Development of an Experimental Model to Study the Relationship Between Day-to-Day Variability in Blood Pressure and Aortic Stiffness

Abstract

We aimed to develop an animal model of long-term blood pressure variability (BPV) and to investigate its consequences on aortic damage. We hypothesized that day-to-day BPV produced by discontinuous treatment of spontaneously hypertensive rats (SHR) by valsartan may increase arterial stiffness. For that purpose, rats were discontinuously treated, 2 days a week, or continuously treated by valsartan (30 mg/kg/d in chow) or placebo. Telemetered BP was recorded during 2 min every 15 min, 3 days a week during 8 weeks to cover the full BP variations in response to the treatment schedule. Pulse wave velocity (PWV) and aortic structure evaluated by immunohistochemistry were investigated in a second set of rats treated under the same conditions. Continuous treatment with valsartan reduced systolic BP (SBP) and reversed the aortic structural alterations observed in placebo treated SHR (decrease of medial cross-sectional area). Discontinuous treatment with valsartan decreased SBP to a similar extent but increased the day-to-day BPV, short term BPV, diastolic blood pressure (DBP), and PWV as compared with continuous treatment. Despite no modifications in the elastin/collagen ratio and aortic thickness, an increase in PWV was observed following discontinuous treatment and was associated with a specific accumulation of fibronectin and its αv-integrin receptor compared with both groups of rats. Taken together the present results indicate that a discontinuous treatment with valsartan is able to induce a significant increase in day-to-day BPV coupled to an aortic phenotype close to that observed in hypertension. This experimental model should pave the way for future experimental and clinical studies aimed at assessing how long-term BPV increases aortic stiffness.

Keywords: aortic stiffness; diastolic blood pressure; fibronectin; long-term blood pressure variability; pulse wave velocity; spontaneously hypertensive rats; telemetry.

Figure 1

Schematic representation of a week schedule of treatment and blood pressure (BP) recording. The total duration of treatment was 8 weeks. Int. treatment, intermittent (i.e., discontinuous) treatment.

Figure 2

Time-course evolution of the blood pressure in conscious rat. Systolic (A) and diastolic (B) blood pressure during the 8 weeks study. Each point is the mean ± SEM of five rats. For each week and for each rat, the mean of 288 BP values was calculated (four values of BP per hour during 3 days recording). ^*P < 0.05 vs. placebo; ^†P < 0.05 vs. continuous treatment. The inter-day evolution of blood pressure during the 8 weeks study in response to the discontinuous administration of Valsartan is showing for the systolic (C) and diastolic (D) mean blood pressure. Each point is the mean ± SEM of the five rats of the discontinuous group. Day 1: Day of administration of valsartan. Day 2 and Day 3: days of Valsartan's withdrawal. The within-day variation of systolic (E) and diastolic (F) blood pressure is expressed through the difference between the first and the fourth quartile of blood pressure for the continuously (CT) and the discontinuously (DT) treated rats with valsartan.

Figure 3

Short term variability evaluated by spectral analysis. Modifications of the low frequencies of systolic blood pressure (A) and high frequencies of interbeat interval (B) in response to the different treatments schedules. Each bar is the mean ± SEM of five rats. ^*P < 0.05 vs. placebo.

Figure 4

The Day-to-day variability of diastolic blood pressure (A) and systolic blood pressure (B) estimated via their coefficient of variation at the end of the experiments (the 8 week). Each bar is the mean ± SEM of five rats. ^*P < 0.05 vs. placebo; ^†P < 0.05 vs. continuous treatment.

Figure 5

Effect of discontinuous treatment by valsartan on abdominal aorta morphological changes examined by adhesion proteins staining (x40).