RVR, whereas decreased GFR is negated by treatment of a selective and competitive CYP4A inhibitor. These results demonstrate that the interaction between renal 20-HETE and NO is important in the regulation of renal function and blood pressure in pregnant rats.

Gender differences of renal CYP-derived eicosanoid synthesis in rats fed a high-fat diet.

BACKGROUND: Renal cytochrome P450 (CYP)-derived eicosanoids, hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DHETs), have been shown to affect renal function and blood pressure (BP). We recently reported that high fat (HF) diet treatment in male rats increases BP and decreases production of these eicosanoids in the kidneys. However, at what level the downregulation of renal eicosanoid synthesis occurs and whether the HF diet has any effects on the regulation of renal eicosanoid synthesis in female rats are not known. The purpose of this study was to determine renal CYP-derived eicosanoid synthesis and its association with BP regulation in HF male and female rats. METHODS: In the first set of experiments, male and female rats were fed the HF or control diet for 10 weeks. In the second set of experiments, male and female rats were fed the HF diet for 10 days. In the third set of experiments, HF-fed and control female rats were treated with 5alpha-dihydrotestosterone for 4 weeks. After treatment, BP, urinary sodium, sodium balance, eicosanoid production, and CYP enzyme expression were determined. RESULTS: An elevation of BP and a decrease of renal cortical eicosanoid production were found in HF male rats, but no BP and eicosanoid production changes were observed in HF female rats. The HF treatment also caused a significant decrease of eicosanoid production and a decrease of CYP4A and 2C23 expression in the proximal tubules of HF male rats. Moreover, the HF diet treatment in male rats caused an increase in cumulative sodium balance and an elevation of BP, whereas no change in cumulative sodium balance and BP was observed in female rats. The treatment of 5alpha-dihydrotestosterone increased BP and 20-HETE production in the renal microvessels, but had no effect on urinary sodium excretion and renal microvessel EET production in both control and HF-fed female rats. CONCLUSIONS: These results demonstrate that there are gender-specific differences in regulation of renal eicosanoid synthesis, sodium balance, and BP caused by HF treatment, and it appears that androgens play some role in upregulation of renal microvessel 20-HETE production in both HF and control female rats.

Renal epoxyeicosatrienoic acid synthesis during pregnancy.

Epoxyeicosatrienoic acids (EETs), which belong to cytochrome P-450 (CYP)-derived eicosanoids, have been implicated to vasodilate renal arterioles, inhibit sodium transport in the nephron, and regulate blood pressure in several animal models. Because pregnancy is associated with changes of blood pressure, the aim of this study was to examine whether renal EET synthesis is altered and whether EETs are involved in blood pressure regulation during pregnancy in rats. Renal microsomal epoxygenase activity increased by 47, 97, and 63% on days 6, 12, and 19 of gestation, respectively. The elevation of epoxygenase activity during pregnancy was associated with an increase in CYP2C11, CYP2C23, and CYP2J2 protein expression on days 6, 12, and 19 of gestation. Moreover, immunohistochemical analysis showed that renal tubular CYP2C11, CYP2C23, and CYP2J2 expression was significantly increased in pregnant rats on days 6, 12, and 19 of gestation. Administration of 6-(2-propargyloxyphenyl)hexanoic acid (PPOH), a selective epoxygenase inhibitor, caused a dose-dependent inhibition of microsomal expoxygenase activity without a significant effect on omega-hydroxylase activity in female rats. Interestingly, administration of PPOH (20 mg.kg(-1).day(-1) for 4 days starting on day 15 of pregnancy) increased blood pressure by 21 mmHg and caused a significant decrease in the body weight of fetal pups (1.3 +/- 0.08 g in control vs. 1.1 +/- 0.06 g in PPOH). Moreover, PPOH treatment significantly decreased renal microsomal epoxygenase activity and the expression of CYP2C11, CYP2C23, and CYP2J in pregnant rats. This study demonstrates that EET synthesis in the kidney is elevated during pregnancy, and CYP2C11, 2C23, and CYP2J2 are responsible for the change of renal EET synthesis. The inhibition results demonstrate that the downregulation of renal epoxygenase activity by PPOH causes hypertension in pregnant rats. This study suggests that EETs may contribute to the control of blood pressure during pregnancy.

