Eicosapentaenoic acid reduces inflammation and apoptosis by SREBP1/TLR4/MYD88.

AIM: Podocytes dysfunction including the cell integrity, apoptosis and inflammation plays crucial role in diabetic nephropathy. Current exploration evaluated the protective role of eicosapentaenoic acid (EPA) in high glucose-treated podocytes and the underlying mechanisms. METHOD: MPC5 cell were stimulated by high glucose or treated by EPA of different concentrations. CCK8 assay was utilized to assess MPC5 cell viability, flow cytometry analyzed cell apoptosis. RESULTS: Data showed that EPA prominently alleviated the high glucose-induced apoptosis and inflammation. Besides, the disruption of the podocytes structure certifying by podocin and synaptopodin induced by hyperglycemia was hindered by EPA administration. In addition, overexpression of the sterol regulatory element-binding protein-1 (SREBP-1) reversed the protective effects of EPA in high glucose-treated podocytes. EPA inhibits the SREBP-1/TLR4/MYD88 signaling in high glucose treated cells. CONCLUSIONS: This study suggests that EPA protects against podocytes dysfunction by regulating SREBP-1 and these findings provide a better understanding for diabetic nephropathy and a novel therapeutic strategy (Fig. 7, Ref. 24).

Correlation of increased MALAT1 expression with pathological features and prognosis in cancer patients: a meta-analysis.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been identified as a potential cancer biomarker, yet the mechanism by which it influences the development of cancer remains unknown. In this study, we aimed to correlate MALAT1 expression with pathological features and prognosis in cancer patients. Several databases were searched using combinations of keywords relating to MALAT1 and cancer. After selection of relevant cohort studies according to strict criteria, a meta-analysis was conducted. Twelve studies were analyzed, involving 958 cancer patients. Elevated MALAT1 expression was associated with poor prognosis and larger tumors [prognosis: hazard ratio = 3.11, 95% confidence interval (CI) = 1.98-4.23, P = 0.000; tumor size: odds ratio (OR) = 0.40, 95%CI = 0.21-0.74, P = 0.003]. However, no connection with histological grade, T-stage, lymph node (LN) metastasis, or distant metastasis was established (all P > 0.05). A correlation between increased expression and poor prognosis was observed in the large and small sample-size subgroups (all P< 0.05), as was a relationship with large tumor size (OR = 0.30, 95%CI = 0.13-0.71, P = 0.006). Expression was correlated with T-stage and distant metastasis in the small sample-size subgroup (all P < 0.05), but no association was detected regarding histological grade, LN metastasis in either subgroup (all P > 0.05). Our findings demonstrate that elevated MALAT1 expression correlates with large tumor size, advanced tumor stage, and poor prognosis, and might therefore be utilized to evaluate clinical pathological features and prognostic out come for cancer patients.

[Exploring the causality between intestinal flora and hyperplastic scars of human based on two-sample Mendelian randomization analysis].

