Mechanisms Of Blood Pressure Control Research Articles

The relationship between SGLT2 and systemic blood pressure regulation.

The sodium-glucose cotransporter 2 (SGLT2) is a glucose transporter that is located within the proximal tubule of the kidney's nephrons. While it is typically associated with the kidney, it was later identified in various areas of the central nervous system, including areas modulating cardiorespiratory regulation like blood pressure. In the kidney, SGLT2 functions by reabsorbing glucose from the nephron's tubule into the bloodstream. SGLT2 inhibitors are medications that hinder the function of SGLT2, thus preventing the absorption of glucose and allowing for its excretion through the urine. While SGLT2 inhibitors are not the first-line choice, they are given in conjunction with other pharmaceutical interventions to manage hyperglycemia in individuals with diabetes mellitus. SGLT2 inhibitors also have a surprising secondary effect of decreasing blood pressure independent of blood glucose levels. The implication of SGLT2 inhibitors in lowering blood pressure and its presence in the central nervous system brings to question the role of SGLT2 in the brain. Here, we evaluate and review the function of SGLT2, SGLT2 inhibitors, their role in blood pressure control, the future of SGLT2 inhibitors as antihypertensive agents, and the possible mechanisms of SGLT2 blood pressure control in the central nervous system.

Overexpression of Regulator of G-Protein Signaling 2 in the Paraventricular Nucleus Reduces Blood Pressure in Spontaneously Hypertensive Rats

The hypothalamic paraventricular nucleus (PVN) is important in mediating sympathetic activity to regulate blood pressure. The regulator of G protein signaling 2 (RGS2) is a negative G protein regulator. RGS2 selectively regulates Gαq signaling, an important cause of hypertension and cardiac hypertrophy. However, little-to-no studies are being done related to G-protein-RGS2 signaling on the central mechanisms of blood pressure control and sympathetic activation. In this study, we use spontaneously hypertensive rats (SHR) to aim for the pressor effects of central viral transfection over-expressing RGS2 in the PVN compared to a Wistar-Kyoto (WKY) control. These rats were outfitted with telemetry and measurements of blood pressure and heart rate over the next 14 days, with or without RGS2 adenovirus (AV) injection into the PVN. Metabolic experiments were conducted at the 7-day mark to examine kidney function, sodium excretion, urine output, and water and food intake. We saw significant ( p<0.05) decreases in blood pressure for the SHR with AV-RGS2 throughout our telemetry experiment. In our metabolic experiments, sodium excretion significantly ( p<0.05) increased in the SHR group with AV-RGS2 compared to the SHR with AV-GFP. Water intake, food intake, and urine output remained unchanged. Following this experiment, we gave capsaicin injections into the renal pelvis at 5, 10, and 20 μM to measure blood pressure and heart rate responses. Also, blood pressure responses to renal pelvis capsaicin injection appear to be attenuated in SHR and WKY rats with AV-RGS2 injection but was not significant ( p>0.05). In addition, we conducted real-time qPCR on collected PVN tissue to evaluate gene expression changes over time. We saw expression peak at 3-days in G⍺q, G⍺s, G⍺i, and RGS2, and progressively decrease as time progressed. This study provides a value insight of central mechanisms related to G-protein-RGS2 signaling on blood pressure regulation. This study was funded by NIH R01-DK-129311 and USD G-RISE, NIH T32GM-136503. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Regulation of body temperature and blood pressure in women: Mechanisms and implications for heat illness risk.

Increasing global temperatures due to ongoing climate change phenomena have resulted in increased risk of exertional heat illness in otherwise healthy, young individuals who work or play in the heat. With increasing participation of women in athletic, military and industrial activities that involve exertion in the heat, there is a growing need to study female physiology in this context. Mechanisms controlling blood pressure and body temperature have substantial overlap in humans, largely due to autonomic mechanisms which contribute to both. Similarly, illnesses that result from excessive heat exposure can often be traced back to imbalances in one or more of these autonomic mechanisms. In recent years, there has been increased recognition of the importance of sex as a biological variable for basic and applied research in these areas. The goal of this paper is to present an update on the integrative physiology and pathophysiology of responses to heat stress in women (thermoregulation and blood pressure regulation). In this context, it is often the case that differences between sexes are presented as 'advantages' and 'disadvantages' of one sex over the other. In our opinion, this is an over-simplification of the physiology which ignores the nuances and complexities of the integrative physiology of responses to heat exposure and exercise, and their relevance for practical outcomes.

