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One of the essential regulators of arterial blood pressure, the renin-angiotensin-aldosterone system (RAAS) seems to be one of the most complex mechanisms in the human body. Since the discovery of its key components and their actions, new substances and functions are still being unraveled. The main pathway begins with the secretion of renin in the kidney and culminates with the synthesis of angiotensin II (Ang II)—a strong vasoconstrictor—thanks to the angiotensin-converting enzyme (ACE). Research conducted in 2000 identified another enzyme, named ACE2, that converts Ang II into Ang-(1–7), a heptapeptide with opposing effects to those of Ang II: vasodilation and anti-inflammatory properties. This particular enzyme became of paramount importance during the last two decades, as a result of the confrontation of the human race with life-threatening epidemics. Multiple studies have been performed in order to uncover the link between ACE2 and human coronaviruses, the results of which we systemized in order to create an overview of the pathogenic mechanism. Human coronaviruses, such as SARS-CoV and SARS-CoV-2, attach to ACE2 via their spike proteins (S), causing the destruction of the enzyme. Because ACE2 limits the production of Ang II (by converting it into Ang-(1–7)), its destruction leads to a dysregulated inflammatory response. The purpose of this review is to decipher the complex pathophysiological mechanisms underlying the multiorgan complications (oral, cardiac, pulmonary, systemic) that appear as a result of the interaction of the SARS CoV-2 virus with the angiotensin-converting enzyme type 2.

Calcific aortic valve disease (CAVD) is a major cause of cardiovascular mortality and morbidity, with increased prevalence and incidence. The underlying mechanisms behind CAVD are complex, and are mainly illustrated by inflammation, mechanical stress (which induces prolonged aortic valve endothelial dysfunction), increased oxidative stress (OS) (which trigger fibrosis), and calcification of valve leaflets. To date, besides aortic valve replacement, there are no specific pharmacological treatments for CAVD. In this review, we describe the mechanisms behind aortic valvular disease, the involvement of OS as a fundamental element in disease progression with predilection in AS, and its two most frequent etiologies (calcific aortic valve disease and bicuspid aortic valve); moreover, we highlight the potential of OS as a future therapeutic target.

Arterial hypertension (HTN) is one of the most prevalent entities globally, characterized by increased incidence and heterogeneous pathophysiology. Among possible etiologies, oxidative stress (OS) is currently extensively studied, with emerging evidence showing its involvement in endothelial dysfunction and in different cardiovascular diseases (CVD) such as HTN, as well as its potential as a therapeutic target. While there is a clear physiological equilibrium between reactive oxygen species (ROS) and antioxidants essential for many cellular functions, excessive levels of ROS lead to vascular cell impairment with decreased nitric oxide (NO) availability and vasoconstriction, which promotes HTN. On the other hand, transcription factors such as nuclear factor erythroid factor 2-related factor 2 (Nrf2) mediate antioxidant response pathways and maintain cellular reduction–oxidation homeostasis, exerting protective effects. In this review, we describe the relationship between OS and hypertension-induced endothelial dysfunction and the involvement and therapeutic potential of Nrf2 in HTN.

Pain continues to be a global unmet medical need, and the current recommendations for its management require a constant exploration of new drugs that target multiple pain mechanisms, with an improved safety profile and increased treatment adherence. Currently, the enriched distribution and localization within nociceptors of the selective channel blockers and the critical role played by sodium channels in neuronal excitability nominate isoforms as specific targets to generate innovative compounds. In the present report, we verified the hypothesis that coadministration of Protoxin-II, a selective sodium channel inhibitor, and trace elements has direct and improved antinociceptive effects. Groups of seven Wistar rats were treated intracerebroventricularly with a combination of MgCl2, CdCl2, and ZnCl2and Protoxin-II, respectively, and with Protoxin-II alone (positive) or saline (negative) for controls. Evaluations were performed by nociception assay. Coadministration of these drugs caused an increase in the maximum possible effect of up to 40% as compared with the control groups. Our findings indicate that selective channel blockers continue to be an important nociception target and that the use of trace elements may provide simple but effective means of control over sodium channel blockers’ risks, potentially lowering the necessary analgesic doses, thus improving the efficacy and safety profile.

The effect of mild hyperthermia (MHT) on nanoparticle (NP) accumulation in rat model liver metastasis and the contribution of neoplastic and non-neoplastic cells were characterized. CdSe/ZnS QD-doped poly(lactic-co-glycolic acid) (PLGA) NPs (155 ± 10 nm) were delivered via the ileocolic vein to metastatic livers 15 min after localized MW irradiation (1 min, 41 °C) or in normothermia (37 °C, NT). Quantitative analysis of tissue sections by confocal fluorescence microscopy 1 h after NP injection showed no NP tumor accumulation in NT. On the contrary, MHT increased NP association with tumor, compared to normal tissue. Counterstaining of specific markers showed that the MHT effect is due to an increased NP endocytosis not only by tumor cells, but also by hepatocytes at the growing tumor edge and, to a minor extent, by tumor-associated macrophages. High-NP capturing hepatocytes, close to the tumor, may be a relevant phenomenon in MHT-induced increased targeting of NPs to liver metastasis, influencing their therapeutic efficacy.

