Basal BP Research Articles

Sex differences in a novel transgenic mouse model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia characterized by memory deficits, cognitive impairment, and presence of amyloid plaques and tau tangles in the brain. In the United States, six million people over the age of 65 live with AD, four million of whom are women. The apolipoprotein ( APOE) gene is the strongest genetic risk factor for late-onset AD, with the ε4 allele increasing AD risk relative to the ε3 allele. Mechanisms driving sex-based prevalence in the APOE4 genotype remain unknown. Previously, we have reported that female APOE4 mice develop hypertension and increased levels of vasoconstrictor angiotensin II (Ang II) in CSF with aging [FASEB J 2022: 36S1]. To better recapitulate human AD pathology and phenotype, we have recently generated unique mouse strains - 3XE4 and 3XE3 mice, by breeding human APOE4/APOE3-knockin with APPsw, PS1dE9, and tauP301S transgenes. Our goal is to study sex differences in the 3XE4 mice with AD. Blood pressure (BP, tail cuff), cognition (novel object recognition test), and cardiac function (echocardiography) were measured in both control 3XE3 (n=6) mice and 3XE4 (n=6) mice before and after Ang II (osmotic minipump, 1000 ng/kg/min). As expected, female mice weighed less than the male mice (Table). Basal BP and ejection fraction were higher in male 3XE4 mice compared to female 3XE4 mice (p<0.05). Total exploration time of novel object was significantly delayed in 3XE4 mice (p<0.05); the impairment was greater in the female 3XE4 mice. Notably, Ang II increased BP in male 3XE4 mice (151±5 mmHg) but not in female 3XE4 mice (125±2 mmHg). Unlike the 3XE3 mice, total exploration time of novel object was delayed (impaired) in both male and female 3XE4 mice at baseline and during Ang II. Although additional studies are needed to explore the underlying mechanisms, our results implicate potential sexual dimorphism in blood pressure regulation and cognition in Alzheimer’s Disease. [Formula: see text] Funding: NIH R01HL149677 and R21AG070188. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Assessment of sympathovagal balance by HRV analysis in alcoholic and nonalcoholic fatty liver disease patients

BACKGROUND: Heart rate variability (HRV) is the variation in the time intervals between continuous heartbeats also called interbeat intervals to give information related to the heart, blood pressure, gaseous exchange, and sympathetic and parasympathetic balance. Abnormalities in the conduction of the cardiac system alter the measurements of heart rate variability and lead to alteration in autonomic function with a higher risk of mortality. So, our objective includes the assessment of sympathovagal balance in AFLD and NAFLD patients. MATERIALS AND METHODS: The study included 78 alcoholic and 54 nonalcoholic fatty liver patients. A room temperature of 23°C with 25–35% humidity will be maintained in a recording room. Basal supine heart rate and BP will be recorded by the oscillometric method using an automated blood pressure monitor Omron MX3, India. Lead II ECG will be recorded for the next 5 minutes in total resting condition for short-term HRV analysis. Short-term HRV indices including time domain and frequency domain were recorded from each patient. Under time domain, SDNN, RMSSD, and average RR were noted. Under frequency domain, LF, HF, VLF, LF (nu), HF (nu), and LF/HF were calculated. The data were collected by using a 16-bit, power lab 8/30 data acquisition system (New South Wales, Australia) with acknowledge 3.8.2 software. Inferential analyses such as independent t-tests and Mann–Whitney tests were used to compare NAFLD and AFLD patient groups. Carl Pearson correlation analysis was performed to obtain a relationship between variables. RESULTS: SDNN in (ms) which represents the overall HRV found to be decreased in both alcoholic (32.84 ± 79.08) and nonalcoholic fatty liver disease (22.04 ± 13.85) compared to the normal range (50 ± 16)) from 27 studies. The value of RMSSD in (ms) was decreased in both alcoholic (17.00 ± 12.48) and nonalcoholic fatty liver disease patients (14.00 ± 9.44) with the normal range of (42 ± 15) from 15 studies. Pearson correlation analysis showed the age of AFLD patients significantly and positively correlated with average RR. Pearson correlation analysis for the age of NAFLD patients was significantly and positively correlated with the average RR, HF, SDNN, RMSSD, and LF. CONCLUSION: Altered autonomic activity was noted in both alcoholic and nonalcoholic fatty liver disease patients. An early prognosis of fatty liver is very necessary to prevent the disease progress into later fatal life-threatening stages.

