Circadian variation of blood pressure and the vascular response to asynchronous stress

Abstract

The diurnal variation in the incidence of myocardial infarction and stroke may reflect an influence of the molecular clock and/or the time dependence of exposure to environmental stress. The circadian variation in blood pressure and heart rate is disrupted in mice, Bmal1(-/-), Clock(mut), and Npas2(mut), in which core clock genes are deleted or mutated. Although Bmal1 deletion abolishes the 24-h frequency in cardiovascular rhythms, a shorter ultradian rhythm remains. Sympathoadrenal function is disrupted in these mice, which reflects control of enzymes relevant to both synthesis (phenylethanolamine N-methyl transferase) and disposition (monoamine oxidase B and catechol-O-methyl transferase) of catecholamines by the clock. Both timing and disruption or mutation of clock genes modulate the magnitude of both the sympathoadrenal and pressor but not the adrenocortical response to stress. Despite diurnal variation of catecholamines and corticosteroids, they are regulated differentially by the molecular clock. Furthermore, the clock may influence the time-dependent incidence of cardiovascular events by controlling the integration of selective asynchronous stress responses with an underlying circadian rhythm in cardiovascular function.

Fig. 1.

BMAL1 and CLOCK and NPAS2 differ in severity of BP variation and maintenance according to the severity of the genotype. (A) MAP telemetry recordings averaged each hour from three 24-h periods in WT, Bmal1^−/−, Clock^mut, and Npas2^mut mice. MAP recordings were significantly different (Kruskal–Wallis test) for Bmal1^−/− (light phase, P < 0.05; dark phase, P < 0.0001) and Npas2^mut mice (both light and dark phase. P < 0.0001). Clock^mut mice were significantly different only during the light phase (P < 0.05). MAP recordings taken separately during light and dark phases in Bmal1^+/+ vs. Bmal1^−/− (B) (n = 8; ∗, P < 0.05; †, P < 0.001), WT vs. Clock^mut (C) (n = 4–8) WT vs. Npas2^mut mice (D) (n = 8; ∗, P < 0.05), and delayed acrophase (time of peak) of MAP rhythm in Npas2^mut vs. WT (D) (n = 8, P < 0.05). White boxes denote lights on, and dark boxes denote lights off.

Fig. 2.

Circadian but not ultradian rhythmicity depends on BMAL1 and CLOCK. Twenty-four-hour period harmonic (A) and log ratio of circadian and ultradian spectal values (B) were calculated for Bmal1^+/+, Bmal1^{−/[supi]−}, Clock^mut, WT, and Npas2^mut mice.

Fig. 3.

Pnmt, maoB, and comt are under clock control in hearts and adrenals. mRNA was analyzed by real-time PCR at ZT2, ZT6, ZT14, and ZT18 for pnmt expression (A) and maoB expression (D) in hearts of Bmal1^+/+ vs. Bmal1^−/− mice (n = 4–8; ∗, P < 0.01) pnmt expression (B) and maoB expression (E) in adrenals of Bmal1^+/+ vs. Bmal1^−/− mice (n = 4–8; ∗, P < 0.01) maoB and pnmt expression in WT and Npas2^mut (C) (n = 4–5; ∗, P < 0.05), and comt and pnmt expression in WT and Clock^mut (F) (n = 4; ∗, P < 0.05).

Fig. 4.

The circadian clock modulates pressor and hormonal but not adrenocortical responses to stress. (A) Telemetry recordings of MAP were taken at baseline and after restraint within each mouse. Delta MAP values were calculated for Bmal1^+/+ and Bmal1^−/− at ZT0, ZT6, ZT12, and ZT18, (n = 4–8; ANOVA, ∗, P < 0.05). (B) Serum was collected by retroorbital bleed from naïve (baseline) Bmal1^+/+ and Bmal1^−/− mice and naïve Bmal1^+/+ and Bmal1^−/− mice after 15-min restraint at ZT0, ZT6, ZT12, and ZT18, and delta Epi values were calculated for both Bmal1^+/+ and Bmal1^−/− responses (n, 4–8; ∗, P < 0.05). (C) Glucocorticoid analysis from serum collected as in B from animals at ZT12 at baseline (B) or immobilized (I).