Current Hypertension Reviews - Volume 18, Issue 2, 2022

The production of renin by the principal cells of the collecting duct has widened our understanding of the regulation of intrarenal angiotensin II (Ang II) generation and blood pressure. In the collecting duct, Ang II increases the synthesis and secretion of renin by mechanisms involving the activation of Ang II type 1 receptor (AT1R) via stimulation of the PKCα, Ca²⁺, and cAMP/PKA/CREB pathways. Additionally, paracrine mediators, including vasopressin (AVP), prostaglandins, bradykinin (BK), and atrial natriuretic peptide (ANP), regulate renin in principal cells. During Ang II-dependent hypertension, despite plasma renin activity suppression, renin and prorenin receptor (RPR) are upregulated in the collecting duct and promote de novo formation of intratubular Ang II. Furthermore, activation of PRR by its natural agonists, prorenin and renin, may contribute to the stimulation of profibrotic factors independent of Ang II. Thus, the interactions of RAS components with paracrine hormones within the collecting duct enable tubular compartmentalization of the RAS to orchestrate complex mechanisms that increase intrarenal Ang II, Na+ reabsorption, and blood pressure.

The renin-angiotensin system (RAS) is classically described as a hormonal system in which angiotensin II (Ang II) is one of the main active peptides. The action of circulating Ang II on its cognate Ang II type-1 receptor (AT1R) in circumventricular organs has important roles in regulating the autonomic nervous system, blood pressure (BP) and body fluid homeostasis, and has more recently been implicated in cardiovascular metabolism. The presence of a local or tissue RAS in various tissues, including the central nervous system (CNS), is well established. However, because the level of renin, the rate-limiting enzyme in the systemic RAS, is very low in the brain, how endogenous angiotensin peptides are generated in the CNS—the focus of this review—has been the subject of considerable debate. Notable in this context is the identification of the (pro)renin receptor (PRR) as a key component of the brain RAS in the production of Ang II in the CNS. In this review, we highlight cellular and anatomical locations of the PRR in the CNS. We also summarize studies using gain- and loss-of function approaches to elucidate the functional importance of brain PRR-mediated Ang II formation and brain RAS activation, as well as PRR-mediated Ang II-independent signaling pathways, in regulating BP. We further discuss recent developments in PRR involvement in cardiovascular and metabolic diseases and present perspectives for future directions.

The prorenin receptor (PRR) is a complex multi-functional single transmembrane protein receptor that is ubiquitously expressed in organs and tissues throughout the body. PRR is involved in different cellular mechanisms that comprise the generation of Angiotensin II, the activation of Wnt/β-catenin signaling, the stimulation of ERK 1/2 pathway, and the proper functioning of the vacuolar H+-ATPase. Evidence supports the role of PRR and its soluble form, sPRR, in the classical features of the metabolic syndrome, including obesity, hypertension, diabetes, and disruption of lipid homeostasis. This review summarizes our current knowledge and highlights new advances in the pathophysiological function of PRR and sPRR in adipogenesis, adipocyte differentiation, lipolysis, glucose and insulin resistance, lipid homeostasis, energy metabolism, and blood pressure regulation.

Cannabis sativa has chemically active compounds called cannabinoids, where Δ9- tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the major ones responsible for the various pharmacological effects. The endocannabinoid system is an endogenous system considered a unique and widespread homeostatic physiological regulator. It is made up of type 1 (CB1) and type 2 (CB2) cannabinoid receptors. CBD, in turn, has a low affinity for CB1 and CB2 receptors, and regulates the effects arising from THC as a CB1 partial agonist, which are tachycardia, anxiety, and sedation. It also acts as a CB2 inverse agonist, resulting in anti-inflammatory effects. Furthermore, its anticonvulsant, neuroprotective, antipsychotic, antiemetic, anxiolytic, anticancer, and antioxidant effects seem to be linked to other discovered receptors such as GRP55, 5TH1a, TRPV I, TRPV II and the regulation of the intracellular concentration of Ca²⁺. Regarding oxidative stress, O^2- can act as an oxidizing agent, being reduced to hydrogen peroxide (H2O2), or as a reducing agent, donating its extra electron to NO to form peroxynitrite (ONOO-). The ONOO- formed is capable of oxidizing proteins, lipids, and nucleic acids, causing several cell damages. In this sense, CBD can prevent cardiac oxidative damage in many conditions, such as hypertension, diabetes, or even through the cardiotoxic effects induced by chemotherapy, which makes it a potential target for future clinical use to minimize the deleterious effects of many pathophysiologies.