Sex differences in weight gain, blood pressure control, and responses to melanocortin-4 receptor antagonism in offspring from lean and obese parents.

We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet-fed parents were fed N (NN) or high-fat (H) diets (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diets (HH). Adult male and female offspring were implanted with BP telemetry probes and intracerebroventricular cannulas to infuse MC4R antagonist or vehicle. Infusion of the MC4R antagonist SHU-9119 (1 nmol/h) for 7 days caused larger increases in calorie intake and body weight in obese compared with lean offspring. In male offspring, HH and HN groups exhibited higher baseline BP compared with NN and NH, and HH showed a greater reduction in BP during SHU-9119 infusion. In female offspring, HH also showed higher baseline BP and greater reduction in BP during MC4R blockade. SHU-9119 reduced heart rate in all groups, but reductions were more pronounced in offspring from lean parents. Combined α and β-adrenergic blockade reduced BP more in male HH offspring compared with NN controls. Losartan reduced BP more in male NH, HN, and HH offspring compared with NN controls. Losartan and α- and β-adrenergic blockade reduced BP similarly in all female groups. These results suggest that endogenous MC4R activity contributes to elevated BP in obese offspring from obese parents. Our findings also indicate important sex differences in the mechanisms of BP control in male and female offspring of obese parents.

Blood pressure regulation change with ageing: in-depth analysis of 1439 subjects with arterial hypertension and autonomic neuropathy.

Introduction: Blood pressure (BP) regulation is affected by ageing through different mechanisms, including alteration of neural control. Blood pressure variability (BPV) and heart rate variability (HRV) reflect the interaction of BP control mechanisms, and both increased BPV and reduced HRV have been associated to increased cardiovascular morbidity and mortality. The objective of this study was to assess BPV and HRV in hypertensive subjects in different age ranges and to compare them with subjects with established primary cardiovascular dysautonomia, i.e., Parkinson and related diseases. Methods: The study will include 1,439 subjects, divided in three groups: 777 hypertensive subjects aged 40-55 years, 601 hypertensive subjects aged 75-95 years, and 61 patients with primary cardiovascular autonomic neuropathy. Short-term BPV will be assessed through standard deviation (SD), weighted standard deviation (wSD), average real variability (ARV), coefficient of variation (CV), and variability independent of mean (VIM) of 24h ambulatory BP monitoring (ABPM). HRV will be evaluated by SD and CV of heart rate measured during ABPM. Expected outcomes: The expected outcomes of this study include the comparison of overall BPV and mid-term HRV among the three study subgroups, in order to identify similarities and differences in these indexes and to highlight possible common pathophysiological pathways. Furthermore, the characteristics associated with higher BPV and HRV will be analyzed in the three subgroups and compared among them. Similarly, differences in dipping and orthostatic hypotension prevalence will be assessed and characteristics associated with non-dipping status and presence of orthostatic hypotension will be reported. Finally, the association of increased BPV and reduced HRV with organ damage and cardiovascular morbidity will be evaluated.

Abstract 041: Renal-derived Human Sprr Increases Blood Pressure In Female Mice But Not In Male Mice