Objective: To investigate the causality between intestinal flora and hypertrophic scars (HS) of human. Methods: This study was a study based on two-sample Mendelian randomization (TSMR) analysis. The data on intestinal flora (n=18 473) and HS (n=208 248) of human were obtained from the genome-wide association study database. Genetically variable genes at five levels (phylum, class, order, family, and genus) of known intestinal flora, i.e., single nucleotide polymorphisms (SNPs), were extracted as instrumental variables for linkage disequilibrium (LD) analysis. Human genotype-phenotype association analysis was performed using PhenoScanner V2 database to exclude SNPs unrelated to HS in intestinal flora and analyze whether the selected SNPs were weak instrumental variables. The causal relationship between intestinal flora SNPs and HS was analyzed through four methods of TSMR analysis, namely inverse variance weighted (IVW), MR-Egger regression, weighted median, and weighted mode. Scatter plots of significant results from the four aforementioned analysis methods were plotted to analyze the correlation between intestinal flora SNPs and HS. Both IVW test and MR-Egger regression test were used to assess the heterogeneity of intestinal flora SNPs, MR-Egger regression test and MR-PRESSO outlier test were used to assess the horizontal multiplicity of intestinal flora SNPs, and leave-one-out sensitivity analysis was used to determine whether HS was caused by a single SNP in the intestinal flora. Reverse TSMR analyses were performed for HS SNPs and genus Intestinimonas or genus Ruminococcus2, respectively, to detect whether there was reverse causality between them. Results: A total of 196 known intestinal flora, belonging to 9 phyla, 16 classes, 20 orders, 32 families, and 119 genera, were obtained, and multiple SNPs were obtained from each flora as instrumental variables. LD analysis showed that the SNPs of the intestinal flora were consistent with the hypothesis that genetic variation was strongly associated with exposure factors, except for rs1000888, rs12566247, and rs994794. Human genotype-phenotype association analysis showed that none of the selected SNPs after LD analysis was excluded and there were no weak instrumental variables. IVW, MR-Egger regression, weighted median, and weighted mode of TSMR analysis showed that both genus Intestinimonas and genus Ruminococcus2 were causally associated with HS. Among them, forest plots of IVW and MR-Egger regression analyses also showed that 16 SNPs (the same SNPs number of this genus below) of genus Intestinimonas and 15 SNPs (the same SNPs number of this genus below) of genus Ruminococcus2 were protective factors for HS. Further, IVW analysis showed that genus Intestinimonas SNPs (with odds ratio of 0.62, 95% confidence interval of 0.41-0.93, P<0.05) and genus Ruminococcus2 SNPs (with odds ratio of 0.62, 95% confidence interval of 0.40-0.97, P<0.05) were negatively correlated with the risk of HS. Scatter plots showed that SNPs of genus Intestinimonas and genus Ruminococcus2 were protective factors of HS. Both IVW test and MR-Egger regression test showed that SNPs of genus Intestinimonas (with Q values of 5.73 and 5.76, respectively, P>0.05) and genus Ruminococcus2 (with Q values of 13.67 and 15.61, respectively, P>0.05) were not heterogeneous. MR-Egger regression test showed that the SNPs of genus Intestinimonas and genus Ruminococcus2 had no horizontal multiplicity (with intercepts of 0.01 and 0.06, respectively, P>0.05); MR-PRESSO outlier test showed that the SNPs of genus Intestinimonas and genus Ruminococcus2 had no horizontal multiplicity (P>0.05). Leave-one-out sensitivity analysis showed that no single intestinal flora SNP drove the occurrence of HS. Reverse TSMR analysis showed no reverse causality between HS SNPs and genus Intestinimonas or genus Ruminococcus2 (with odds ratios of 1.01 and 0.99, respectively, 95% confidence intervals of 0.97-1.06 and 0.96-1.04, respectively, P>0.05). Conclusions: There is a causal relationship between intestinal flora and HS of human, in which genus Intestinimonas and genus Ruminococcus2 have a certain effect on inhibiting HS.

Association of arterial stiffness in non-hypertensive offspring with parental hypertension: the Hanzhong adolescent hypertension cohort study.

OBJECTIVE: Arterial stiffness may be an early marker for vascular changes associated with hypertension in young adults. Individuals with a family history of hypertension are at high risk of developing hypertension. We investigated whether arterial stiffness measured, such as mean arterial pressure (MAP) and brachial to ankle pulse wave velocity (baPWV), were increased in normotensive offspring with a parental history of hypertension. PATIENTS AND METHODS: We compared MAP and baPWV in a sample of 1953 non-hypertensive participants (974 men, mean age 42±3 years) recruited in the previous Hanzhong adolescent hypertension cohort study. Standardized questionnaires, physical examinations and laboratory tests were used to obtain information, with a particular focus on family hypertension history, anthropometric, hemodynamic, and biochemical factors. RESULTS: A total of 1039, 759, 155 participants had 0, 1, and 2 parents with hypertension, respectively. Parental hypertension was associated with elevated offspring MAP (in multivariable-adjusted models, B=1.5 mm Hg, 95% CI 0.8-2.2 for 1 parent with hypertension; B=3.0 mm Hg, 95% CI 1.8-4.3, for 2 parents with hypertension; p<0.001 for each). A significant positive correlation was also observed between MAP and baPWV (r=0.543, p<0.001). BaPWV displayed a similar correlation with parental hypertension in age-adjusted, sex-adjusted and body mass index (BMI)-adjusted models (B=23.1 cm/s, 95% CI 8.0-38.1, for 1 parent with hypertension, p<0.01; B=53.0 cm/s, 95% CI 25.8-80.2, p<0.001 for 2 parents with hypertension), but associations were attenuated in multicovariate models after adjustment for MAP. In multivariable-adjusted models, logistic regression analysis showed that the risk of belonging to the upper quartile of MAP was significantly increased for offspring whose parents had hypertension (OR=1.5, 95% CI 1.2-1.9, for 1 parent with hypertension; OR=2.3, 95% CI 1.6-3.4, for 2 parents with hypertension; p<0.001 for each). Similarly, the odds ratios of belonging to the upper quartile of baPWV increased (OR=1.3, 95% CI 1.1-1.6, for 1 parent with hypertension, p<0.05; OR=2.1, 95% CI 1.5-3.0, for 2 parents with hypertension, p<0.001, in age-sex-BMI-adjusted models), and were then brought down in the fully adjusted models including MAP, but the increase remained significant for 2 parents with hypertension (OR=1.6, 95% CI 1.0-2.3, p<0.05). CONCLUSIONS: These findings provide evidence that arterial stiffness is higher in young-to middle-aged normotensive subjects with a family history of hypertension, suggesting that increased arterial stiffness may occur in the early stages during the pathogenesis of hypertension.

