Modifiers of hypertension (2018)

Regulation of blood pressure and the understanding of its mechanisms have been one focus of current publications in Acta Physiologica. Among those are many publications that investigate mechanistic aspects of blood pressure regulation. A number of papers in Acta Physiologica deal with modifiers of blood pressure that received attention only recently. One of those is the interesting conjecture between the toll-like receptor TLR4 that belongs to the innate immune system and blood pressure regulation that has been investigated by van Beusecum et al1 The authors investigate the effect of stimulation with lipopolysaccharide (LPS) on hemodynamic parameters on in vitro perfused nephron preparations. LPS is a substance that is part of the outer membrane of gram-negative bacteria. Upon binding of LPT to TLR4, the NF-kB pathway is activated.2 In their analysis, van Beusecum et al. focus on autoregulation. To assess the autoregulatory behaviour, the authors measure vessel diameter after stepwise changing the perfusion pressure. The authors find that after LPS intervention the autoregulatory response of the vessels is diminished as compared to untreated controls. The autoregulation was preserved when the predations were pretreated with anti-TLR4 antibody of TLR4 antagonists, indicating that the observed effects depend on the TLR4 receptor. The substance tempol that has been implicated in a mimetic action of the superoxide dismutase (SOD) restored the vasoactive behaviour in afferent arterioles. Therefore, the authors conclude that the ROS system is involved in the effects observed. Additional experiments show that the angiotensin type 1 receptor (AT1) blocker losartan did not change the LPS effect on the arterioles. The relation between blood pressure, high-fat diet and the intervention with a selective immunosuppressive drug (Tacrolimus) was investigated in a rat animal model by Khan et al3 The high-fat diet led to obesity, higher blood pressure, higher creatinine clearance, renal TNF-a, and IL-6 concentrations were elevated fourfold to fivefold in high-fat animals when compared to controls. Obese rats showed lower baroreflex sensitivity as determined by the baroreflex gain curve method after bolus phenylephrine injection. However, this baroreflex sensitivity impairment was restored to control by tacrolimus. The authors conclude that the autonomous dysregulation in conjunction with the renal inflammation because of high-fat diet may be a focus for targeted therapy. Looking at the causal chain, it would be interesting to know whether a change to normal diet in the obese animals would reverse the inflammatory hemodynamic changes to control levels. If so, this would save a lot of resources since a simple life style adjustment would do the trick. In a study by Solocinski et al., the role of the circadian clock in blood pressure regulation was studied in a knock out (KO) model of the Per1 gene under the intervention of high salt and application of the mineralocorticoid deoxycorticosterone pivalate. Interestingly, in wild type blood pressure was not affected by high salt plus pivalate. KO mice exhibited higher blood pressure under these conditions. Blood pressure typically exhibits a typical day/night rhythm which (anti-)correlates with active/inactive pattern depending on the species. The lower blood pressure values are also referred to as pressure dips in the inactive phase. This pressure dip is almost lost during the high salt plus pivalate treatment in the Per1 KO mice. The authors conclude that they have found a none-dipping phenotype and emphasize that the Per1 gene plays an important role in the circadian modulation of arterial blood pressure. Clinical aspects of renal denervation in humans have recently been discussed controversially. A study in rats has been reported by Lu et al.4 In this work, a cardiac pressure overload was induced by a transverse aortal constriction. The effect of renal denervation on cardiac function and immunochemistry parameters was measured. Cardiac collagen volume fraction, a measure of fibrosis, was much lower in the denervated group. Denervated rats had higher cardiac capillary density than sham rats. The authors conclude that renal denervation is beneficial for cardiac angiogenesis in the context of pressure overload. The knowledge about the potential dangers of a high-salt diet has already been reflected in guidelines as issued by the American Centers for Disease Control and prevention (CDC) (https://www.cdc.gov/salt/sodium_reduction_initiative.htm) for example. One possible damaging mechanism has been studied by Zhao et al5 in a mouse model. Here, the authors show a reduced renal mass because of increased oxidative stress in the kidney under high-salt diet. This in turn leads to a remodelling process in renal arterioles leading to lower glomerular filtration rate (GFR). This review exemplifies that we can find mechanisms6, 7 of regulation of blood pressure at various levels8-12 and in multiple organs.13 That is why we are able to compile an almost endless list of potential modifiers. The individual relevance of those for human health and disease, quality of life, or human life expectancy might perhaps only be measured in large human interventional studies or with new epidemiological observational approaches. In terms of clinical guidelines, a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines was published in 2017.14 In this new guideline, the definition of hypertension, systolic and diastolic blood pressure thresholds for initiation of antihypertensive medication, and blood pressure target goals are revised and newly defined. As pointed out by Muntner et al15, the current modification of the thresholds leads to a substantial larger number of patients with arterial hypertension and to a small increase in the percentage of U.S. adults recommended for antihypertensive medication. Some authors regard the new guidelines as major paradigm shifts in the approach to hypertension16 and that some recommendations are likely to generate controversy.17 Many individuals will be newly classified as advised to adapt their lifestyles. Whether this will occur and whether it will improve global health remains to be demonstrated.16 There is no conflict of interest to declare.