How Does Circadian Rhythm Impact Salt Sensitivity of Blood Pressure in Mice? A Study in Two Close C57Bl/6 Substrains

Background Mouse transgenesis has provided the unique opportunity to investigate mechanisms underlying sodium kidney reabsorption as well as end organ damage. However, understanding mouse background and the experimental conditions effects on phenotypic readouts of engineered mouse lines such as blood pressure presents a challenge. Despite the ability to generate high sodium and chloride plasma levels during high-salt diet, observed changes in blood pressure are not consistent between wild-type background strains and studies. Methods The present work was designed in an attempt to determine guidelines in the field of saltinduced hypertension by recording continuously blood pressure by telemetry in mice submitted to different sodium and potassium loaded diets and changing experimental conditions in both C57BL/6N and C57BL/6J mice strain (Normal salt vs. Low salt vs. High-salt/normal potassium vs. High salt/low potassium, standard vs. modified light cycle, Non-invasive tail cuff blood pressure vs. telemetry). Results In this study, we have shown that, despite a strong blood pressure (BP) basal difference between C57BL/6N and C57BL/6J mice, High salt/normal potassium diet increases BP and heart rate during the active phase only (dark period) in the same extent in both strains. On the other hand, while potassium level has no effect on salt-induced hypertension in C57BL/6N mice, high-salt/low potassium diet amplifies the effect of the high-salt challenge only in C57BL/6J mice. Indeed, in this condition, salt-induced hypertension can also be detected during light period even though this BP increase is lower compared to the one occurring during the dark period. Finally, from a methodological perspective, light cycle inversion has no effect on this circadian BP phenotype and tail-cuff method is less sensitive than telemetry to detect BP phenotypes due to salt challenges. Conclusions Therefore, to carry investigations on salt-induced hypertension in mice, chronic telemetry and studies in the active phase are essential prerequisites

J Hypertens

OBJECTIVE: Heart failure with preserved left-ventricular ejection fraction (HF-PEF) is an entity leading to pulmonary congestion because of impaired diastolic filling. This syndrome usually strikes those who have experienced a long history of hypertension or metabolic risk factors. Pathophysiological mechanisms are not fully understood, and standard therapy is not established. Relevant preclinical models are still lacking. The aim of this work was to evaluate aging spontaneously hypertensive rats (SHRs) as a model of HF-PEF. METHODS: Serial echocardiographic and blood pressure (BP) measurements were performed in 28, 36, 43, 47 and 51-week-old SHRs and their normotensive controls (Wistar-Kyoto rats). In 52-53-week-old animals, final investigations included ECG, invasive left-ventricular (LV) and aortic catheterization, brain natriuretic peptide (BNP) plasma concentrations, ventricular reverse transcription-qPCR evaluations (beta-myosin heavy chain, atrial natriuretic peptide, BNP, sarco/endoplasmic reticulum calcium ATPase 2a and collagens 1a, 3a and 2a) and cardiac histology. RESULTS: SHRs develop a progressive alteration of the early diastole, some of the echocardiographic parameters being not sensitive to BP reduction by the calcium blocker, nicardipine. The systolic function evaluated by echocardiography and invasive catheterization was preserved. When the observation period was over, an increase in collagen synthesis and deposits were identified in subendocardial layers. This attested a probable myocardial ischemia that was confirmed by ECG changes of the ST segment. BNP increased in the blood and at the mRNA level in the myocardium. CONCLUSION: When aging, SHRs progressively develop HF-PEF showed by impaired LV relaxation and hypertrophy, BNP increase but preserved contractility and fibrosis. This model seems pertinent for further pharmacological preclinical studies in the field

Contribution of serotonin to cardiac remodeling associated with hypertensive diastolic ventricular dysfunction in rats

International audienceLeft-ventricular hypertrophy and interstitial fibrosis are the main pathophysiological factors of heart failure with preserved ejection fraction. Blockade of the serotonin 5-HT2B receptor (5-HT2BR) has been shown to reduce cardiac hypertrophy, oxidative stress, and extracellular cell matrix activation. In this study, we evaluated the effects of the 5-HT2BR blockade, on hemodynamic and cardiac remodeling, in spontaneously hypertensive rats (SHRs) that display a diastolic dysfunction with preserved ejection fraction