[The influence of apolipoprotein A1 on the prognosis of multiple myeloma].

Objective: In this study, we aimed to determine the change and clinical significance of serum level Apo A1 in MM patients. Methods: In total, 412 multiple myeloma patients were examined. SPSS 22.0 was used for data analysis. Correlation analysis was performed using linear correlation or Spearman rank correlation coefficients. Measurement data were analyzed with the t-test, Mann-Whitney U-test, or oneway analysis of variance (ANOVA) . Used the ROC curve to calculate the cutoff value and compared the OS and PFS between high Apo A1 subgroup and low Apo A1 subgroup with Kaplan-Meier survival analysis. Results: Our study showed that value of Apo A1 in the patient group was lower than that in the control group (0.89 g/L vs 1.24 g/L, P<0.05) . We found that Apo A1 dynamically changed with different MM stages. As it was increased when the disease was in remission, and decreased after disease in progression. According the result of multivariate analysis Apo A1 reduction become the independent risk factors of MM. On the basis of Kaplan-Meier survival analysis between high Apo A1 subgroup and low Apo A1 subgroup, we found higher Apo A1 patienta had longer OS rate and PFS. Conclusions: Apo A1 is a useful biomarker of tumor burden and a prognostic factor of multiple myeloma.

MiRNA-365a-3p promotes the progression of osteoporosis by inhibiting osteogenic differentiation via targeting RUNX2.

OBJECTIVE: The aim of this study was to explore the exact role of miRNA-365a-3p in the progression of osteoporosis, as well as its function in regulating osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). PATIENTS AND METHODS: The serum level of miRNA-365a-3p in osteoporosis patients and normal controls was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). After transfection of miRNA-365a-3p mimics, miRNA-365a-3p inhibitor or si-RUNX2 in hBMSCs, the relative expression levels of miRNA-365a-3p, osteocalcin (OCN), osteopontin (OPN) and collagen I were determined by qRT-PCR. Western blot was conducted to examine the protein expression of RUNX2 influenced by miRNA-365a-3p. Subsequently, the regulatory effects of miRNA-365a-3p and RUNX2 on osteogenic differentiation and capability of mineralization were evaluated by alkaline phosphatase (ALP) determination and alizarin red staining, respectively. Furthermore, the binding relationship between miRNA-365a-3p and RUNX2 was predicted and verified by miRanda and Dual-Luciferase reporter gene assay, respectively. RESULTS: MiRNA-365a-3p was highly expressed in osteoporosis patients. The expression of miRNA-365a-3p in hBMSCs decreased gradually with the prolongation of osteogenic differentiation. The subsequent results showed that RUNX2 could bind to miRNA-365a-3p, which was negatively regulated by miRNA-365a-3p in hBMSCs. Down-regulation of miRNA-365a-3p significantly decreased the expression levels of OCN, OPN and collagen I. Furthermore, overexpression of miRNA-365a-3p markedly weakened the capability of mineralization of hBMSCs, whereas was further reversed by transfection of si-RUNX2. CONCLUSIONS: MiRNA-365a-3p negatively regulates osteogenic differentiation of hBMSCs by targeting RUNX2, thus promoting the progression of osteoporosis.

Atrial natriuretic peptide attenuates the development of pulmonary hypertension in rats adapted to chronic hypoxia.