The soluble prorenin receptor (sPRR) plays an important role in blood pressure regulation. In rodent models, sPRR contributes to Ang II production by increasing renin activity and systolic blood pressure (SBP). However, there is a gap of knowledge concerning the functional role of locally produced human sPRR from the kidney in blood pressure regulation. Therefore, we evaluated the role of renal-derived human sPRR in SBP control.Human sPRR-Myc-tag transgenic mice were bred with mice expressing Hoxb7/Cre to selectively express human sPRR in the collecting duct (RHsPRR). RHsPRR and control (CTL) male and female mice were fed a standard diet for 10 months (n=8-11/group). Body weight was examined weekly and SBP measured by radio-telemetry. Western blot analysis depicted the presence of human sPRR-Myc-tag (28 KDa) in the cortex and medulla of RHsPRR male mice which validated the humanized mouse model. Renal-derived human sPRR did not change body weight in male or female mice (M: CTL: 34±1, RHsPRR: 33±1 g; F: CTL: 28±1, RHsPRR: 30±1 g). Circulating sPRR was also unchanged in male and female mice (M: 3995±643 and 4342±500pg/ml, F: 3479±194 and 3948±238pg/ml). SBP increased significantly in female RHsPRR mice compared to CTL (F: 118.7±2 and 127.2±3 mmHg, P<0.05) but not in male mice (M: 123.8±2 and 119.9±6 mmHg). In female mice, renal-derived human sPRR increased significantly renal AT1R gene expression (F: 1.7±0.5 and 2.6±0.4 2 -ΔΔCT , P<0.05) and stimulated ERK1/2 (F: 0.3±0.0 and 0.6±0.1 AU, P<0.05) suggesting that human sPRR increases blood pressure in female mice likely via AT1R-ERK1/2 pathway activation. In contrast, in male mice, AT1R-ERK1/2 pathway was not up-regulated and renal ACE2 gene expression was significantly increased in RHsPRR males (M: 1.0±0.2 and 3.3±1.1 2 -ΔΔCT , P<0.05). Mechanistically, in male mice, our results indicated that the lack of activation of AT1R-ERK1/2 pathway combined with the increase of ACE2 could have prevented RHsPRR-induced increase in SBP. Together, our data highlighted the contribution of renal human sPRR to blood pressure control in a sex-dependent manner and a new mechanism of blood pressure control that involved the renin angiotensin system.

Abstract P232: Endothelin B Receptor Modulation Of Diurnal Blood Pressure Amplitude During High Salt Diet

High salt diet can alter baroreflex sensitivity. We have previously shown that rats deficient in endothelin B receptors (ET B -R) demonstrate an exaggerated diurnal blood pressure amplitude similar to that seen in rats with sinoaortic denervation fed a high salt diet. However, it remains unclear if ET B -R influence on baroreflex function is due to sensory or efferent mechanisms of autonomic blood pressure control. We employed selective ET B -R antagonism using A192621 in ET B -R deficient rats (ET B -def) that only express functional ET B -R on efferent nerves and transgenic controls (TG) to isolate the role of efferent vs sensory pathways. Rats with telemetry were fed a normal salt diet (0.49% NaCl) during baseline and osmotic minipump infusion of 10 mg/kg/day A192621 or vehicle. After one week of infusion, animals were fed a high salt (4.0% NaCl) diet. Selective ET B -R blockade increased 24 hr MAP in TG animals during normal salt diet (+16.4 ± 1.0 mmHg from baseline; n = 10; p < 0.001) but had no effect on ET B -def (-1.2 ± 1.8 mmHg; n = 7; p > 0.99 ). A192621 treated TG rats did not exhibit a further increase in pressure following high salt diet (+5.5 ± 1.3 mmHg; n = 6; p = 0.25), but both vehicle and A192621 treated ET B -def rats displayed a salt-sensitive increase in MAP (+15.9 ± 4.2 and +14.4 ± 4.5 mmHg; n = 3 and 4; p = 0.003 and 0.001, respectively). A192621 treatment had no significant effect on MAP amplitude (light-dark difference) in any group during normal salt diet. However, during high salt, A192621 treated TG animals had an increase in MAP amplitude (+9.7 ± 0.7 mmHg; n = 6; p = 0.002), and vehicle had no effect (+0.8 ± 0.8 mmHg; n = 5; p = 0.97). Both A192621 and vehicle treated ET B -def rats had a similar increase in amplitude following high salt diet (+9.3 ± 0.6 and +8.6 ± 1.4; n = 4 and 3; p = 0.001 and 0.018, respectively). In summary, antagonism of ET B -R increased MAP only in TG rats but did not have an effect on diurnal amplitude during normal salt in any group. Antagonism of ET B -R during high salt diet caused TG rats to exhibit a similarly high diurnal amplitude as ET B -def rats. These data suggest that blocking ET B -R on baroreflex sensory pathways are the mitigating cause for increased diurnal blood pressure rhythms during high salt diet.

