Abstract
The purpose of this study was to evaluate the relationship between the circadian profile of the vasorelaxing substances calcitonin gene-related peptide (CGRP) and epoxyeicosatrienoic acids (EETs) and the vasconstrictive agent endothelin-1 (ET1) and the daily rhythms of cardiac hemodynamic indices (CHI) and baroreflex (BRS) in Wistar rats with 1 kidney-1 clip model of arterial hypertension (1K-1C AH). The animals were divided into 3 groups: I- sham-operated (SO), II- 4-week and III- 8-week 1K-1C AH rats. Plasma concentration of ET1, CGRP and EET’s were investigated every 4 h. In conscious freely moving 1K-1C AH rats unlike SO animals blood pressure (BP), heart period (HP) and BRS underwent significant circadian fluctuations, with more marked increase in mean values of BP in 8-week hypertensive rats in comparison to 4-week hypertensive rats (179 ± 5 vs. 162 ± 4 mm Hg, p < 0.05). These alterations correlated with more significant reduction in HP (138 ± 5 vs. 150 ± 6 ms, p < 0,05) and BRS (0.44 ± 0.04 vs. 0.58 ± 0.04 ms mm Hg–1, p < 0.05) in 8-week 1K-1C AH rats. The acrophases of BP in 8-week 1K-1C AH rats in comparison with 4-week were shifted to more late night hours (1:58 a.m. vs. 11:32 p.m.) and in both groups of animals corresponded to lowest circadian plasma levels of CGRP and EETs and to greatest level of ET1. SO rats were characterized by lower values of BP (121 ± 3 mm Hg, p < 0,05) and higher indices of HP (158 ± 2 ms, p < 0,05) and BRS (0.86 ± 0.02 ms mmHg–1, p < 0,001) in comparison with 1K-1C AH rats 4-week duration. The acrophases of BP, HP and BRS in hypertensive animals were revealed at 14.8 ± 0.5 h, 13.6 ± 0.4 h and 13.1 ± 0.2 h, which correlated with maximal circadian contents of ET1 and CGRP at 24:00 h and EETs at 12:00 h and were shifted in comparison to sham-operated group. In rats with 1K-1C AH, plasma levels of ET1, CGRP and EETs undergo circadian fluctuation with corresponding alterations in CHI and BRS which are more markedly expressed on the late stage of diseases and could be used in future for predictive, preventive, and personalized treatment of arterial hypertension.
Highlights
The association between diurnal variation of the heart rate, blood pressure (BP), vascular tone, and QT interval and predisposition to cardiovascular disease has been noted in both normotensive and hypertensive individuals
The purpose of this study was to evaluate the relationship between the circadian profile of plasma levels of ET1, calcitonin gene-related peptide (CGRP) and epoxyeicosatrienoic acids (EETs) and circadian rhythms of cardiac hemodynamic indices (CHI) and baroreflex sensitivity (BRS) in the 1 kidney-1 clip (1K-1C) model of hypertension in rats, which is characterized by modest changes in renin and pronounced reduction in glomerular filtration rate, sodium retention and high volume [36,37]
In 8-week hypertensive rats in comparison to 4-week hypertensive rats the mean value of BP was markedly increased (179 ± 5 mm Hg. p < 0.05), associated with decreased heart period (HP) (138 ± 6 ms, p < 0.05) and blunted BRS (0.44 ± 0.02 ms mm Hg–1, p < 0.05). In both groups of animals, CHI and BRS underwent diurnal variation with circadian acrophases of BP in 4 and 8-week hypertensive rats (174 ± 4 mm Hg vs. 188 ± 8 mm Hg, p < 0.05) in nighttime at 23:32 h and 01:58 h, while its lowest level was revealed in the light period (156 ± 6 mm Hg vs. 170 ± 8 mm Hg) between 14:00 h and 18:00 h, respectively (Figure 1)
Summary
The association between diurnal variation of the heart rate, blood pressure (BP), vascular tone, and QT interval and predisposition to cardiovascular disease has been noted in both normotensive and hypertensive individuals. The circadian variation in vascular events corresponds to that in blood pressure and to the oscillation of genes relevant to hemostasis, but whether this reflects an important role for the molecular clock or merely the physical and emotional stress remains unknown. The presence of a close correlation between the circadian rhythm of BP and glomerular filtration rate diseases and decrease in creatinine clearance in patients with chronic kidney led to the conclusion that lack of nocturnal dipping (i.e. typically considered a nocturnal decline of 10% or more [3]) could be independent predictive factors of cardiovascular events and target organ damage [6,7]. The ET system consists of two G protein coupled-receptors, ETA and ETB, Art. 10, page 2 of 8
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