Given the subject matter, a brief introduction to the mechanisms of biological time-keeping is central to appreciating the materials subsequentially presented. Circadian rhythms in pressor and all other biological processes are generated and orchestrated by a self-oscillating master brain clock, the suprachiasmatic nuclei (SCN) of the hypothalamus [10, 11]. The clock mechanism in the SCN and peripheral oscillators is similar; it consists of a network of transcriptional–translational feedback loops that drive rhythmic, i.e., ∼24 h, expression patterns of the core clock components—clock genes such as Clock, Bmal, Per, and Cry—whose protein products generate and regulate cellular circadian rhythms of all tissues, organs, and systems. Because the inherited period of the SCN and peripheral oscillators differs somewhat from exactly 24.0 h, external time cues are required to synchronize it for efficient functioning. The primary environmental time cue is the 24 h light/day cycle. Environmental time information in the form of the onset (sunset) and offset (sunrise) of darkness is sensed by intrinsic non-rod/non-cone ganglion cells (ipRGC) of the retinae and conveyed via the retinohypothalamic neural pathway first to the SCN and thereafter via the paraventricular nucleus, hindbrain, spinal cord, and superior cervical ganglion pathways to β- and α-receptors within the pineal gland to initiate melatonin synthesis [12]. Accordingly, the period of the SCN and subservient peripheral clocks, and the circadian rhythms they drive, is synchronized, i.e., set and reset from one day to the next, to 24.0 h, and additionally, the phasing (peak and trough) of these circadian oscillators and the rhythms they generate is correctly timed to support optimal biological efficiency during daytime wakefulness and activity and rest and repair during nighttime sleep.

The short-half-life molecule melatonin, the so-called hormone of darkness, plays a central role in biological time-keeping. Its synthesis and circulation take place only during the nighttime dark span; thus, in humans plasma and tissue melatonin concentration peaks during nocturnal sleep, while it is essentially undetectable during the daytime [12]. Normal daytime and artificial nighttime light, especially of the blue spectrum, inhibits melatonin synthesis. The period and phasing of the melatonin synthesis circadian rhythm of the pinealocytes are synchronized to external time by the onset, duration, and cessation of environmental darkness, and the circulation of melatonin, in turn, synchronizes the period and phasing of the other 24 h bodily rhythms [10].

The melatonin 24 h rhythm, itself, appears to play a role in the observed BP day/night variation via its direct effects on the arterial wall [13], cardiomyocytes [14], baroreflex set point [15], and sympathetic nervous system (SNS) through modulation in the adrenal medulla of the catecholamine synthesis circadian rhythm [16]. Moreover, bedtime melatonin supplementation reduces human BP, particularly sleep-time BP [15, 17]. Such observations are consistent with the contention that the BP day/night variation is endogenous in origin, even though it is often masked by the more dominant external influences [18], especially those of physical and mental activity [19] as clearly demonstrated by studies of rotating shift workers [20].

SNS tone dominates during the daytime wake span, while vagal tone dominates during the nighttime sleep span [32–34]. Plasma norepinephrine and epinephrine plus urinary catecholamine concentrations are greatest during the initial span of diurnal activity, i.e., morning to early afternoon, when SBP and DBP attain near peak or peak values and lowest during nocturnal sleep when SBP and DBP are least [35, 36]. The temporal relationship between the 24 h alteration in plasma dopamine and norepinephrine/epinephrine concentrations is strong, suggesting dopaminergic modulation of the circadian rhythm of SNS activity [36, 37]. In human beings, catecholamine sulfates are biologically inactive, and in normotensive recumbent persons the circadian pattern is opposite that of biologically active free catecholamines [38]: plasma noradrenaline and adrenaline sulphates rise to peak levels early during the nighttime sleep span, and plasma-free noradrenaline and adrenaline rapidly increase before morning awakening.