CHARACTERISTIC OF RESPONDERS TO RENAL DENERVATION - CROATIAN REAL-LIFE STUDY

Objective: Heterogeneity in response to renal denervation (RDN) is acknowledged phenomena and one of most important tasks in this field is to find reliable predictive biomarker for positive response. Our aim was to analyse characteristics of resistant hypertensive patients who were responders 6 months after RDN. Design and method: Out of 31 truly resistant patients whom secondary forms of hypertension were ruled out and were enrolled into the Croatian Spyral RDN registry, 18 (10 m, 8 w, average age 49.3) were eligible for analyses. Office BP, ABPM, central BP and PWV were measured with Omron M6, Molbilograph and Sphygmocor devices, respectively. Sympathetic/parasympathetic activity was measured with ANX-3.0 ANSAR device. Results: Responders were 6.7 years older, less obese with at basal slightly higher eGFR (88.6 vs. 79.8), uric acid (406.5 vs. 376.4), salt intake (12.6 g/day vs.9.8 g/day) and had significantly higher basal office BP (169.5/99.7 vs. 153.3/96.5) as well as ABPM values. Central aortic systolic BP and Aix were higher in responders (154.5 vs, 147.1; 31.5 vs 27.3) without difference in PWV (10.1 vs. 9.6). Responders had lower values of PP amplification (1.22 vs. 1.33). Significantly higher basal sympathetic activity (LFa/RFa) was determined in responders than in non-responders (6.68 vs. 1.25). Conclusions: Responders were older with higher basal office BP, ABPM but also higher central BP and Aix with lower pulse pressure amplification. They ingested more salt, had higher values of uric acid and importantly had more exaggerated sympathetic activity. Whether some of identified parameters could be considered as a biomarker for positive response in resistant hypertensive patients should be determined in larger cohort of patients.

Abstract P333: Influence Of RSK2 On Blood Pressure In Aging

Hypertension (HTN) is highly prevalent and is a significant risk factor for CVD. Excessive vasoconstriction contributes to HTN. Recently, p90 ribosomal S6 kinase, isoform 2 (RSK2) signaling has been shown to play a significant role in the regulation of basal vascular tone and BP control by phosphorylating RLC20 to promote smooth muscle contractility. Young adult Rsk2 KO mice have lower BP than WT littermates. Here, we examine the role of RSK2 in a geriatric HTN mouse model. Male >2-year old WT and Rsk2 KO mice underwent daily BP measurements using tail cuff manometry. After 2 weeks of training, baseline (BL) BP was recorded, followed by 2 weeks of HTN induced by 20 mg/kg/day of L-N G -Nitroarginine methyl ester (L-NAME) via drinking water. Echocardiographic studies were performed at BL. WT mice had significant mortality (7 of 11 died), not seen in KO (1 of 8 died). At BL, WT mice had a significantly higher SBP compared to KOs (123±10 vs. 99±12 mmHg). L-NAME elevated SBP in WT but not KO mice (137±2 vs. 97±8 mmHg). Echocardiographic studies at BL showed no differences between genotypes. However, when ejection fraction (EF) was correlated with SBP, EF was negatively correlated with SBP in WT (-0.94 %/mmHg, p = 0.046, R 2 = 0.59, n = 6) but not KO mice (p = 0.15, n = 7). Clinically, HTN-associated mortality and morbidity primarily affects older populations. Here, we show that the loss of RSK2 reduces BP in geriatric mice, similar to findings in young adult mice, and that it also abolished the hypertensive effects of L-NAME. Aged Rsk2 KO mice appear to be protected from cardiovascular effects of aging. RSK2 is a potential target for pharmacologic inhibition to treat HTN and related risks in geriatric populations.

The Blood-Pressure-Lowering Effect of Food-Protein-Derived Peptides: A Meta-Analysis of Recent Clinical Trials.

Although clinical trials of food-protein-derived peptides in the management of hypertension have been published, the results are controversial, which compelled us to conduct a meta-analysis to evaluate the pooled effect of peptide intervention. In this study, we searched for studies published between 2010 and 2021 and selected 12 eligible studies for a meta-analysis. The pooled effect of peptide intervention for systolic blood pressure (SBP) and diastolic blood pressure (DBP) was −3.28 mmHg (95% CI: −4.54, −2.03, p < 0.001) and −1.82 mmHg (95% CI: −3.46, −0.18, p = 0.03), respectively. Sub-group analyses showed that the reduction in BP in participants with higher basal BP (>140/85 mmHg) was greater (p = 0.007 for SBP and p = 0.01 for DBP), and the effect was stronger in Asian participants as compared with non-Asian participants (p = 0.01 for SBP and p = 0.04 for DBP). In addition, the effect of peptide intervention was more pronounced on SBP in participant groups with a lower ratio of male to female (≤0.5) as well as in participants with a mean age ≥50 years old. In conclusion, food-protein-derived antihypertensive peptides can significantly reduce BP in prehypertensive and hypertensive patients. Findings from this study could provide guidance for the design of clinical trials of antihypertensive peptides.

