Role of Chrononutrition in the Antihypertensive Effects of Natural Bioactive Compounds

Abstract

Hypertension (HTN) is one of the main cardiovascular risk factors and is considered a major public health problem. Numerous approaches have been developed to lower blood pressure (BP) in hypertensive patients, most of them involving pharmacological treatments. Within this context, natural bioactive compounds have emerged as a promising alternative to drugs in HTN prevention. This work reviews not only the mechanisms of BP regulation by these antihypertensive compounds, but also their efficacy depending on consumption time. Although a plethora of studies has investigated food-derived compounds, such as phenolic compounds or peptides and their impact on BP, only a few addressed the relevance of time consumption. However, it is known that BP and its main regulatory mechanisms show a 24-h oscillation. Moreover, evidence shows that phenolic compounds can interact with clock genes, which regulate the biological rhythm followed by many physiological processes. Therefore, further research might be carried out to completely elucidate the interactions along the time-nutrition-hypertension axis within the framework of chrononutrition.

Keywords: biological rhythms; blood pressure; hypertension; peptides; phenolic compounds.

Figure 1

Schematic representation of the components of the renin–angiotensin–aldosterone system (RAAS) and some of their main effects, modulating blood pressure (BP). RAAS is activated when the blood volume decreases, plasma Na⁺ levels are low or a renal artery stenosis is suffered (2K1C experimental animal model). Juxtaglomerular cells (kidney) are activated to produce renin from prorenin, which is released to the bloodstream. Renin degrades hepatic angiotensinogen to form the angiotensin I (Ang I). Then, Ang I is hydrolyzed by the endothelial angiotensin-converting enzyme (ACE), mainly when it goes through the lung capillaries, releasing Ang II. Ang II produces vasoconstriction, acting directly on vascular smooth muscle cells after it binds to Ang type 1 receptor (AT1R). In addition, it also induces an increase in BP, stimulating (i) the production of reactive oxygen species (ROS) in the endothelium, (ii) the release of endothelin-1 (ET-1; an endothelial vasoconstrictor factor), (iii) the release of antidiuretic hormone (ADH) by the posterior pituitary gland, which produces reabsorption of water in the nephrons and (iv) the release of aldosterone by the suprarenal glands, which also produces reabsorption of water and Na⁺ and excretion of K⁺. Ang II also stimulates nephrons to Na⁺ reabsorption and regulates glomerular filtration rate (GFR). Ang II can also bind to AT2R, producing vasodilatation effects. Ang II is quickly degraded by aminopeptidase A (APA), releasing Ang III, which can bind to AT1R and AT2R producing the same effects described for Ang II. Ang III is further metabolized to Ang IV by the aminopeptidase N (APN), which also exerts central pressor effects via AT1R. Moreover, Ang II can also be hydrolyzed by ACE 2 or prolylcarboxypeptidase (PCP), producing Ang-(1-7). Ang-(1-7) can be also produced by the degradation of Ang-(1-9) by ACE. Ang-(1-9) is produced from Ang I after being hydrolyzed by ACE 2. Ang-(1-7) exerts nitric oxide (NO)–dependent vasodilatation via the G-protein–coupled Mas receptor (MasR).

Figure 2

Schematic representation of the main vasodilator and vasoconstrictor factors produced by the endothelium. Cell (A) Phospholipase A₂ (PLA₂) releases arachidonic acid (AA) from membrane glycerophospholipids. AA is transformed into prostaglandin (PG) G₂, which is further reduced to PGH₂ by the cyclooxygenase 1 (COX-1). Finally, prostacyclin synthase (PGIS) converts PGH₂ into PGI₂, which exerts vasodilation of vascular smooth muscle binding to prostacyclin receptors (IPR) and peroxisome proliferator-activated receptor (PPAR) β/δ. (B) Nitric oxide (NO) is the main endothelial vasodilator factor which is synthesized through the oxidation of L-arginine (L-Arg) to L-citrulline (L-Citr) by the endothelial NO synthase (eNOS). eNOS expression is stimulated by Kruppel-like-factor 2 (KLF2), and eNOS is activated by sirtuin 1 (SIRT-1), which deacetylates it. Furthermore, SIRT-1 stimulates eNos transcription. NO diffuses into vascular smooth cells and produces vasodilatation by the activation of guanylate cyclase (GC), which converts GTP to cGMP. (C) eNOS can also produce ROS (superoxide anions) when it is uncoupled. These anions can scavenge NO, generating peroxynitrites (ONOO−), reducing NO bioavailability and NO-dependent vasodilatation. (D) ROS is produced by other enzymes, such as the NADPH oxidase 4 (NOX-4), which catalyzes the transfer of electrons from NADPH to molecular oxygen. NOX-4 activity is stimulated by angiotensin (Ang) II and peroxynitrite. (E) Ang II is formed from Ang I by the action of angiotensin-converting enzyme (ACE). Ang II produces the constriction of vascular smooth cells via Ang type 1 receptor (AT1R). Endothelin 1 (ET-1) is produced by the action of endothelin-converting enzyme 1 (ECE-1) on the big ET-1. ET-1 vasoconstrictor effects are mediated by its interaction with ETA receptors (ETAr), located in the vascular smooth cells. ET-1 synthesis or release is favored by Ang II and ROS. ET-1 can stimulate the vascular Nox expression. Green lines indicate stimulation/modulation.

Figure 3

Schematic representation of the molecular mechanism of the molecular clock. Circadian locomotor output cycles kaput (CLOCK) and brain and muscle Arnt-like 1 (BMAL1) dimerize to bind to the E-box elements in promoter regions of clock-controlled genes such as Per and Cry. CRY and PER form a complex that represses the heterodimer CLOCK–BMAL1 in the nucleus, inhibiting the transcription of clock genes by a negative feedback loop within a 24-h period. The heterodimer CLOCK–BMAL1 also drives a regular expression of nicotinamide phosphoribosyltransferase (Nampt). NAMPT triggers the release of NAD⁺, a cofactor needed for Sirtuin 1(SIRT1), which modulates the activation of clock genes via deacetylation of histones.

Figure 4

Schematic representation of a normal dipper 24-h BP cycle (black line) and different BP behavior in hypertensive patients: dipper (orange line), non-dipper (green line), extreme dipper (violet line) and reverse dipper/riser (pink line) effect. Adapted from Hermida et al., 2007 [95].