Environmental cycles, especially the one of light and darkness, in conjunction with the activity/sleep circadian rhythm, significantly influence catecholamine concentration [39]. The day/night change in plasma norepinephrine and metabolite 3-methoxy-4-hydroxyphenylglycol, but not epinephrine, is strongly affected by activity, arousal, posture, and food consumption [36, 39, 40]. Nonetheless, nocturnal decline in norepinephrine is observed even in sleep-deprived individuals, suggesting the inherent 24 h variation in norepinephrine secretion is controlled by an endogenous circadian clock [41].

The ANS nyctohemeral variation, together with the day-night pattern in physical activity, mental and emotional stress, and posture, plays a prominent role in the BP 24 h profile of both normotensive and uncomplicated hypertension [4–9]. In most normotensive subjects the sleep-time heart rate decreases by 18 beats/min, cardiac output by 29 %, stroke volume by 7 %, and vascular total peripheral resistance (TPR) although declining early in sleep increases by 22 % compared to average daytime values [42]. Comparable changes are observed in uncomplicated essential dipper hypertensive subjects [43].

The renin–angiotensin–aldosterone system (RAAS) modulates BP through various mechanisms—body sodium (Na) and water (H₂O), SNS, and vasomotor tone balance. Renal blood flow reduction induces renal juxtaglomerular cells to release the enzyme renin. Liver-derived angiotensinogen is converted by renin to angiotensin I, which in turn is converted by lung tissue-derived angiotensin-converting (ACE) enzyme to angiotensin II (ANG II). ANG II elevates BP by signaling aldosterone release from the adrenal cortex, which acts to increase renal Na and H₂O reabsorption, stimulate SNS activity, and initiate blood vessel vasoconstriction.

Circadian rhythms of prorenin, plasma renin activity (PRA) and serum ACE activity, plasma ANG II and aldosterone concentration, plus tissue angiotensin type-1 (AT1) receptor expression contribute strongly to the BP day/night oscillation in both normotensive and uncomplicated hypertensive conditions, and for some of the variables even under conditions of long-term recumbence [6, 44–51]. The RAAS activates during the night, i.e., mid-sleep span, with highest and lowest PRA and ANG II concentration found in the morning and late evening, i.e., at the commencement of the wake and sleep span, respectively. However, this temporal patterning persists in the absence of the wake/sleep cycle, i.e., in sleep-deprived subjects, although generally with reduced amplitude [52]. Some investigators have failed to detect PRA circadian patterning [53–55], finding instead an ultradian periodicity of ~100 min strongly correlated with sleep staging—PRA declining during REM sleep and peaking during deep and light sleep transitions. SNS and dopaminergic mechanisms appear to be important modulators of the PRA, ANG II, and aldosterone circadian rhythms [56]. The PRA circadian rhythm determines the magnitude of response to external challenge, explaining why the exercise-induced PRA response is markedly greater in the afternoon at 16:00 h than middle of the night at 04:00 h [57]. Plasma aldosterone 24 h variation is predominantly regulated by the ACTH circadian rhythm that peaks between the middle and late portion of sleep [24]; although, during the wake span aldosterone is modulated mainly by the renin-angiotensin system [58].

ACE circadian rhythmicity has been demonstrated in both healthy normotensive and uncomplicated essential hypertensive individuals studied under a controlled meal-time and activity/rest routine. Two Italian studies [48, 49] reported a late afternoon rather than the expected morning peak, while a third Japanese study reported a late nighttime sleep/early daytime activity peak (06:00–09:00 h) [50], both in normotensive and essential hypertensive subjects. Inconsistency in the circadian time of peak ACE activity between studies could represent differences during the 24 h in meal composition and liquid consumption and their timings, subject activity and posture patterning, and blood sampling paradigm. Moreover, in the two Italian studies [48, 49], absence of the early morning peak in ACE activity might be indicative of a circadian rhythm of ACE turnover: during sleep when ANG II generation is maximum, ACE consumption is maximum, and circulating ACE level is reduced, and during the daytime when ANG II generation is minimal, ACE consumption is minimal, and circulating ACE level is elevated. Finally, it is of interest that circadian rhythmicity in SCN AT1-receptor expression has been demonstrated in laboratory animals with peak expression early during the nocturnal activity span and lowest expression during the middle to late rest span [51]. This finding implicates central clock modulation of the BP 24 h variation [51] and further suggests the possibility of AT1-expression circadian rhythmicity in other tissues.