Nox4 genetic inhibition in experimental hypertension and metabolic syndrome

BACKGROUND: Metabolic syndrome is a combination of symptoms including obesity, dyslipidaemia, glucose intolerance and hypertension. Oxidative stress appears to be a pathophysiological factor that links these signs and encourages progression towards heart failure and diabetes. Nox4 is a hydrogen peroxide nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoform - found in various cardiovascular cells and tissues, but also in tissues such as the liver - which is involved in glucose and lipid homeostasis. AIMS: To test whether inhibition of the Nox4 enzyme could improve blood pressure and metabolic parameters in mice receiving either angiotensin II or a high-fat diet. METHODS: Systolic and diastolic arterial pressures, pulse rate and heart rate were obtained in 24 male mice (12 wild-type [WT] and 12 Nox4(-/-)) before and during 14 days of angiotensin II infusion. After angiotensin II infusion, cardiac histological remodeling was assessed. Weight and biochemical parameters were measured in 18 male and 18 female mice (nine WT and nine Nox4(-/-) per gender) after 10 weeks on a standard chow diet, then 15 weeks on a high-fat diet. Glucose tolerance and insulin sensitivity were tested at age 25 weeks. RESULTS: Knock-out animals did not demonstrate a baseline blood pressure phenotype, but blocking Nox4 protected against angiotensin II-mediated arterial and pulse pressure increases. No protection against angiotensin II-induced cardiac fibrosis was observed. From a metabolic point of view, Nox4 inhibition reduced plasma triglycerides in male and female mice under a chow diet. However, Nox4 deletion did not affect the metabolic profile under a high-fat diet in males or females, but increased glucose intolerance in females. CONCLUSION: Our data identify Nox4 as a key source of radical oxygen species involved in hypertension and some metabolic problems

Comparison between C57BL/6N and C57BL/6J for their systolic blood pressure and heart rate responses to various salt challenges measured by NIBP.

<p>Measurements were made during the dark periods of a modified light/dark cycle. NS = normal salt diet (n = 20 and n = 20, for C57BL/6N and C57BL/6J respectively), LS = low salt diet (n = 20 and n = 20, for C57BL/6N and C57BL/6J respectively), HS = high Na⁺/normal K⁺ diet (n = 9 and n = 10, for C57BL/6N and C57BL/6J respectively) and HS/LK = high Na⁺/low K⁺ diet (n = 9 and n = 10, for C57BL/6N and C57BL/6J respectively). One-way ANOVA per light phase followed by Tukey Kramer’s post-hoc test; #: p<0.05 HS/LK compared to HS.</p

Plasma ion, aldosterone and renin activity measurements in C57BL/6N and C57BL/6J male mice.

<p>Plasma ion, aldosterone and renin activity measurements in C57BL/6N and C57BL/6J male mice.</p

Effects of high-salt/normal potassium and high-salt/low potassium on mean blood pressure and heart rate in C57BL/6N mice.

<p>Mice were monitored with telemetry in the dark (A, B, C) and light (C) periods of a modified light/dark cycle. NS = normal salt diet (n = 17), LS = low salt diet (n = 15), HS = high Na⁺/normal K⁺ diet (n = 8) and HS/LK = high Na⁺/low K⁺ diet (n = 6). One-way ANOVA per light phase followed by Tukey’s post-hoc test; *: p<0.05 compared to NS diet; #: p<0.05 HS/LK compared to HS.</p

Effects of various salt challenges on mean blood pressure and heart rate in C57BL/6N male mice.

<p>Mice were monitored with telemetry and placed in a standard (A, C) or modified light/dark cycle (B, D). NS = normal salt diet (n = 12 and n = 17, for the standard and modified light cycle respectively), LS = low salt diet (n = 11 and n = 15, for the standard and modified light cycle respectively), HS = high Na⁺/normal K⁺ diet (n = 5 and n = 6, for the standard and modified light cycle respectively). One-way ANOVA per light phase followed by Tukey’s post-hoc test; *: p<0.05 compared to NS diet.</p

Comparison between C57BL/6N and C57BL/6J for their mean blood pressure and heart rate responses to various salt challenges.

<p>Mice were monitored with telemetry during the dark (A, B) and light (C) periods of a modified light/dark cycle. NS = normal salt diet (n = 17 and n = 17, for C57BL/6N and C57BL/6J respectively), LS = low salt diet (n = 15 and n = 17, for C57BL/6N and C57BL/6J respectively), HS = high Na⁺/normal K⁺ diet (n = 8 and n = 8, for C57BL/6N and C57BL/6J respectively) and HS/LK = high Na⁺/low K⁺ diet (n = 6 and n = 9, for C57BL/6N and C57BL/6J respectively). One-way ANOVA per light phase followed by Tukey’s post-hoc test; *: p<0.05 compared to NS diet; #: p<0.05 HS/LK compared to HS.</p