Downregulation of renal CYP-derived eicosanoid synthesis in rats with diet-induced hypertension.

The incidence of essential hypertension increases with obesity; however, the mechanisms that link obesity with hypertension are unclear. Renal cytochrome P450 (CYP)-derived eicosanoids--hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DHETs)--have been shown to play an important role in the regulation of renal function, vascular tone, and blood pressure. The objective of this study was to examine CYP-derived eicosanoid synthesis in the different renal zones (cortex, medulla, and papilla) of rats fed a high fat diet (HF). Male Sprague-Dawley rats were fed a HF diet or regular rat chow for 10 weeks. After 10 weeks, HF rats showed significantly higher systolic blood pressure, body weight, and fat:body weight ratio. The renal omega-hydroxylase activity was decreased by 46% in cortex, 43% in medulla, and 46% in papilla of HF rats. The renal epoxygenase activity was decreased by 46% in cortex, 31% in medulla, and 56% in papilla of HF rats. Interestingly, the changes in the rate of 20-HETE and EET formation in different renal zones were consistent with the levels of expression of CYP4A and CYP2C23 proteins, respectively. Furthermore, there were no significant changes in the synthesis of these metabolites in the renal microvessels. These results demonstrate that HF diet causes the downregulation of CYP4A and CYP2C23 in renal tubules, and these proteins are responsible for renal 20-HETE and EET formation. The reduction in the synthesis of these eicosanoids may play an important role in the regulation of renal function and blood pressure in obesity-induced hypertension.

Regulation of renal CYP4A expression and 20-HETE synthesis by nitric oxide in pregnant rats.

20-Hydroxyeicosatetraenoic acid (20-HETE), which promotes renal vasoconstriction, is formed in the rat kidney primarily by cytochrome P-450 (CYP) 4A isoforms (4A1, 4A2, 4A3, 4A8). Nitric oxide (NO) has been shown to bind to the heme moiety of the CYP4A2 protein and to inhibit 20-HETE synthesis in renal arterioles of male rats. However, it is not known whether NO interacts with and affects the activity of CYP4A1 and CYP4A3, the major renal CYP4A isoforms in female rats. Incubation of recombinant CYP4A1 and 4A3 proteins with sodium nitroprusside (SNP) shifted the absorbance at 440 nm, indicating the formation of a ferric-nitrosyl-CYP4A complex. The absorbance for CYP4A3 was about twofold higher than that of CYP4A1. Incubation of SNP or peroxynitrite (PN; 0.01-1 mM) with CYP4A recombinant membranes caused a concentration-dependent inhibition of 20-HETE synthesis, with both chemicals having a greater inhibitory effect on CYP4A3-catalyzed activity. Moreover, incubation of CYP4A1 and 4A3 proteins with PN (1 mM) resulted in nitration of tyrosine residues in both proteins. In addition, PN and SNP inhibited 20-HETE synthesis in renal microvessels from female rats by 65 and 59%, respectively. We previously showed that microvessel CYP4A1/CYP4A3 expression and 20-HETE synthesis are decreased in late pregnancy. Therefore, we investigated whether such a decrease is dependent on NO, the synthesis of which has been shown to increase in late pregnancy. Administration of NG-nitro-l-arginine methyl ester (l-NAME) to pregnant rats for 6 days (days 15-20 of pregnancy) caused a significant increase in systolic blood pressure, which was prevented by concurrent treatment with the CYP4A inhibitor 1-aminobenzotriazole (ABT). Urinary NO2/NO3 excretion decreased by 40 and 52% in l-NAME- and l-NAME + ABT-treated groups, respectively. Interestingly, renal microvessel 20-HETE synthesis showed a marked increase following l-NAME treatment, and this increase was diminished with coadministration of ABT. These results demonstrate that NO interacts with CYP4A proteins in a distinct manner and it interferes with renal microvessel 20-HETE synthesis, which may play an important role in the regulation of blood pressure and renal function during pregnancy.