Adrenocortical hormones, in general, mediate electrolyte, extracellular fluid, and plasma volume balance through effects on epithelial, smooth muscle, and cardiac cells [59]. They and their active metabolites also modulate energy and other processes of adipose, liver, kidney, and vascular tissue; they also play a role in atherogenesis, vascular homeostasis, and vascular remodeling following intra-vascular injury or ischemia [60, 61]. Additionally, they are involved in the elevated vascular risk induced by long-term stress [62]. Several studies suggest the late sleep/morning-time marked rise in glucocorticoids may up-regulate at the commencement of the diurnal activity span both α₂ and β₂-adrenergic receptor expression in heart, blood vessel, and other tissues, which may explain the greater morning-time effects of certain adrenergic agonist and antagonist agents as well as marked SNS-driven increase in morning heart rate and BP [63–65].

The master SCN oscillator drives the ACTH circadian rhythm, and this along with circadian SCN-mediated SNS activity gives rise to cortisol 24 h periodicity [24]; plasma ACTH concentration peaks during the latter span of sleep, and cortisol adrenocortical synthesis and circulation is highest just prior to or upon waking and lowest early during sleep [24]. The sensitivity of the adrenal cortex to both endogenously produced and exogenously administered ACTH, itself, is circadian-time dependent [24], explaining in part the enhanced secretion of cortisol in response to stressful stimuli in the morning [66]. The ACTH and ACTH-dependent 24 h oscillation of cortisol contributes to the nyctohemeral variation in cardiac output and SBP, but without effect upon blood vessel peripheral resistance [59, 67]. The BP 24 h pattern is disrupted, especially BP sleep-time decline, in Cushing’s syndrome and also Addison’s disease, in which the adrenocortical-derived circadian rhythms of cortisol and aldosterone are abnormal or absent, thereby implicating the significance of hypothalamic–pituitary–adrenal axis (HPAA) periodicity in the BP day/night variation under normal conditions [56, 68].

Plasma thyroid stimulation hormone (TSH) concentration exhibits circadian variation, rising during the afternoon and peaking after midnight [24]. The hypothalamic–pituitary-thyroid axis (HPTA) exerts effects on the CV system at multiple levels, including direct positive inotropic and cronotropic actions on the myocardium plus stimulation of tissue metabolic rate and positive modulation of the agonistic sensitivity of heart tissue ß-adrenergic receptors [69]. Surprisingly, there have been few studies of the exact role of the HPTA nyctohemeral cycle on BP day/night variation. Evidence of its effects is based on clinical observations of persons with abnormal thyroid states—increased vascular resistance, often depressed systolic function, left ventricular diastolic dysfunction at rest, systolic and diastolic dysfunction on effort, endothelial dysfunction, arterial wall thickness, atherosclerotic injury [69–71], plus altered BP regulation and 24 h non-dipping patterning [72].

Various opioid peptides and receptors are present in the central nervous system and peripheral neural elements, some of which exert CV system effects. In normotensive and spontaneously hypertensive rats, both free and cryptic metenkephalin heart tissue concentration exhibits circadian rhythmicity [73]. In humans, plasma ß-endorphins (but not metenkephalin) also are circadian rhythmic [74], as is the binding of ligand to opiate receptors [75]. Involvement of both the sympathetic and parasympathetic nervous systems in the actions of these peptides on CV function is established; although little is known to date about underlying mechanisms in humans. In man, endogenous opioids modulate central nervous system BP control, particularly its nocturnal decline [76]. ∂-Opioid receptors, in particular, are suspected of playing a role in BP nocturnal decline through suppression of the SNS and HPAA [77, 78] and the phase (peak and trough) relationships of the respective circadian rhythms.