Antihypertensive Effect of Long-Term Monotherapy with Esaxerenone in Patients with Essential Hypertension: Relationship Between Baseline Urinary Sodium Excretion and Its Antihypertensive Effect.

IntroductionThe blood pressure (BP) control mechanism for mineralocorticoid receptor blockers is unclear, and analysis of their use as a single agent in the clinical setting is required to resolve this uncertainty. There is a paucity of data on esaxerenone monotherapy assessing its long-term antihypertensive effect and urinary biomarkers.MethodsThis post hoc exploratory substudy of a long-term phase 3 study evaluated the effect of esaxerenone monotherapy (2.5 or 5 mg/day) in treatment-naïve patients who continued the therapy during the 52-week study period (n = 25). In addition to blood biomarkers, urinary biomarkers were also assessed in 24-h urine collection samples.ResultsEsaxerenone monotherapy was associated with consistent reductions in systolic/diastolic BP in the substudy population (− 23.5/− 13.1 mmHg at week 52, p < 0.001 vs baseline). Plasma aldosterone concentrations and plasma renin activity significantly increased during esaxerenone monotherapy at all time points. On the basis of the observations that both urine volume and urinary sodium excretion also decreased up to the end of the study, and were significantly lower at 12 weeks, patients were further categorized into higher/lower urinary sodium excretion subgroups according to whether their baseline values were above or below the median. In the group with higher baseline urinary sodium excretion, esaxerenone exhibited a significantly greater decrease in systolic/diastolic BP compared to the lower baseline group.ConclusionEsaxerenone exhibited sustained and stable antihypertensive activity even when administered as a single agent for 52 weeks in patients with essential hypertension. The additional urinary biomarker analysis suggests that the BP-lowering effects of esaxerenone may be partly exerted via mechanisms related to salt and water retention, and that the effect is particularly pronounced in patients with hypertension and higher baseline urinary sodium excretion, which may reflect a state of excessive salt intake.Trial registrationNCT02722265.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02282-3.

DIURETIC ASSOCIATED WITH CONCURRENT EXERCISE PROMOTES ADDITIONAL PHYSICAL, AUTONOMIC AND INFLAMMATORY ADAPTATIONS IN HYPERTENSIVE RATS SUBMITTED TO OVARIAN HORMONE PRIVATION