ESTIMATED PULSE WAVE VELOCITY (EPWV) AND MORTALITY IN SUBJECTS WITH HEALTHY VASCULAR AGEING (HVA) AND EARLY VASCULAR AGEING (EVA) IN GENERAL POPULATION. EH-UH STUDY

Objective: Arterial stiffness (cfPWV) is acknowledged biomarker of ageing having significant predictive value for cardiovascular (CV) events in hypertensive patients. It was observed that ePWV calculated by equation using age and mean blood pressure (MBP) improved risk prediction compared with traditional risk scores in healthy subjects, untreated hypertensives and very high risk patients. Our aim was to analyze association of ePWV with mortality in subjects with EVA and HVA in general Croatian population. Design and method: In a stratified random sample of 1087 subjects from the general Croatian adult population which was enrolled in a nationwide survey (EH-UH 1) from 2000–2005 analyses on ePWV were done and subjects were followed-up for 17years. ePWV was calculated using formula: ePWV = 9.587–0.402 × age+4.560 × 10-3 × age2–2.621 × 10-5 × age2 × MBP+3.176 × 10-3 × age × MBP-1.832 × 10-2 × MBP. MBP = (DBP)+0.4(SBP-DBP). HVA was defined as the lowest 10%, EVA as the highest10% of the standardized PWV distribution, adjusted for age quintiles. Subjects with MI, stroke/TIA, DM were excluded. Mortality data were collected from National Public Health Institute records. Results: At the end of follow up period 228 deaths (20.9%) were recorded in the whole group (CV43.4%, stroke10.5%, cancer28.5%, dementia and degenerative diseases5.2%, COPD3.1%). There were 16.5% and 14.2% deaths in EVA and HVA groups, respectively (p &gt; 0.05). Significantly more CV/stroke deaths were observed in EVAvs.HVA (X2 = 5.488;p = 0.0019). In a subgroup of subjects who died, at basal EVA subjects were older, obese, more frequently hypertensives, had higher BMI, BP, heart rate and ePWV compared to HVA (13.8 ± 1.1vs.10.5 ± 2.5;p &lt; 0.0001). Both died HVA and EVA were at basal less physically active than survivors. In a subgroup of EVA subjects, those who died, at basal were older, had higher systolic BP, lower eGFR and higher ePWV (13.8 ± 1.1vs.9.9 ± 2.3;p &lt; 0.0001) and were less physically active (X2 = 1.54;p = 0.01) compared to survivors. We failed to find differences between dead and alive EVA in basal diastolic BP, BMI, heart rate, prevalence of hypertension. Conclusions: Age, systolic BP, eGFR and ePWV were associated with mortality risk in EVA subjects. Physical inactivity was associated with higher mortality both in EVA and HVA participants. Comparing to HVA, in addition to aforementioned parameters, EVA subjects had higher BMI, diastolic BP and heart rate.

Gender Differences in Response to Cold Pressor Test in the Age Group of 18-30 Years

Introduction: The Cold Pressor Test (CPT) was first introduced by Hines and Brown in 1932. It was designed to measure the reactivity of the blood vessels to a standard stimulus2 . Cold Pressor Test is an established challenge test of sympathetic vascular regulation. Sympathetic nervous system activity varies in males and females. Aim: To study the response of Cold Pressor Test on blood pressure in normal healthy young adult males and females. Materials and Method: After Institutional ethics committee approval, a total of 104 subjects in the age group of 18-30 years were recruited with informed consent for the study, after considering inclusion and exclusion criteria. Subjects were explained about the test procedure. Basal blood pressure (pre-test BP) was recorded after 20 min. of rest. Systolic and diastolic blood pressure was measured in mmHg (pre-test). Subject was asked to dip left hand till the wrist in cold water (40-80 C) for 1 min. (minute).Blood pressure was recorded from right arm during the test, 1 minute, 2 minutes, 3 minutes and 4 minutes after the test. Result: Basal BP was significantly higher in males than in females. Systolic BP(SBP) response, Diastolic BP response (DBP) to CPT were statistically higher in males compared to females. Conclusions: The gender variations are seen due to differences in the sympathetic nervous system activity and due to the effect of sex hormones. Males are more prone to develop hypertension and other cardiovascular disorders when compared to females due to higher sympathetic activity.

