Recent advances in blood pressure research (2019)

According to the World Health Organization (WHO) elevated blood pressure, known as arterial hypertension, is a condition in which the arterial blood vessels have persistently raised pressure, putting them under increased stress. The higher the blood pressure, the higher the risk of damage to the heart and blood vessels in major organs such as the brain and kidneys. Hypertension is the most important preventable cause of heart disease and stroke worldwide.1 Investigating the mechanisms of blood pressure regulation was again a focus of a number of articles2-9 published in Acta physiologica in the recent year. The research on basic physiological questions and mechanism in model organisms is complemented with studies that include clinical patient data.9-12 It is clear from previous work that factors such as diet are important for blood pressure regulation. A new piece in the puzzle has been added by the work of Toral et al in which they investigated the role of specific gut microbiota to vascular function and blood pressure.13 In various faecal microbiota transplantation experiments, they identified that the bacterial abundance of Turicibacter and S24-7_g positively and negatively correlated with systolic blood pressure, respectively.13 Furthermore, they show that the immune system, namely T-cell activation in the gut immune system and vascular T-cell accumulation, is involved in the underlying mechanism. Pathological processes are sometimes the result of vicious circles. In a review by Rippe et al14 highlighting the role of soluble guanylyl cyclase (sGC) and the NOTCH signalling pathway, the authors describe a potential example. It is proposed that arterial hypertension-induced repression of sGC starts a vicious circle that can be initiated by periods of stress, diet or genetic factors, and a key principle is that reduction in sGC further raises blood pressure.14 From this observation, it is suggested that the sGC would be an ideal target for pharmacological intervention in the fight against cardiovascular disease. Arterioles play a major role in the control of blood pressure. Due to their high haemodynamic resistance, a little change in diameter will lead to a tremendous change in total peripheral resistance and this in turn will highly affect blood pressure. Arteriolar endothelial cells can talk to each other and one structural prerequisite is that they are connected by connexin molecules. Ions such as calcium or potassium and second messengers, such as IP3, cAMP or ATP, may travel from one cell to another through those connexin molecules that connect the cells. In a review by Pogoda et al, it is discussed in detail how the endothelium exerts a coordinating function to regulate vasomotor reactions of blood vessels locally and on a larger scale in vascular networks.15 In this work, the authors elaborate on many aspects of connexin-related signalling such as electrical signalling and calcium signalling and human pathophysiology. Interestingly, only few mutations in connexin genes in rare cases are known and the lack of further known mutations or gene defects may be due to the fact that the connexins encoded by these genes play an important role in the development leading to embryonal lethality.15 In the year 2004, the Nobel Prize in Physiology or Medicine was awarded to Richard Axel and Linda B. Buck for their discoveries of “odorant receptors and the organization of the olfactory system.”16 This might have encouraged researches to focus their work on olfactory input and aspects of blood pressure blood pressure regulation. In the National Health and Nutrition Examination Survey (NHANES), Gallo et al report on associations of olfactory dysfunction with anthropometric and cardiometabolic measures. They report lower body mass indices (BMI) and lower waist circumferences in older men. In contrast, dysfunction was associated with higher BMI in middle-aged women. With regard to blood pressure, no significant associations were observed in the NHANES study.17 In a study by Lee et al, wherein the olfactory calcium-sensing receptor was activated the researchers found that arterial blood pressure was elevated in a rat model by affecting sympathetic control through olfactory G-protein-coupled receptors. Given the enormous complexity of olfactory input to the brain, it is difficult to translate single findings to general conclusions with regard to blood pressure regulation. Thus, there is still some way to go to establish beneficial therapeutic effects of smelling specific volatile compounds, but a potential link between olfactory G-protein-coupled receptors and cardiovascular control is now established in a rat model as was stated by Boye L. Jensen in a recent contribution related to that topic.18 Diuretics may be part of therapy according to the current guideline for the prevention, detection, evaluation and management of high blood pressure in adults.19 In a study by Ydegaard et al, it was investigated whether the effect of the diuretic drug amiloride depends on the amiloride-sensitive epithelial sodium channel (ENaC) in conjunction with the endothelial NO synthase (eNOS).10 The researchers performed experiments in eNOS knockout mice and measured NO products in urine and plasma samples of diabetic patients before and after amiloride treatment. Their data showed that amiloride reduced arterial blood pressure in patients and acutely in mice; however, this was not corroborated in mice by ENaC-selective benzamil. This would mean that blood pressure decline in patients did not relate to NO products/cGMP and did not depend on eNOS or NOS activity in mice.10 Ydegaard et al conclude that amiloride has an acute hypotensive action not dependent on ENaC and eNOS but is likely related to the heart. Klotho is a protein that is highly expressed in the kidney (data set from,20 may be visualized with the online BIOGPS tool,21 see Figure 1). A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility and arteriosclerosis.22 So it may be tempting to supplement exogenous klotho in a disease model. This exactly was done by Takenaka et al in a diabetic db/db model. The researchers found several molecular effects in the kidney such as an increase in superoxide dismutase expression (SOD) and decreased TGF-β expression, for example, after klotho supplementation, and a drop in blood pressure from (113 ± 2) mmHg in the db/db to (105 ± 2) mmHg in the db/db + klotho group. The authors conclude that their data indicate that klotho supplementation reduces blood pressure and albuminuria along with ameliorating renal renin angiotensin system activation in db/db mice. How the results of the recent research in the field will have an impact on clinical translation will be seen in the future. A hot candidate may be perhaps the study of Toral et al13 that extends our understanding of the mechanisms linking alterations of the gut microbiota to hypertension.23 There is no conflict of interest to declare.