To test the hypothesis that chronic infusion of atrial natriuretic peptide (ANP) instituted before hypoxic exposure attenuates the development of pulmonary hypertension in hypoxia adapted rats, ANP (0.2 and 1.0 microgram/h) or vehicle was administered intravenously via osmotic minipump for 4 wk beginning before exposure to 10% O2 or to room air. Low dose ANP increased plasma ANP levels by only 60% of vehicle controls after 4 wk and significantly decreased mean pulmonary arterial pressure (MPAP) (P less than 0.01), the ratio of right ventricular weight to body weight (RV/BW) (P less than 0.01), and the wall thickness of small (50-100 microns) pulmonary arteries (P = 0.01) in hypoxia-adapted rats. ANP did not alter any of these parameters in air-control rats. High dose ANP increased plasma ANP levels by 230% of control and produced greater reductions in MPAP (P less than 0.001) and RV/BW) (P less than 0.05), but not in pulmonary arterial wall thickness, than the low dose. Neither dose of ANP altered mean systemic arterial pressure in either hypoxic or normoxic rats. The data demonstrate that chronic infusion of exogenous ANP at a dose that does not affect MPAP or RV weight in air-control rats attenuates the development of pulmonary hypertension and RV enlargement in rats adapted to chronic hypoxia.

Blockade of endogenous anterior hypothalamic atrial natriuretic peptide with monoclonal antibody lowers blood pressure in spontaneously hypertensive rats.

We have previously shown that the atrial natriuretic peptide (ANP) content of the anterior hypothalamic region of NaCl-sensitive spontaneously hypertensive rats (SHR-S) is higher than that of Wistar-Kyoto (WKY) rats. ANP has been shown to inhibit neuronal norepinephrine release and to reduce the excitability of hypothalamic neurons. This study tested the hypothesis that blockade of endogenous ANP in the anterior hypothalamus by local microinjection of a monoclonal antibody to ANP (MAb KY-ANP-II) lowers blood pressure in SHR-S. Purified MAb KY-ANP-II (0.055 and 0.55 micrograms) or control mouse IgG in 200 nl saline was microinjected into the anterior hypothalamic area (AHA) of conscious SHR-S and control WKY rats. As a further control, Mab KY-ANP-II (0.55 microgram) was microinjected into the posterior hypothalamic area (PHA) of SHR-S. Anterior hypothalamic microinjection of MAb KY-ANP-II caused significant dose-related decreases in mean arterial pressure (MAP) and heart rate (HR) in SHR-S but not in WKY rats. Control injections of equal volumes of IgG had no effect on MAP or HR. Microinjection of Mab KY-ANP-II into PHA produced no significant alteration in MAP or HR in SHR-S. These data provide the first demonstration that endogenous ANP in a region of brain known to influence cardiovascular function mediates BP and HR control in the rat. These findings suggest that the increased endogenous ANP in the anterior hypothalamus of SHR-S may be involved in the central regulation of BP in the model.

MicroRNA-645 is an oncogenic regulator in colon cancer.

Despite advances in early diagnosis and the development of molecularly targeted therapy, curative treatment of colon cancer once it has metastasized is yet to be accomplished. This is closely associated with deregulated CRC cell proliferation and resistance to apoptosis. Here we reveal that upregulation of microRNA-645 (miR-645) through DNA copy number gain is responsible for enhanced proliferation and resistance to apoptosis in colon cancer. MiR-645 was upregulated in most colon cancer tissues related to adjacent normal mucosa. This appeared to be associated with amplification of a section of chromosome 20q13.13, where miR-645 is located. Inhibition of miR-645 reduced proliferation and enhanced sensitivity to apoptosis triggered by the chemotherapeutic drugs 5-fluorouracil and cisplatin in CRC cells, and retarded colon cancer xenograft growth. Conversely, overexpression of miR-645 in normal colon epithelial cells enhanced proliferation and triggered anchorage-independent cell growth. Although SRY-related HMG-box 30 (SOX30) was identified as a miR-645 target, its expression was only partially affected by miR-645, suggesting that miR-645 is a fine-tuning mechanism of SOX30 expression. Moreover, overexpression of SOX30 only moderately inhibited promotion of CRC cell proliferation by miR-645, indicating that miR-645 may have more targets that contribute to its pro-proliferation effect in colon cancer. Together, this study reveals that miR-645 can regulate oncogenesis in colon cancer with SOX30 being one of its targets.

[Relationship between overweight/obesity and hypertension among adults in China: a prospective study].