Abstract P413: Vascular AT1 Receptors Control Blood Pressure by Augmenting Peripheral Vascular Resistance in Female Mice

Angiotensin (Ang) II is a major mediator of hypertension pathogenesis and end organ damage. Our understanding of how Ang II elicits these effects on a cellular level continues to evolve. However, the majority of these studies utilize male subjects, despite the awareness that males and females differ in mechanisms of BP regulation. Here we investigated the role of vascular smooth muscle cell (VSMC) AT1A receptors to BP control in female mice. Using Loxp technology and Cre transgenes, we created female mice with cell-specific deletion of AT 1A receptors in smooth muscle cells (SMKO mice). We found that elimination of these receptors led to a significant (8 mmHg) reduction in baseline BP in female SMKO mice (similar to male SMKO mice) compared with controls (108±2 versus 116±1 mmHg; P =0.004) with no effect on modulating sodium sensitivity in female SMKO mice (unlike male SMKO mice in which sodium sensitivity was enhanced). Over a 4-week Ang II infusion, the severity of Ang II - dependent hypertension was minimally affected during the first 2 weeks of Ang II infusion, corresponding to no difference in sodium excretion. However, female SMKO mice had a 35% less BP elevation compared to controls over the final 2 weeks of Ang II infusion (SMKO, 20±2 versus control, 30±3 Change in SBP mmHg; P =0.01). The acute vasoconstrictor responses to Ang II in the systemic vasculature were reduced (by approximately 50-75%) in female SMKO mice (0.1 μg/kg- SMKO, 3.6±1.2 mmHg versus control, 7.3±0.7 mmHg; P =0.01, 0.3 μg/kg- SMKO, 3.3±1.8 mmHg versus control, 12.1 ± 1.3 mmHg; P =0.0008, 1.0 μg/kg- SMKO, 8.5±1.9 mmHg versus control, 19.4±2.0 mmHg; P =0.002). In addition, the acute Ang II reduction in renal tissue perfusion was nearly eliminated in female SMKO mice. In contrast, we previously reported that in male SMKO mice have a much larger (50%) reduction in BP during chronic Ang II infusion associated with increased natriuresis, but relatively preserved vasoconstrictor response (25% reduction) during acute Ang II infusions. These findings suggest that in female mice, direct actions of AT 1A receptors in VSMCs are essential for regulation of basal BP and Ang II-dependent hypertension. However, this effect is mediated by reductions in peripheral vascular resistance rather than sodium retention.

Validity of a protocol to estimate patients’ pre-morbid basal blood pressure

Purpose: The pre-illness basal mean arterial BP (MAP) is an important reference point to gauge the degree of relative hypotension among unwell patients. We aimed to assess mean bias, correlation, and agreement between basal MAP measured during nighttime ambulatory BP monitoring (ABPM) and basal MAP estimated using a standardized protocol.Materials and methods: For a cohort of 137 consecutive patients, aged ≥40 years, who recently underwent ABPM, a blinded investigator estimated basal MAP from up to five most recent clinic BP measurements. Both basal MAP values, measured and estimated, were compared pairwise for each participant.Results: We traced a median of 4 [interquartile range 3–5] previous BP measurements per patient over a median period of 132 [interquartile range 55–277] days up until the ABPM test. The estimated basal MAP (mean 88 ± 8 mmHg) was linearly related (Pearson’s r = 0.41, p = 0.0001) to the measured basal MAP (mean 88 ± 12 mmHg). Bland-Altman plot revealed a mean bias of 0.3 mmHg with agreement limits of ±22 mmHg.Conclusions: The mean bias between estimated and measured values for basal MAP was insignificant and modest. When a recent nighttime ABPM is unavailable, a protocol based on recent clinic BP readings can be used to estimate patient’s basal MAP.Study registration: Australian New Zealand Clinical Trials Registry ACTRN12613001382763.