Objective: To evaluate the effects of hydrochlorothiazide (HCTZ) combined or not with concurrent exercise training on physical capacity and neurohumoral mechanism of blood pressure (BP) control in a model of hypertension and menopause. Design and method: Female spontaneously hypertensive rats were allocated into sedentary (S) and ovariectomized groups: sedentary (OS), sedentary treated with HCTZ (OSH) and trained treated with HCTZ (OTH). Ovariectomy procedure was performed at initial of protocol. HCTZ (30 mg/kg) was administrated orally in drinking water. Aerobic and resistance exercises (40–60% maximal capacity) were conducted 3 days/wk for 8 weeks. BP, heart rate and its variabilities were nalysed using signals of direct recording of BP. Vasopressin receptor antagonist, losartan and hexamethonium were sequentially injected to evaluate vasopressor system. Inflammatory profile was evaluated. Results: Systolic and mean BP (mmHg) were lower in OTH (178 ± 17 and 153 ± 17, respectively) compared with OS group (205 ± 15 and 176 ± 16, respectively). Treadmill (OTH vs. OSH) and ladder physical test performance (OTH vs. OS, OS and OSH) were higher in OTH group. Baroreflex sensitivity (bpm/mmHg) was lower in OS group (vs. S) and both bradycardic (OTH:- 1.6 ± 0.3 vs. OS:-0.6 ± 0.3) and tachycardic response (OSH:-2.2 ± 0.7 and OTH:-2.4 ± 0.8 vs. OS:- 1.3 ± 0.4) were improved after HCTZ treatment. OTH showed higher (high-frequency band: OTH:77.8 ± 4.9 vs. OS:69.8 ± 4.0nu) and lower cardiac sympathetic modulation (low-frequency band: OTH:22.2 ± 4.9 vs. OS:30.2 ± 4.0nu) and LF/HF ratio (OTH:0.30 ± 0.08 vs. OS:0.45 ± 0.09). In addition, reduced variance (OTH:30.3 ± 10.5 vs. OS:60.1 ± 13.1) and low-frequency band of systolic BP (mmHg2) (OTH:6.2 ± 5.2 vs. S:16.3 ± 6.7, OS:18.8 ± 6.1 and OSH:15.8 ± 5.5) was observed in trained group. Drop in BP (mmHg) after hexamethonium was higher in OS group (- 75.7 ± 19.2 vs. S:-53.2 ± 12.6, OSH:-54.9 ± 9.0 and OTH:-49.8 ± 12.4). IL-10 (OTH:78.1 ± 17.3 vs. OS:52.8 ± 23.2 and OSH:45.1 ± 10.6) and IL-10/TNF-a ratio (OTH:1.99 ± 0.07 vs. S:1.32 ± 0.21, OS: 1.18 ± 0.12 and OSH:1.18 ± 0.27) was higher in trained group. Conclusions: We concluded that HCTZ combined with exercise training is more efficient than HCTZ alone to improve BP control, probably due to a better adjustment on autonomic modulation and inflammation profile, in addition to induce cardiofunctional benefits. This data reinforces the key role of exercise in the attenuation of hypertension-induced damage in menopaused rats. Grants: FAPESP (2019/06277–0).

Sex differences in TLR4 expression in SHR do not contribute to sex differences in blood pressure or the renal T cell profile.

Hypertension is a primary risk factor for the development of cardiovascular disease. Mechanisms controlling blood pressure (BP) in men and women are still being investigated; however, there is increasing evidence supporting a role for the innate immune system. Specifically, Toll-like receptors (TLRs), and TLR4 in particular, have been implicated in the development of hypertension in male spontaneously hypertensive rats (SHR). Despite established sex differences in BP control and inflammatory markers in hypertensive males and females, little is known regarding the role of TLR4 in hypertension in females. Our hypotheses were that male SHR have greater TLR4 expression compared with females, and that sex differences in TLR4 contribute to sex differences in BP and the T cell profile. To test these hypotheses, initial studies measured renal TLR4 protein expression in 13-wk-old male and female SHR. Additional SHR were implanted with telemetry devices and randomized to treatment with either IgG or TLR4 neutralizing antibodies. Untreated control male SHR have greater TLR4 protein expression in the kidney compared with females. However, treatment with TLR4 neutralizing antibody for 2 wk did not significantly alter BP in either male or female SHR. Interestingly, neutralization of TLR4 increased renal CD3+ T cells in female SHR, with no alteration in CD4+ T cells or CD8+ T cells in either sex. Taken together, our data indicate that although male SHR have greater renal TLR4 expression than females, TLR4 does not contribute to the higher BP and more proinflammatory renal T cell profile in males versus females.

Coenzyme Q10 effects in neurological diseases.

Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson´s disease, Huntington´s disease, Alzheimer´s disease, amyotrophic lateral sclerosis, Friedreich´s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson´s disease) or rather vague (e.g. Friedreich´s ataxia or amyotrophic lateral sclerosis).

Coenzyme Q10 effects in neurological diseases

Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson´s disease, Huntington´s disease, Alzheimer´s disease, amyotrophic lateral sclerosis, Friedreich´s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson´s disease) or rather vague (e.g. Friedreich´s ataxia or amyotrophic lateral sclerosis).

Blood Pressure Management After Endovascular Thrombectomy.