OBJECTIVE: To evaluate the influence of overweight/obesity on the incidence of hypertension among adults in China. METHODS: The subjects of this prospective study were 13 739 Chinese adults aged 35-74 years recruited at the baseline surveys of China Multicenter Collaborative Study of Cardiovascular Disease Epidemiology and International Collaborative Study of Cardiovascular Disease in Asian. Baseline surveys were conducted in 1998 and during 2000-2001, respectively, and the follow-up was conducted during 2007-2008. According to the body mass index, the subjects were divided into four groups: underweight group(<18.5 kg/m(2)), normal weight group(18.5-23.9 kg/m(2)), overweight group(24.0-27.9 kg/m(2))and obesity group(≥28.0 kg/m(2)). Age-standardized cumulative incidence of hypertension was calculated for each group, respectively. The relative risks(RRs)and 95% confidence intervals(CIs)for the incidence of hypertension of underweight, overweight and obesity groups were estimated by using generalized linear regression model with normal weight group as reference. RESULTS: During 8.1 years of follow-up, 4 271 hypertension cases were detected(2 012 in men and 2 259 in women). Age-standardized cumulative incidence of hypertension for the underweight, normal weight, overweight and obesity groups were 20.3%, 30.9%, 43.6% and 50.8% in men, respectively; and 22.9%, 30.4%, 41.1% and 50.8% in women, respectively. Compared with the normal weight group, multivariate-adjusted RR(95% CI)for the incidence of hypertension in underweight, overweight and obesity groups were 0.78(0.64-0.95), 1.22(1.13-1.30)and 1.28(1.16-1.42)in men, respectively; and 0.89(0.77-1.03), 1.16(1.09-1.23)and 1.28(1.18-1.38)in women, respectively. The overweight and obese subjects had higher risk for the incidence of hypertension, with the population attributable risk proportion of 7.4% in men and 8.8% in women, respectively. CONCLUSION: Overweight or obese people are at an increased risk of developing hypertension, thus prevention and control of overweight/obesity are needed to reduce hypertension incidence among adults in China.

INPP4B is an oncogenic regulator in human colon cancer.

Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and is a tumor suppressor in some types of cancers. However, we have found that it is frequently upregulated in human colon cancer cells. Here we show that silencing of INPP4B blocks activation of Akt and serum- and glucocorticoid-regulated kinase 3 (SGK3), inhibits colon cancer cell proliferation and retards colon cancer xenograft growth. Conversely, overexpression of INPP4B increases proliferation and triggers anchorage-independent growth of normal colon epithelial cells. Moreover, we demonstrate that the effect of INPP4B on Akt and SGK3 is associated with inactivation of phosphate and tensin homolog through its protein phosphatase activity and that the increase in INPP4B is due to Ets-1-mediated transcriptional upregulation in colon cancer cells. Collectively, these results suggest that INPP4B may function as an oncogenic driver in colon cancer, with potential implications for targeting INPP4B as a novel approach to treat this disease.

Depressor effect of blocking angiotensin subtype 1 receptors in anterior hypothalamus.

Previous studies have shown that the anterior hypothalamic area participates in the centrally mediated pressor response to exogenous angiotensin II. The current study was designed to test the hypothesis that endogenous anterior hypothalamic angiotensin II plays a significant role in blood pressure control. Type 1 angiotensin II receptors in the anterior hypothalamic area were blocked by local microinjection of DuP 753 (2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole, potassium salt), a highly selective nonpeptide antagonist. DuP 753 (20 or 40 micrograms; in 100 nl artificial cerebrospinal fluid) or vehicle alone was microinjected into the anterior hypothalamic area of conscious NaCl-sensitive spontaneously hypertensive rats and Wistar-Kyoto controls. DuP 753 caused significant dose-related decreases in mean arterial pressure (maximal decrease, 22.5 +/- 1.8 mm Hg) with unchanged heart rate in NaCl-sensitive spontaneously hypertensive rats but effected no change in Wistar-Kyoto rats. Injections of equal volumes of artificial cerebrospinal fluid into the anterior hypothalamic area had no effect in either strain. Further, microinjection of DuP 753 into the posterior hypothalamic area produced no significant effect on blood pressure or heart rate in NaCl-sensitive spontaneously hypertensive rats. Microinjection into the anterior hypothalamic area of the selective type 2 angiotensin II receptor antagonist PD 123319 did not affect blood pressure or heart rate in NaCl-sensitive spontaneously hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic factor prevents NaCl-sensitive hypertension in spontaneously hypertensive rats.