Abstract P148: Connecting Tubule-glomerular Feedback (ctgf) in Renal Hemodynamics and Blood Pressure (bp) After Unilateral Nephrectomy (unx)

Afferent arteriole resistance is regulated in part by myogenic response, tubuloglomerular feedback (TGF) and connecting tubule-glomerular feedback (CTGF). CTGF dilates afferent arteriole in response to high sodium in connecting tubule (CNT) counteracting and shifting to the right the TGF response (resetting); CTGF increases renal blood flow and glomerular pressure, both favoring glomerular filtration and sodium excretion. CTGF is initiated by epithelial sodium channel (ENaC) in CNT and inhibited by Benzamil. Unilateral nephrectomy (UNx) is accompanied by TGF resetting, increase in renal blood flow (RBF) and single nephron GFR in the remnant kidney, without any changes in systemic BP. We evaluated the effects of CTGF in TGF resetting, RBF and BP after UNx. UNx was performed on Sprague-Dawley rats and 24h later TGF was evaluated in vivo by renal micropuncture techniques by measure stop flow pressure (Psf). CTGF was evaluated by the differences between TGF maximal responses (TGFmax) with or without tubular benzamil perfusion. Another set of animals received chronic infusion of benzamil directly into the kidney, that started 1 week before UNx. Renal blood flow (RBF) was measured by arterial spin labeling-MRI 24h before and 24h after the UNx. Direct BP measurement was performed before and 3 weeks after the UNx. After UNx, TGF resetting was observed in UNx rats (TGFmax 8±1 vs. 1±1 mmHg, Sham vs. UNx; p&lt;0.05). This TGF resetting was inhibited by benzamil. RBF increased after the UNx in comparison to sham and this increase was prevented by chronic infusion of Benzamil into the kidney (Sham: 3±0.6; UNx: 4.6±0.3; UNx+Benzamil 3.5±0.6 ml/min/g tissue p&lt;0.002). Basal mean BP values were not different between the vehicle or treated rats before the UNx; however 3 weeks after the UNx, rats receiving benzamil into the kidney showed higher mean BP values than vehicle (88±0.3 vs. 97±4 mmHg, p&lt;0.01). We conclude that CTGF participates in TGF resetting and RBF regulation after UNx, and that could participate in BP regulation after UNx.

JS ISH-ESH-2 UPDATE ON THE DETECTION AND FOLLOW-UP OF EARLY HYPERTENSIVE HEART DISEASE

JS ISH-ESH-2 UPDATE ON THE DETECTION AND FOLLOW-UP OF EARLY HYPERTENSIVE HEART DISEASE

Orthostatic intolerance and autonomic dysfunction following bariatric surgery: A retrospective study and review of the literature.

The prevalence and costs of the obesity epidemic and obesity-related conditions, including diabetes mellitus, is consistently increasing worldwide. Bariatric medicine is attempting to address this with weight loss and exercise programmes, and with increasing frequency, various forms of bariatric surgery. There has been considerable success reported after bariatric surgery but not without. We describe 14 patients with orthostatic intolerance (OI) post bariatric surgery. We report on OI (postural dizziness, palpitations and fainting), the results of cardiovascular autonomic testing and the associated and/or causative findings as well as reviewing the literature to consider the possible mechanisms. Comprehensive autonomic testing revealed that 35.7% (Buchwald et al., 2004) of these patients fulfilled the criteria for the Postural Tachycardia Syndrome (PoTS), 57.1% (Cremieux et al., 2008) had low levels of basal BP and 42.9% (Cammisotto & Bendayan, 2007) patients were presyncopal and 14.3% (Billakanty et al., 2008) experienced syncope. We propose that the incidence of OI post-bariatric surgery is higher than considered, that certain cohorts may be more susceptible to complications, and that further research is needed to identify the prevalence and, ideally anticipate occurrence. With the increasing prevalence of obesity and required clinical interventions, further understanding of the pathophysiological processes causing autonomic dysfunction after bariatric interventions will aid management, which may differ in those with an underlying disposition to autonomic involvement, such as diabetics, in whom such procedures are increasingly used.

