Pressed for time: the circadian clock and hypertension

Abstract

Hypertension is a major risk factor for cardiovascular disease and death. The "silent" rise of blood pressure that occurs over time is largely asymptomatic. However, its impact is deafening-causing and exacerbating cardiovascular disease, end-organ damage, and death. The present article addresses recent observations from human and animal studies that provide new insights into how the circadian clock regulates blood pressure, contributes to hypertension, and ultimately evolves vascular disease. Further, the molecular components of the circadian clock and their relationship with locomotor activity, metabolic control, fluid balance, and vascular resistance are discussed with an emphasis on how these novel, circadian clock-controlled mechanisms contribute to hypertension.

Fig. 1.

Counter “clockwise” productivity to hypertension. Behavioral disorders such as sleep apnea, shift work, or inadequate sleep impair central clock function, which may affect the release of hormones such as melatonin (Mel), which then impinge on blood pressure-regulating organs (heart, kidney, vasculature). Similarly, diet or other disturbances that originate from aberrations peripheral to the central nervous system may modify circadian clock function (depicted as distortion in the components Bmal1, Per, Cry, and Clock along black arrow) in peripheral tissues that are extrinsic to the organs/tissues important in the pressor response. These extrinsic peripheral tissues such as liver or the adrenal gland may affect release of pressor-modifying mediators [liver/angiotensin-converting enzyme; adrenal/epinephrine (Epi)], which then impinge on the pressure-regulating tissues. There may also be direct peripheral clock dysfunction in tissues such as heart, kidney, and vasculature that are intrinsically critical in blood pressure regulation by modulating the expression of ion channels (αENAC), paracrine signals (nitric oxide/NO), and receptors (adrenergic receptor/AR). An additional level of complexity is that hypertension itself alters circadian clock function in peripheral tissues (red dashed arrow) to induce a feedforward spiral of dysfunction.