Endovascular thrombectomy (EVT) has changed the landscape of acute stroke therapy and has become the standard of care for selected patients presenting with anterior circulation large-vessel occlusion (LVO) stroke. Despite successful reperfusion, many patients with LVO stroke do not regain functional independence. Particularly, patients presenting with extremes of blood pressure (BP) or hemodynamic variability are found to have a worse clinical recovery, suggesting blood pressure optimization as a potential neuroprotective strategy. Current guidelines acknowledge the lack of randomized trials to evaluate the optimal hemodynamic management during the immediate post-stroke period. Following reperfusion, lower blood pressure targets may be warranted to prevent reperfusion injury and promote penumbral recovery, but adequate BP targets adjusted to individual patient factors such as degree of reperfusion, infarct size, and overall hemodynamic status remain undefined. This narrative review outlines the physiological mechanisms of BP control after EVT and summarizes key observational studies and clinical trials evaluating post-EVT BP targets. It also discusses novel treatment strategies and areas of future research that could aid in the determination of the optimal post-EVT blood pressure.

Sex differences in hypertension: lessons from spontaneously hypertensive rats (SHR).

Although numerous clinical and experimental studies have clearly identified a sexual dimorphism in blood pressure control, the mechanism(s) underlying gender differences in blood pressure remain unclear. Over the past two decades, numerous laboratories have utilized the spontaneously hypertensive rats (SHR) as an experimental model of essential hypertension to increase our understanding of the mechanisms regulating blood pressure in males and females. Previous work by our group and others have implicated that differential regulation of adrenergic receptors, the renin–angiotensin system, oxidative stress, nitric oxide bioavailability and immune cells contribute to sex differences in blood pressure control in SHR. The purpose of this review is to summarize previous findings to date regarding the mechanisms of blood pressure control in male versus female SHR.

Hypertension in African Populations: Review and Computational Insights.

Hypertension (HTN) is a persistent public health problem affecting approximately 1.3 billion individuals globally. Treatment-resistant hypertension (TRH) is defined as high blood pressure (BP) in a hypertensive patient that remains above goal despite use of ≥3 antihypertensive agents of different classes including a diuretic. Despite a plethora of treatment options available, only 31.0% of individuals have their HTN controlled. Interindividual genetic variability to drug response might explain this disappointing outcome because of genetic polymorphisms. Additionally, the poor knowledge of pathophysiological mechanisms underlying hypertensive disease and the long-term interaction of antihypertensive drugs with blood pressure control mechanisms further aggravates the problem. Furthermore, in Africa, there is a paucity of pharmacogenomic data on the treatment of resistant hypertension. Therefore, identification of genetic signals having the potential to predict the response of a drug for a given individual in an African population has been the subject of intensive investigation. In this review, we aim to systematically extract and discuss African evidence on the genetic variation, and pharmacogenomics towards the treatment of HTN. Furthermore, in silico methods are utilized to elucidate biological processes that will aid in identifying novel drug targets for the treatment of resistant hypertension in an African population. To provide an expanded view of genetic variants associated with the development of HTN, this study was performed using publicly available databases such as PubMed, Scopus, Web of Science, African Journal Online, PharmGKB searching for relevant papers between 1984 and 2020. A total of 2784 articles were reviewed, and only 42 studies were included following the inclusion criteria. Twenty studies reported associations with HTN and genes such as AGT (rs699), ACE (rs1799752), NOS3 (rs1799983), MTHFR (rs1801133), AGTR1 (rs5186), while twenty-two studies did not show any association within the African population. Thereafter, an in silico predictive approach was utilized to identify several genes including CLCNKB, CYPB11B2, SH2B2, STK9, and TBX5 which may act as potential drug targets because they are involved in pathways known to influence blood pressure. Next, co-expressed genes were identified as they are controlled by the same transcriptional regulatory program and may potentially be more effective as multiple drug targets in the treatment regimens for HTN. Genes belonging to the co-expressed gene cluster, ACE, AGT, AGTR1, AGTR2, and NOS3 as well as CSK and ADRG1 showed enrichment of G-protein-coupled receptor activity, the classical targets of drug discovery, which mediate cellular signaling processes. The latter is of importance, as the targeting of co-regulatory gene clusters will allow for the development of more effective HTN drug targets that could decrease the prevalence of both controlled and TRH.