Abstract 627: The Smooth Muscle-selective RhoGAP Graf3 Is A Critical Regulator Of Vascular Tone And Hypertension

Our ability to effectively treat hypertensive patients is limited by an incomplete understanding of its origin. Activation of RhoA in vascular smooth muscle cells (SMC) has been implicated in the development of vasoconstrictor-induced hypertension (HTN), but until now, the extent that RhoA contributed to basal BP was unknown and the mechanisms that limit RhoA activity in SMC were undetermined. We identified GRAF3 as a RhoA-GAP expressed specifically in SMC in mice and humans and reported that our novel global GRAF3-deficient mice exhibit significant basal HTN (+ 25 mm Hg) that was fully reversed by treatment with a Rho-kinase inhibitor ( Nature Comm. 2013;4:2910 ). One objective of this new study was to test if elevated RhoA-dependent myogenic tone was causal for HTN in global GRAF3-deficient (GRAF3 gt/gt ) mice. Importantly, normal GRAF3 expression can be permanently restored by Cre recombinase-dependent excision in our model. Thus, we crossed the GRAF3 gt/gt mice to the tamoxifen-inducible SM-specific SM MHC- CreER T2 line and measured BP before and after tamoxifen treatment (1mg i.p. for 5 consecutive days). Tamoxifen induced SMC-GRAF3 re-expression and resulted in a complete reversal of MAP (from 123 mmHg to 95 mm Hg). Moreover, RhoA activity and myosin light chain phosphorylation were elevated 2-fold in GRAF3-depleted SMC in vitro and in vivo and isolated vessel segments from GRAF3-deficient mice showed a 2.5 fold increase in Rho kinase-dependent Ang II-induced contractility. Collectively, these findings provide unequivocal evidence that GRAF3 levels in SMC control basal BP homeostasis and that elevated BP in GRAF3 gt/gt mice is due to an enhanced, reversible, SMC contractile phenotype. A second objective was to determine whether GRAF3 variations are causally linked to cardiovascular outcomes in hypertensive patients. We found a clear and significant increase in minor allele frequency of a hypertensive GRAF3 locus in patients with HTN and coronary artery disease versus healthy volunteers (0.19 versus 0.30; p&lt;0.05; N=920) and this association was significant regardless of race. Our studies provide a potential mechanism for the hypertensive locus identified within GRAF3 and provide the foundation for the future development of innovative HTN therapies.

Brain‐derived neurotrophic factor causes chloride gradient collapse in supraoptic neurons inducing vasopressin‐mediated blood pressure increase (LB847)

Vasopressin (VP), an antidiuretic hormone, is also a potent vasoconstrictor and has been found at high levels in salt‐sensitive hypertensives. Hypertension normally reduces VP secretion by MNCs in the SON, by GABA‐dependent synaptic inhibition of their firing activities. However, in rats under chronic hypernatremia, GABAA receptor‐mediated synaptic inhibition is abolished in SON neurons due to a depolarization in chloride reversal potential (ECl), suggesting that continued VP secretion despite BP elevations may underlie the development of salt‐dependent hypertension. In order to test this hypothesis, we measured the mean arterial pressure (MAP) by radio telemetry in freely moving rats made chronically hypernatremic by 2% saline drinking. MAP of these rats rose steadily rise during the course of the 7‐day SL treatment (basal BP: 97.7±1.9 mmHg; day 7: 113.5±2.1 mmHg; n=10; P&lt;0.05), however remained stable in euhydrated rats over the same time period (basal BP: 98.3±2.5 mmHg; day 7: 100.6±2.2 mmHg; n=6; P=0.50). Furthermore, the SL‐mediated increase in MAP was significantly reduced by continuous systemic infusion of a VP receptor type 1 (V1R) antagonist (αday 7; +8.8±2.5 mmHg; n=6) when compared to SL controls (α15.1±1.0 mmHg; n=10; P&lt;0.05). These findings confirm our hypothesis that circulating VP contributes to increases in BP during chronic hypernatremia. Brain‐derived neurotrophic factor (BDNF) is a high‐affinity TrkB agonist previously shown to be responsible for chloride gradient collapse. In order to investigate this possibility in the SON, we induced a specific knockdown of this protein in SL rats in vivo by stereotaxic injections of adeno‐associated virus (AAV) containing BDNF‐shRNA into the SON. ECl measurements via Gramicidin perforated patch‐clamp revealed that this treatment significantly hyperpolarized the ECl of SON neurons (‐56.2±5.4 mV; n=10) when compared to values measured in SL rats injected with control AAV containing a scrambled sequence of shRNA (‐40.1±2.4 mV; n=7; p&lt;0.05). These results strongly suggest that BDNF is the TrkB agonist responsible for producing the chloride gradient collapse in SON neurons under chronic hypernatremia, a phenomenon which potentially underlie the development of salt‐sensitive hypertension. Funding source: Canadian Institutes of Health Research.Grant Funding Source: CIHR

Selection of candidate genes for hypertension on rat chromosome 4 from shr using expression profilling in kidney and subcongenic strain development