Our previous studies demonstrated that acute infusion of atrial natriuretic factor (ANF) produces an enhanced depressor response in NaCl-sensitive spontaneously hypertensive rats (SHR-S) fed a high (8%) NaCl diet compared with control SHR-S fed a normal (1%) NaCl diet and that dietary NaCl loading increases circulating ANF levels in Wistar-Kyoto (WKY) rats but not in SHR-S. The current study tested the hypotheses that 1) long-term infusion of ANF at a dose that elevates plasma ANF to levels comparable with those seen in high NaCl-fed WKY rats prevents the NaCl-induced exacerbation of hypertension in SHR-S and 2) ANF lowers blood pressure in this model by a sympatholytic effect. Male SHR-S received infusions of ANF (0.1 microgram/hr) or vehicle intravenously via osmotic minipump for 3 weeks beginning immediately before initiation of 1% or 8% NaCl diets at age 7 weeks. Chronic ANF infusion prevented the increase in arterial pressure in response to a high NaCl diet in SHR-S but had no effect in 1% NaCl-fed SHR-S. Thus, the NaCl-sensitive component of hypertension in SHR-S was more sensitive to ANF than the non-NaCl-sensitive component. Plasma norepinephrine was significantly increased in ANF-treated, 8% NaCl-fed SHR-S compared with vehicle controls, suggesting that ANF did not prevent NaCl-sensitive hypertension by a sympatholytic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic factor in NaCl-sensitive and NaCl-resistant spontaneously hypertensive rats.

Our previous studies demonstrated that chronic dietary NaCl supplementation is associated with significant increases in plasma atrial natriuretic factor in Wistar-Kyoto (WKY) rats but not in NaCl-sensitive spontaneously hypertensive rats (SHR-S). The current study tested the hypotheses that 1) acute volume-induced atrial natriuretic factor release is impaired in SHR-S compared with control NaCl-resistant SHR (SHR-R) and WKY rats maintained on basal (1%) NaCl diets; 2) dietary NaCl supplementation (8% NaCl for 2 weeks) alters acute volume-dependent atrial natriuretic factor release in these strains; and 3) replacement of the deficiency in circulating atrial natriuretic factor seen in NaCl-supplemented SHR-S can reverse the NaCl-sensitive component of hypertension. SHR-S and control SHR-R and WKY rats were placed on 1% or 8% NaCl diets at age 7 weeks; 2 weeks later, right atrial pressure and plasma atrial natriuretic factor were measured in conscious rats before and after acute volume expansion (7, 20, and 60 ml/kg, 5% dextrose, for 1 minute). The slopes of the right atrial pressure x plasma atrial natriuretic factor linear regression for the SHR-S fed both 1% and 8% NaCl were significantly shallower (p less than 0.01) than those of 1% NaCl-fed SHR-R or WKY rats. Dietary NaCl supplementation did not alter right atrial pressure in any strain and blunted acute volume-induced atrial natriuretic factor release in WKY rats, but not in SHR-S or SHR-R, suggesting the dietary NaCl-induced elevation in plasma atrial natriuretic factor levels in WKY rats may be related to impaired clearance, as well as enhanced release, of the peptide. The plasma levels of exogenous atrial natriuretic factor required to abolish the NaCl-induced pressor effect in SHR-S were 12-fold greater than endogenous plasma atrial natriuretic factor levels in 8% NaCl-fed WKY rats, suggesting that impairment of atrial natriuretic factor release does not play a major role in the pathogenesis of NaCl-sensitive hypertension in SHR-S.

Intrahypothalamic clonidine infusion prevents NaCl-sensitive hypertension.

