Mild and Severe Hypertension Differentially Induce Internal Circadian Misalignment, Sleep-Wake Fragmentation, and...

Hypertension is a major cardiovascular risk factor that perturbs neurohumoral regulation, yet its integrated effects on circadian sleep-wake organization and neurocardiac coupling remain unclear. We examined whether the severity of hypertension induces internal circadian misalignment and neurocardiac desynchronization. Male Wistar rats were assigned to the control, high-fructose (HF; mild hypertension), and DOCA-salt (severe hypertension) groups. Across 24 h, we evaluated neurohumoral markers (melatonin, norepinephrine, angiotensin II, vasopressin, and corticosterone), calcium, cardiovascular function (blood pressure, ECG, HRV, and echocardiography), sleep-wake behavior (EEG/EMG), and molecular oscillations of Bmal1, Per1, CACNA1C, and ANP in the SCN and heart. Temporal allostatic load and causal network inference were applied to assess the systemic strain. Both hypertensive models established new blood pressure set points, with HF rats stabilizing at mild hypertension levels and DOCA-salt rats stabilizing at severe hypertension levels. Both exhibited increased neurohumoral load, autonomic imbalance, and ECG/HRV alterations, while DOCA-salt rats showed marked melatonin suppression, sustained elevations of norepinephrine, AVP, corticosterone, and calcium and pronounced NREM-REM fragmentation. Cardiac Bmal1 and Per1 were phase-shifted, CACNA1C was upregulated, and ANP was downregulated, while SCN rhythms were preserved, indicating peripheral desynchronization. Allostatic load analysis revealed an early and persistent burden in DOCA-salt rats and delayed but significant increases in HF rats. Causal network modeling demonstrated a progressive loss of melatonin's upstream regulation, replaced by neurohumoral dominance, indicating potential pathways in the treatment of hypertension-induced sleep-wake disturbances. These findings indicate that the severity of hypertension reorganizes systemic temporal architecture, amplifying circadian misalignment and SCN-heart decoupling, highlighting the need for stage-specific chronotherapeutic strategies.