Using total genome scan, we previously mapped 5 BP‐related QTLs that explain 38% of the BP variance in a progeny derived from Spontaneous Hypertensive Rat (SHR) and Brown Norway (BN) rats. The QTLs were then validated by derivation of congenic strains, including one for chromosome 4 (SHR.BN4) in which a segment from BN replaced the SHR sequences reducing basal systolic BP (~15 mmHg). To select the putative candidate genes, we used genomic approaches based on differential expression in kidney samples and development of subcongenic strains. Sixteen genes were differentially expressed in samples from adult renal tissues from congenic strain SHR.BN4 compared with SHR. Of those, seven remained differentially expressed in the kidney from pre‐hypertensive animals displaying comparable levels of blood pressure. We then verified which of those candidate genes were expressed along the nephron and if they were differentially expressed in mRNA samples from 5 microdissected nephron segments from the two groups. All 7 genes were differentially expressed in one or more of the nephron segments between the 2 strains. Meanwhile, two nonoverlapping congenic substrains were obtained from SHR.BN4, which maintained its phenotype, and one of those harbours 2 of the candidate genes (MGC95152 and Aqp1). Taken together, the combined approaches resulted in selection of 2 hypertensive candidate genes that deserve to be further explored.Supported by FAPESP, CNPq and E.J. Zerbini

Improvement and influencing factors of blood pressure control by nephrologist referral in chronic kidney disease patients in China: a cohort study

Hypertension is an independent risk factor for mortality in chronic kidney disease (CKD) and is suboptimally controlled worldwide. Therefore, this study aimed to examine the rate of BP control and the main barriers to achieving target BP, according to K/DOQI guidelines, in China. We performed a single-center, prospective cohort study. Two hundred and sixty CKD patients were referred by general physicians to nephrologists, and their BP was treated in accordance with K/DOQI guidelines for a 1-year follow-up. We evaluated improvement of BP target achievement and factors affecting BP control. We defined "not-at-goal" as persistence of systolic BP ≥ 130 mmHg and/or diastolic BP ≥ 80 mmHg after 1 year. The BP decreased from 138 ± 12/84 ± 7 mmHg at baseline to 124 ± 13/73 ± 7 mmHg after 1 year. The rate of achieving the BP goal (<130/80 mmHg) increased from 25.4 to 61.5 %. The decrease in BP was associated with a significant reduction of proteinuria (median, 0.14 vs 0.06 g/24 h; P < 0.05). Logistic regression analysis identified proteinuria levels ≥1.0 g/24 h (odds ratio [OR]: 5.21; 95 % confidence interval [CI]: 1.37-19.77) and high basal systolic BP (OR: 2.17; 95 % CI: 1.25-3.77) and diastolic BP (OR: 6.62; 95 % CI: 2.03-21.60) as independent predictors of not-at-goal BP. Higher educational level was independently associated with at-goal BP (OR: 0.21; 95 % CI: 0.06-0.78). In CKD patients, BP control is poor when managed by general physicians and may be improved after nephrologist referral. High basal BP and proteinuria levels ≥1.0 g/24 h are the main barriers that preclude the optimal control of BP.

Inhibition Of The Estrogen‐Mediated Cardiac Vagal Control Accounts For The Baroreflex Depressant Effect Of Chronic Nicotine In Female Rats

We previously showed that chronic nicotine dose‐dependently attenuated reflex chronotropic responses in female rats. Here the hypothesis was tested that impairment of the estrogen‐dependent cardiomotor vagal control mediates the nicotine‐baroreflex interaction. Baroreflex curves relating changes in heart rate to increases (phenylephrine, PE) or decreases (sodium nitroprusside, SNP) in blood pressure were constructed in sham‐operated, ovariectomized (OVX), and estrogen‐replaced OVX (OVXE2) rats. Slopes of the curves were taken as a measure of baroreflex sensitivity (BRSPE and BRSSNP). In sham rats, nicotine (2 mg/kg/day for 14 days) produced no changes in basal BP but reduced BRSPE and BRSSNP, suggesting attenuation of reflex bradycardic and tachycardic responses. Compared with sham rats, OVX selectively decreased BRSPE but not BRSSNP and abolished the nicotine‐induced impairment of both responses. The effects of OVX were reversed after treatment with estrogen or with the estrogen receptor modulator raloxifene. Atropine reduced BRS to comparable levels in all rat preparations regardless of the estrogen or nicotine milieu. Thus, nicotine attenuates reflex chronotropic activity via inhibition of the estrogen‐mediated facilitation of vagal cardiomotor activity.This project was supported financially by the Science and Technology Development Fund (STDF), Egypt, Grant No. 502.