Background: This review explores the mechanistic action of angiotensin-converting enzyme- 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) in the renin-angiotensinaldosterone system (RAAS) that predisposes hypertensive patients to the adverse outcome of severe COVID-19. Methods and Results: Entry of SARS-CoV-2 into the host cell via ACE2 disrupts the RAAS system, creating an imbalance between ACE and ACE2, with an increased inflammatory response, leading to hypertension (HTN), pulmonary vasoconstriction and acute respiratory distress. SARSCoV- 2 may also predispose infected individuals with existing HTN to a greater risk of severe COVID-19 complications. In the duality of COVID-19 and HTN, the imbalance of ACE and ACE2 results in an elevation of AngII and a decrease in Ang (1-7), a hyperinflammatory response and endothelial dysfunction. Endothelial dysfunction is the main factor predisposing hypertensive patients to severe COVID-19 and vice-versa. Conclusion: Despite the increase in ACE2 expression in hypertensive SARS-CoV-2 infected patients, ARBs/ACE inhibitors do not influence their severity and clinical outcomes, implicating continued usage. Future large-scale clinical trials are warranted to further elucidate the association between HTN and SARS-CoV-2 infection and the use of ARBs/ACEIs in SARS-CoV-2 hypertensive patients.

Background: The target blood pressure has changed many times in the guidelines in past years. However, there is always a question; is it good to lower blood pressure below 120/80 or not? Control of blood pressure in hypertension is very important in reducing hypertension-modified organ damage. So, the guidelines recommend combining more than one antihypertensive drug to reach the target blood pressure goal. Results: Combination therapy is recommended by guidelines to reach the blood pressure goal. The guidelines recommend many combinations, such as the combination of angiotensin receptor blockers with either calcium channel blockers (CCB) or beta-blocker (BB). Angiotensin receptor blocker (ARB) combination with CCB has gained superiority over other antihypertension drug combinations because it reduces blood pressure and decreases the incidence of CV events and organ damage. BB combinations are recommended by guidelines in patients with ischemic events but not all hypertensive patients. Unfortunately, the new generation BB, for example, nebivolol, has a vasodilator effect, making it new hope for BB. Conclusion: Combination therapy is a must in treating the hypertensive patient. The new generation BBs may change the recommendations of guidelines because they have an effect that is similar to CCBs.

Blood pressure (BP) responses are controlled by various factors and understanding how BP changes is important to occupational health. This paper presents a review of the literature that reports BP responses in the firefighter population. Hypertension is one of the main risk factors underlying the pathophysiology of cardiovascular disease (CVD), and cardiac incidents remain the leading cause of line-of-duty deaths in firefighters. Risk factors for line-of-duty deaths include obesity, previous or underlying heart disease, and hypertension. The occupation of firefighting is one of the most hazardous and dangerous jobs, yet over 50 % of firefighters are volunteers. Tactical operations and the hazardous nature of firefighting are exposures that influence stress responses and, therefore, affect BP. In fact, hypertension in firefighters often remains undocumented or undiagnosed. CVD risk and elevated BP in tactical populations, like firefighters, maybe a combination of physical and emotional stress due to the nature of the job. Cross-sectional studies have reported that firefighters have higher levels of BP and higher rates of hypertension compared to civilians. Interestingly, there is a limited amount of research that reports BP values before and after firefighting- related activities, and very few studies on interventional changes in BP. Here, we synthesize the literature on firefighting and provide a summary of the studies that report pre- and post- BP levels that relate to CVD risk factors, occupational factors, firefighting activities, and the data on exercise training and BP. More studies are needed that examine BP in firefighters and report on the changes in BP with occupational activities.

Background: Impaired fasting glucose (IFG) predisposes to the future development of type 2 diabetes mellitus (T2DM) and may also be associated with increased cardiovascular disease (CVD) risk. Hypertension is an established CVD risk factor. Objective: This study aimed to assess the prevalence of IFG and the associated anthropometric and metabolic disturbances in patients with hypertension. Methods: Consecutive hypertensive patients not on any hypolipidemic treatment and without a diagnosis of T2DM were included. IFG was defined as serum glucose 100 mg/dl according to the American Diabetes Association criteria. Results: The total sample consisted of 1381 participants; between them, 78 patients were diagnosed to have T2DM and they were excluded from the analyses, leaving a final sample of 1303 hypertensive patients [41.0% men; median age 58 (range: 15-90) years] not on any hypolipidemic treatment and without a diagnosis of T2DM. IFG was identified in 469 patients (36%). IFG was more prevalent in males than in females (42.4% vs. 31.8%, p<0.001). Patients with IFG had greater body mass index (BMI), waist-to-hip ratio, systolic blood pressure, pulse pressure, triglycerides, alanine aminotransferase, gamma-glutamyl transferase, and uric acid serum levels compared with patients with normal serum glucose levels. Conclusion: This study reveals that in a sample of patients with hypertension, one out of three has IFG. This is more prevalent among men. IFG is associated with the presence of a more aggravated anthropometric and biochemical profile, possibly associated with an increased CVD risk.

The practice of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARB) in COVID-19 hypertensive patients is still an open question for clinicians to answer. The present study was conducted to find out the association between the use of ACEI/ARB and the mortality rate of COVID-19 patients. The search was conducted from December 2019 to October 2020 in PubMed to identify relevant published studies. RevMan 5 was used for the analysis of the data. The random-effect model was used to calculate the odds ratio. In total, 07 studies were found to be appropriate, reporting a total of 1,566 subjects. The odds ratio was found to be 0.86 [0.41, 1.81], indicating no association between ACEI/ARB and the mortality rate of COVID- 19 patients. In conclusion, we may suggest continuing the use of ACEi/ARB in COVID-19 patients till further pieces of evidence are generated.