Race and sex differences in cardiovascular autonomic regulation

Racial and ethnic differences in cardiovascular morbidity and mortality persist despite advances in risk factor identification and implementation of evidence-based treatment strategies. African American men and women are disproportionately affected by cardiovascular risk factors, particularly hypertension. In this context, previous studies have identified sex and racial differences in autonomic cardiovascular regulation which may contribute to the development of hypertension and its high morbidity burden among African Americans. In this review, we provide a comprehensive evaluation of the potential pathophysiological mechanisms of blood pressure control and their differences based on sex and race. These mechanisms include obesity-induced sympathetic activation, sympatho-vascular transduction, baroreflex sensitivity and adrenoreceptor vascular sensitivity, which have been the subjects of prior investigation in this field. Understanding the racial differences in the pathophysiology of hypertension and its co-morbid conditions would allow us to implement better treatment strategies tailored to African Americans, with the ultimate goal of reducing cardiovascular mortality in this population.

Leptin, Obesity, and Hypertension: A Review of Pathogenetic Mechanisms.

The adipokine leptin is expressed at higher concentrations in obese subjects, who also incidentally have a higher prevalence of hypertension. The pathogenesis of this obesity-related hypertension is controversial and is believed to be related to many factors including increased sympathetic activity, abnormalities of the renin-angiotensin system, sodium retention, and an endotheliopathy acting independently or in concert with increased circulating leptin. This review discusses the potential mechanisms through which changes in leptin signal transduction pathways in tissues with the leptin receptor, especially the hypothalamus, mediate the pathogenetic relationships between obesity and hypertension. The hypothesis is explored that leptin effects on blood pressure (BP) are meditated by the downstream effects of hypothalamic leptin signaling and ultimately result in activation of specific melanocortin receptors located on sympathetic neurons in the spinal cord. The physiological consequences of this sympathetic activation of the heart and kidney are activation of the renin-angiotensin system, sodium retention and circulatory expansion and finally, elevated BP. This sequence of events has been elegantly demonstrated with leptin infusion and gene knockout studies in animal models but has not been convincingly reproducibly confirmed in humans. Further studies in human subjects on the specific roles of hypothalamic leptin in essential hypertension are indicated as elucidation of the signaling pathways should provide better understanding of the role of weight loss in BP control and afford an additional mechanism for pharmacologic control of BP in adults and children at risk of cardiovascular disease.

Greater T Regulatory Cells in Females Attenuate DOCA-Salt-Induced Increases in Blood Pressure Versus Males.

Hypertension is the most common risk factor for cardiovascular disease, causing over 18 million deaths a year. Although the mechanisms controlling blood pressure (BP) in either sex remain largely unknown, T cells play a critical role in the development of hypertension. Further evidence supports a role for the immune system in contributing to sex differences in hypertension. The goal of the current study was to first, determine the impact of sex on the renal T-cell profiles in DOCA-salt hypertensive males and females and second, test the hypothesis that greater numbers of T regulatory cells (Tregs) in females protect against DOCA-salt-induced increases in BP and kidney injury. Male rats displayed greater increases in BP than females following 3 weeks of DOCA-salt treatment, although increases in renal injury were comparable between the sexes. DOCA-salt treatment resulted in an increase in proinflammatory T cells in both sexes; however, females had more anti-inflammatory Tregs than males. Additional male and female DOCA-salt rats were treated with anti-CD25 to decrease Tregs. Decreasing Tregs significantly increased BP only in females, thereby abolishing the sex difference in the BP response to DOCA-salt. This data supports the hypothesis that Tregs protect against the development of hypertension and are particularly important for the control of BP in females.