Sexual Dimorphism in Skulls of the Lowland European Bison,Bison Bonasus Bonasus

The research was conducted on 600 (311 male and 289 female) European bison skulls of the Lowland line collected between 1967 and 2006. The specimens came from the bison breeding centre in Białowieza (n = 67) and from the free-ranging population of the Polish part of the Białowieza Forest (n = 533). Two indices best differentiating male and female skulls were selected: one being the quotient of the orbital breadth EctEct and the length of the splanchnocranium StP, the second being the quotient of the neurocranium length BSt and the basal skull length BP. Using these indices we constructed an equation which produced negative values for females and positive values for males; 223 (74%) of the male skulls produced positive values consistent with sex, and 82 (26%) produced negative values, indicating female features. Those features were present mainly in skulls of young males (< 4 years old). 230 (80%) of the female skulls had shapes typical of the female sex, whereas 59 (20%) displayed male features.

Effects of fluoxetine on cardiac remodeling and autonomic control of blood pressure and heart rate after myocardial infarction in mice

Selective serotonin reuptake inhibitors (SSRIs) are used to treat mental depression after myocardial infarction (MI). It is unknown if SSRIs influence cardiac remodeling after MI. SSRIs may modulate cell proliferation and modify autonomic tone by inhibiting the reuptake of catecholamines. We examined the effects of 2 weeks fluoxetine (FLU) treatment (6 mg/kg.day) on cardiac remodeling in male Swiss mice subjected to coronary artery ligation. 11 days after MI, catheters were implanted and 2 days later blood pressure variability (BPV) and heart rate variability (BPV) were measured (by spectral analysis) in the conscious state as an index of autonomic tone. Compared to non‐treated MI mice, FLU treatment did not alter infarct size, cardiac hypertrophy and cardiac hyperplasia (assessed by BrdU labeling). Basal BP and HR were not altered by FLU treatment. In the absence of treatment low‐frequency BPV and HRV (0.1–1 Hz) were lower in MI than in sham‐MI mice. FLU treatment reduced low‐frequency BPV and HRV in sham and MI mice, reaching values comparable to those observed in non‐treated MI mice. All between group differences in BPV and HRV were eliminated after acute pharmacological blockade with atropine and metoprolol. These data indicate that, in mice, FLU treatment does not aversely modify cardiac remodeling after MI and is associated with a sympatholytic effect.

Integrative pattern of vasomotor efficiency in SHR during ontogenesis

Numerous studies concerning the cardiovascular system in SHR often yield controversial data. The background of this diversity has various roots, ranging from different vascular segments or areas studied up to the different age of experimental animals. Our study aimed to follow the BP as an integrated response of vascular system. This approach was justified since stabilized cardiac output in SHR was proved till 1 year of age. The groups of male SHR (aged 3, 5, 9, 17 and 52 weeks) and age-matched Wistar rats were used. Significant basal BP difference between SHR and Wistar rats was found at 9 weeks of age and continued till the age of 52 weeks, reaching 189.6+/-11.9 mm Hg in SHR and 117.3+/-6.9 mm Hg in Wistar rats P<0.01 . The significant difference in BP increase to two doses of noradrenaline 0.1 microg and 1 microg between SHR and control rats was also found at the age of 9 weeks. At 52 weeks the BP increment to two doses of noradrenaline was in SHR 19.7+/-2.0 mm Hg and 60.5+/-3.9 mm Hg and in Wistar rats 7.4+/-1.9 mm Hg and 40.5+/-3.2 mm Hg P<0.01 . The hypotensive response to acetylcholine 0.1 microg, 1 microg and 10 microg in SHR was enhanced at 17 weeks of age only and this amplification persisted till the age of 52 weeks. In 52-week-old SHR the hypotensive response to three doses was 69.9+/-10.2 mm Hg, 87.5+/-11.8 mm Hg and 103.4+/-10.6 mm Hg, while in Wistar rats it was 37.4+/-4.2 mm Hg P<0.01 , 62.3+/-3.5 mm Hg P<0.01 and 73.5+/-2.8 mm Hg P<0.05 . In conclusion, the efficiency of cardiovascular system of SHR to respond to noradrenaline was already enhanced from 9 weeks of age, whereas the response to acetylcholine was not augmented before the age of 17 weeks.