We have previously shown that dietary NaCl supplementation increases blood pressure and sympathetic nervous system activity in association with decreased norepinephrine release and increased alpha 2-adrenergic receptor number in the anterior hypothalamic area of salt-sensitive spontaneously hypertensive rats (SHR-S) but not in salt-resistant spontaneously hypertensive rats (SHR-R) or Wistar-Kyoto (WKY) rats. Further, acute microinjection of clonidine into the anterior hypothalamic area produced depressor responses that were augmented by high salt feeding in SHR-S but not in SHR-R or WKY rats. The current study tested the hypothesis that chronic infusion of clonidine into the anterior hypothalamic area prevents salt-sensitive hypertension in SHR-S. Beginning at age 7 weeks, immediately before initiation of 1% or 8% salt diets, clonidine (2 ng/min) or saline vehicle was infused into the anterior hypothalamic area or femoral vein of male SHR-S via osmotic minipump for 20 days. In SHR-S fed an 8% salt diet, chronic microinfusion of clonidine into the anterior hypothalamic area offset the hypertensive effect of the dietary salt supplementation and reduced the enhancing effects of dietary salt on left ventricular weight and plasma norepinephrine levels. In contrast, chronic microinfusion of clonidine into the anterior hypothalamic area did not significantly affect any of these measures in 1% salt-fed SHR-S. Intravenous infusion of clonidine at the rate used for the anterior hypothalamic area infusion did not alter any of these measures in 8% salt-fed SHR-S.(ABSTRACT TRUNCATED AT 250 WORDS)

Pressor effect of blocking atrial natriuretic peptide in nucleus tractus solitarii.

Previous studies have shown that microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii produces significant increases in local neuronal firing rate associated with reductions in arterial pressure in anesthetized Wistar rats. Single units excited by microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii were also excited by activation of arterial baroreceptors and inhibited by baroreceptor unloading. To test the hypothesis that endogenous atrial natriuretic peptide in caudal nucleus tractus solitarii is involved in the tonic control of blood pressure in the rat, we administered a blocking monoclonal antibody to atrial natriuretic peptide in a volume of 50 nl artificial cerebrospinal fluid via microinjection into the caudal nucleus tractus solitarii of spontaneously hypertensive and Wistar-Kyoto rats and observed the effects on mean arterial pressure and heart rate. Control injections of monoclonal antibody were administered into the rostral nucleus tractus solitarii, hypoglossal nucleus, spinal trigeminal nucleus, and cuneate nucleus of spontaneously hypertensive rats. Microinjection of monoclonal antibody into the caudal nucleus tractus solitarii caused significant increases in mean arterial pressure in spontaneously hypertensive rats but not in Wistar-Kyoto rats. There was no concomitant change in heart rate. Control injections of purified mouse immunoglobulin into the caudal nucleus tractus solitarii and of monoclonal antibody into the control neuronal groups listed above had no effect on mean arterial pressure. These results suggest that endogenous atrial natriuretic peptide in the caudal nucleus tractus solitarii mediates tonic control of blood pressure in spontaneously hypertensive rats but not in normotensive Wistar-Kyoto rats.

Atrial natriuretic peptide modulates baroreceptor reflex in spontaneously hypertensive rat.

Our previous studies have suggested that atrial natriuretic peptide in the caudal nucleus tractus solitarii is involved in the centrally mediated regulation of blood pressure in the salt-sensitive spontaneously hypertensive rat (SHR). The current study tested the hypothesis that endogenous atrial natriuretic peptide in the caudal nucleus tractus solitarii participates in baroreceptor reflex control of heart rate in this hypertensive model. Salt-sensitive SHR and control Wistar-Kyoto (WKY) rats maintained on basal (1%) salt intake were studied. Arterial baroreceptor reflex-mediated changes in heart rate were recorded in conscious unrestrained rats during phenylephrine (5-40 micrograms.kg-1.min-1 infusion; 30 minutes later, atrial natriuretic peptide (50 ng), monoclonal antibody to atrial natriuretic peptide (0.55 micrograms), purified mouse immunoglobulin G (0.55 micrograms), or artificial cerebrospinal fluid vehicle (50 nl) was microinjected into the caudal nucleus tractus solitarii. Phenylephrine infusion was then repeated and mean arterial pressure and heart rate were monitored as before. The slope of the heart rate/mean arterial pressure relation was significantly less (p less than 0.05) in the salt-sensitive SHR than in the WKY control, indicating that baroreceptor reflex control of heart rate was blunted in this hypertensive model. Microinjection of atrial natriuretic peptide into the caudal nucleus tractus solitarii further blunted (p less than 0.05) baroreceptor reflex control of heart rate in salt-sensitive SHR but not in WKY rats. In contrast, microinjection of the monoclonal antibody enhanced the sensitivity of baroreceptor reflex control of heart rate in salt-sensitive SHR but not in WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Blocking hypothalamic AT1 receptors lowers blood pressure in salt-sensitive rats.