High fat diet in female Dahl salt sensitive rats causes non‐neurogenic hypertension and minimal renal injury

There is evidence in human subjects and animal models that obesity‐associated hypertension has a smaller neurogenic component in females than males. In addition, females typically show less severe hypertension, immune cell infiltration in the kidney and renal injury than males. The mechanistic links between these phenomena, however, are not clear. We previously found that feeding Dahl salt‐sensitive (SS) rats a high fat diet (HFD) from weaning through 6 months caused equivalent hypertension in male and female animals when compared to SS rats fed control diet (CD). Yet female rats exhibited significantly less renal injury than males. Therefore, in the current study, we quantified the contribution of neurogenic and other blood pressure control mechanisms to HFD associated hypertension in female Dahl SS rats. We also reexamined the impact of long‐term hypertension on histological indices of renal injury in these rats. After 24 weeks on diet feeding starting at weaning, all rats were hypertensive (via telemetric measurements), but HFD females (60% kcal from fat, 0.3% NaCl n=10) had significantly higher mean arterial pressure (MAP) than females fed the CD (10% kcal from fat, 0.3% NaCl, n=7) (MAP 165±4mmHg vs 141±3mmHg, p&lt;0.05). Thereafter, all rats were treated sequentially with prazosin (150mg/L, 5days), atenolol (500mg/L, 7days), prazosin+atenolol (7days), trichlormethiazide (250mg/L, 5 days), and enalapril (250mg/L, 7 days) via the drinking water. Each treatment was followed by washout for 7 days. We found that MAP was moderately and similarly reduced by treatment with prazosin (−14±1mmHg vs −17±1mmHg), atenolol (−31±2mmHg vs −27±2mmHg), prazosin+atenolol (−26±1mmHg vs −29±2mmHg) and trichlormethiazide (−16±2mmHg vs −17±2mmHg) in CD versus HFD fed rats. Enalapril treatment caused more reduction of blood pressure than any other treatment, but the decreases of MAP were similar in CD and HFD fed rats (−36±5 mmHg vs −49±9 mmHg) (P&gt;0.05). Renal histological alterations and immune cell infiltration were determined at 34–36 weeks on diet feeding. Overall CD and HFD fed rats showed similar, and low grade, renal injury scores and renal T‐cell (CD3+) and macrophage (CD68+) infiltration. However, a few HFD rats did show severe renal injury and inflammation, and we noted that in each of these animals MAP levels were consistently &gt; 170 mmHg. Splenic immune cell analysis by flow‐cytometry did not support HFD associated alternations in immune cell population/distributions (CD4+, CD8+, NK cells, B cells et al). Taken together the data indicate that in the Dahl SS rats, HFD causes hypertension via mechanisms that do not include increased neurogenic support of blood pressure or volume expansion. Increased activity of the renin‐angiotensin system may play a part but is not wholly responsible. Female Dahl SS rats on HFD are strongly protected against hypertension‐associated renal inflammation and injury, but the mechanisms responsible remain unknown.Support or Funding InformationNHLBI 2P01HL070687 for G.D.F, J.J.G. and H.X

Molecular Implications of Natriuretic Peptides in the Protection from Hypertension and Target Organ Damage Development.

The pathogenesis of hypertension, as a multifactorial trait, is complex. High blood pressure levels, in turn, concur with the development of cardiovascular damage. Abnormalities of several neurohormonal mechanisms controlling blood pressure homeostasis and cardiovascular remodeling can contribute to these pathological conditions. The natriuretic peptide (NP) family (including ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide), and CNP (C-type natriuretic peptide)), the NP receptors (NPRA, NPRB, and NPRC), and the related protease convertases (furin, corin, and PCSK6) constitute the NP system and represent relevant protective mechanisms toward the development of hypertension and associated conditions, such as atherosclerosis, stroke, myocardial infarction, heart failure, and renal injury. Initially, several experimental studies performed in different animal models demonstrated a key role of the NP system in the development of hypertension. Importantly, these studies provided relevant insights for a better comprehension of the pathogenesis of hypertension and related cardiovascular phenotypes in humans. Thus, investigation of the role of NPs in hypertension offers an excellent example in translational medicine. In this review article, we will summarize the most compelling evidence regarding the molecular mechanisms underlying the physiological and pathological impact of NPs on blood pressure regulation and on hypertension development. We will also discuss the protective effect of NPs toward the increased susceptibility to hypertensive target organ damage.