Both atrial natriuretic peptide (ANP) and calcitonin gene-related peptide (CGRP) are circadian rhythmic [79, 80], and both exert regulatory control of the 24 h BP pattern. ANP, a 28 amino acid polypeptide, suppresses PRA, ANG II, aldosterone, and catecholamine concentrations; increases Na excretion and plasma and urinary cGMP levels; and shifts the renal pressure-natriuresis mechanism so Na balance during sleep can take place at lower arterial pressures. ANP is principally involved in short-term electrolyte balance and BP control, while the RAAS primarily exerts long-term BP control [81]. Thus, ANP acts to reduce vascular TPR and as a consequence arterial BP. Peak ANP concentration occurs between 23:00 and 04:00 h and coincides approximately with the nadir of the PRA and aldosterone circadian rhythms of diurnally active normotensive and essential hypertensive persons, with the ANP peak-to-trough 24 h variation that is independent of posture amounting to ~10 pmol/L [79, 81, 82]. Blunting of the nocturnal BP decline, e.g., in chronic renal and congestive heart failure patients, is paralleled by concomitant alteration of the ANP circadian rhythm, both before and after treatment [83–85].

CGRP is a 37 amino-acid peptide involved in various metabolic and behavioral functions [86]. CGRP-containing fibers exist throughout the CV system, particularly within the coronary arteries, sinoatrial and atrioventricular nodes, and papillary heart muscle fibers [87]. CGRP blood levels are most likely representative of peptide spillover from nerve terminals that promote vasodilatation. A circadian rhythm in plasma CGRP has been demonstrated in both normotension and uncomplicated hypertension [80, 88, 89]. The RAAS modulates plasma CGRP secretion, either directly through vasopressor effect on peripheral blood vessels or indirectly through neurohumoral mechanisms that modulate vascular tone and thus BP [90–92]. Intravenous CGRP infusion in pharmacological doses decreases mean BP and increases heart rate in humans [93, 94]. CGRP also plays a role in response to postural and vasomotor changes; plasma CGRP levels rapidly rise, as do those of norepinephrine and aldosterone, in healthy subjects after assuming an upright position or following low-dose ANG II infusion [91].

Circadian rhythms of the endothelial vasodilator and vasoconstrictor factors of nitric oxide (NO) and endothelin 1 (ET-1) modulate vascular tone and BP. In diurnally active healthy individuals, vasodilator NO concentration is lowest around the transition between the sleep and wake span and highest 12 h later [95–97]. Accordingly, brachial artery flow-mediated endothelium-dependent vasodilatation (FMD) is least in the early morning and most elevated in the late afternoon and evening. The FMD circadian rhythm is substantiated in both men and pre-menopausal women, although based on the results of a single investigation not in menopausal women [98]. The vasoconstrictor ET-1 exhibits 12 h variability, with two peaks of equal magnitude, one in the morning at the beginning of the wake span and the other early evening [97].

The peak time of the individual nervous system, endocrine, endothelial, peptide, renal hemodynamic, and other circadian rhythm determinants of the nyctohemeral BP pattern typical of most normotensive and uncomplicated essential hypertensive persons occurs between the last hours of nighttime sleep and initial hours of daytime wakefulness. Clinical trials (Table 6.2) clearly document the BP-lowering effects of conventional long-acting hypertension medications vary, often extensively, according to treatment time [108]. When such medications, especially those that directly or indirectly modulate the SNS and RAAS or their vasomotor effects, i.e., angiotensin converting enzyme inhibitors (ACEIs) , angiotensin receptor blockers (ARBs) , calcium-channel blockers (CCBs) , α-blockers, and ß-blockers, are ingested alone or in combination at bedtime rather than morning, reduction of the asleep SBP and DBP means is vastly enhanced as is the sleep-time relative BP decline, thereby greatly improving the BP 24 h profile toward normal. Such findings indicate features of the innate pressor-affecting circadian rhythms are of greater importance than previous appreciated as determinants of the BP 24 h pattern and, therefore, management of hypertension.