Previous studies from our laboratory have shown that microinjection of DuP 753 (2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]imidazole, potassium salt), a highly selective nonpeptide antagonist of type 1 angiotensin II receptors, into the anterior hypothalamic area produces a dose-related depressor response in salt-sensitive spontaneously hypertensive rats fed a basal (1%) salt diet. The current study tested the hypothesis that the depressor response to anterior hypothalamic type 1 angiotensin II receptor blockade with DuP 753 or its metabolite EXP 3174 is enhanced by high (8%) salt feeding in this model. DuP 753 or EXP 3174 (40 micrograms in 100 nl artificial cerebrospinal fluid vehicle) or vehicle alone was microinjected into the anterior hypothalamic area of conscious salt-sensitive spontaneously hypertensive and Wistar-Kyoto rats that had been fed 1% or 8% salt diets for 3 weeks. Both DuP 753 and EXP 3174 caused significant decreases in mean arterial pressure in spontaneously hypertensive but not in Wistar-Kyoto rats fed either diet. The magnitude and duration of the depressor responses to DuP 753 and EXP 3174 were significantly greater in the 8% salt-fed spontaneously hypertensive rats than in 1% salt-fed rats. Vehicle injections had no effect on blood pressure in either strain-diet group. Microinjection of angiotensin II (2 micrograms in 100 nl artificial cerebrospinal fluid vehicle) into the anterior hypothalamic area caused significant pressor and bradycardiac responses in all strain-diet groups; dietary salt supplementation enhanced these effects in salt-sensitive spontaneously hypertensive rats but not in Wistar-Kyoto rats. These responses were blocked by pretreatment with EXP 3174.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired release of atrial natriuretic factor in NaCl-loaded spontaneously hypertensive rats.

Our previous studies demonstrated that NaCl-sensitive spontaneously hypertensive rats (SHR) of the Okamoto strain exhibit increased blood pressure and reduced noradrenergic input to the anterior hypothalamus area when fed high NaCl diets. The current study tested the hypotheses that 1) release of atrial natriuretic factor (ANF) into the plasma is impaired in NaCl-loaded SHR, a defect that would tend to elevate blood pressure, and 2) ANF levels in regions of brain involved in blood pressure regulation, such as the anterior hypothalamic area, are altered in SHR. SHR and control Wistar-Kyoto rats (WKY) were placed on 1% or 8% NaCl diets at age 7 weeks; 2 weeks later, ANF levels were measured in plasma, left and right atria, anterior hypothalamic area, ventral hypothalamic area, posterior hypothalamic area, pons, and medulla by radioimmunoassay. Blood for ANF assay was obtained from intra-arterial cannulas in conscious, unrestrained rats studied in the resting state. The 8% NaCl diet produced an increase in blood pressure in the SHR, but not in the WKY. Plasma ANF levels were significantly greater in WKY fed 8% NaCl than in WKY fed 1% NaCl, but dietary NaCl loading did not produce similar increases in plasma ANF in the SHR. Plasma ANF levels were not significantly different between SHR and WKY fed the 1% NaCl diet. The observation that dietary NaCl loading stimulated ANF release into the plasma in WKY but not in SHR suggests that the exacerbation in hypertension seen in NaCl-loaded SHR may be related to an impairment in ANF release.(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary Ca2+ prevents NaCl-sensitive hypertension in spontaneously hypertensive rats via sympatholytic and renal effects.

NaCl-sensitive spontaneously hypertensive rats (SHR-S) were used to test the hypotheses that dietary Ca2+ supplementation 1) prevents NaCl-sensitive hypertension via a sympatholytic mechanism, and 2) increases diuretic and natriuretic responses to acute volume loading. SHR-S and control WKY rats were begun on one of four diets at age 8 wk: control, high NaCl, high Ca2+, or high NaCl and high Ca2+. In SHR-S, dietary Ca2+ supplementation prevented the NaCl-induced increases in blood pressure and plasma norepinephrine concentrations, the reductions in anterior hypothalamic norepinephrine stores and turnover, and the secondary increases in alpha 2 adrenoceptor number. Thus, Ca2+ prevented NaCl-sensitive hypertension in SHR-S by increasing noradrenergic input to the anterior hypothalamus. High-NaCl-fed SHR-S had impaired diuretic and natriuretic responses to an isotonic volume load; Ca2+ enhanced the ability of these animals to adjust fluid volume rapidly via diuresis and natriuresis. This alteration in renal function may contribute to the hypotensive effect of a high Ca2+ diet in NaCl-sensitive hypertension.