When introduced clinically 6 years ago, renal denervation was thought to be the solution for all patients whose blood pressure could not be controlled by medication. The initial two studies, SYMPLICITY HTN-1 and HTN-2, demonstrated great magnitudes of blood pressure reduction within 6 mo of the procedure and were based on a number of assumptions that may not have been true, including strict adherence to medication and absence of white-coat hypertension. The SYMPLICITY HTN-3 trial controlled for all possible factors believed to influence the outcome, including the addition of a sham arm, and ultimately proved the demise of the initial overly optimistic expectations. This trial yielded a much lower blood pressure reduction compared with the previous SYMPLICITY trials. Since its publication in 2014, there have been many analyses to try and understand what accounted for the differences. Of all the variables examined that could influence blood pressure outcomes, the extent of the denervation procedure was determined to be inadequate. Beyond this, the physiological mechanisms that account for the heterogeneous fall in arterial pressure following renal denervation remain unclear, and experimental studies indicate dependence on more than simply reduced renal sympathetic activity. These and other related issues are discussed in this paper. Our perspective is that renal denervation works if done properly and used in the appropriate patient population. New studies with new approaches and catheters and appropriate controls will be starting later this year to reassess the efficacy and safety of renal denervation in humans.

Chronic kidney disease is prevalent among patients with resistant hypertension and activation of the sympathetic nervous system is common in both conditions. While renal nerve ablation lowers blood pressure (BP) in some resistant hypertensive patients, the influence of kidney disease on the antihypertensive response is largely unknown. Systemic hemodynamics and sympathetically-mediated low frequency oscillations of systolic BP were determined continuously by telemetry in rats before and after unilateral nephrectomy and surgical excision of the poles of the remaining kidney to reduce renal mass (RRM) ~ 80%. Before RRM, BP was not salt sensitive. However, placing rats with RRM on a high salt diet induced sustained increases in mean arterial pressure (Figure) and cardiac output while suppressing sympathetic activity. After denervation of the remnant kidney, sympathetic activity and heart rate increased, concomitant with reductions in BP and cardiac output. However, these acute responses waned over the 2 weeks of follow up. Subsequent central sympathetic inhibition with clonidine reduced sympathetic activity, heart rate and cardiac output, but not BP as peripheral resistance increased. Finally, when the low salt diet was restored, BP decreased back to normotensive levels. These results show that renal denervation does not chronically lower BP in this model of salt-sensitive hypertension associated with substantial nephron loss, but without active parenchymal disease, thus providing insight into conditions likely to impact the antihypertensive response to renal-specific sympathoinhibition in subjects with advanced kidney disease.

Neurofibromatosis type 1 (also known as von Recklinghausen’s disease) is a genetic disorder characterized by neurofibromas, skin pigmentation, eye and bone abnormalities. It is associated with pheochromocytoma in 1 to 5% of cases which determines symptoms related to catecholamine excessive secretion. We present the case of a 54-year-old man that was admitted to the cardiology clinic due to acute onset of tachyarrhythmia (atrial flutter) and high blood pressure. Neurofibromatosis type 1 was diagnosed by clinical examination while laboratory exams, 24-hour continuous blood pressure monitoring and imaging exams raised the probability of pheochromocytoma. After proper pharmacological stabilization, the patient underwent surgery and the 110/110 mm left adrenal mass was removed via abdominal laparotomy. The patient evolution was favorable and regular follow-up is scheduled. In conclusion, even though asymptomatic screening for pheochromocytoma is not recommended, this pathology should be suspected in all patients with neurofibromatosis especially if they present acute onset of cardiovascular signs.

The sensitivity of baroreflex control of heart rate is depressed in subjects with obesity hypertension, which increases the risk for cardiac arrhythmias. The mechanisms are not fully known, and there are no therapies to improve this dysfunction. To determine the cardiovascular dynamic effects of progressive increases in body weight leading to obesity and hypertension in dogs fed a high-fat diet, 24-h continuous recordings of spontaneous fluctuations in blood pressure and heart rate were analyzed in the time and frequency domains. Furthermore, we investigated whether autonomic mechanisms stimulated by chronic baroreflex activation and renal denervation—current therapies in patients with resistant hypertension, who are commonly obese—restore cardiovascular dynamic control. Increases in body weight to ∼150% of control led to a gradual increase in mean arterial pressure to 17 ± 3 mmHg above control (100 ± 2 mmHg) after 4 wk on the high-fat diet. In contrast to the gradual increase in arterial pressure, tachycardia, attenuated chronotropic baroreflex responses, and reduced heart rate variability were manifest within 1–4 days on high-fat intake, reaching 130 ± 4 beats per minute (bpm) (control = 86 ± 3 bpm) and ∼45% and

A new approach to prepare polymeric capsules was developed to obtain an efficient controlled release system for pain treatment. Capsules with a mean diameter between 400 and 1000 nm were prepared using an interfacial condensation method between a natural polymer, chitosan, and a synthetic one, poly(maleic anhydride- alt-vinyl acetate). The influence of different reaction parameters on capsule diameter and properties was investigated. Zeta-potential determinations indicated a good stability of the capsules in aqueous solution containing KCl. Scanning electron microscopy confirmed the submicron dimensions and the spherical shape of the capsules. The thermal properties of the capsules were determined by differential scanning calorimetry and thermogravimetric analysis. In addition, these particles presented a good swelling capacity, which was influenced by the reaction parameters used in this study (molar ratio between the two polymers, the volume ratio between aqueous and organic phase, the amount of surfactant and the reaction time). The ibuprofen loading and release capacity were influenced by the swelling degree. In vivo, the ibuprofen-loaded capsules presented a delayed effect in peripheral pain inhibition and a sustained effect in central pain inhibition.

We recently reported a linear association between higher systolic blood pressure (SBP) and risk of mortality in hemodialysis (HD) patients when SBP is measured outside of the dialysis unit (“out-of-dialysis-unit-SBP”) despite there being a U-shaped association between SBP measured in the dialysis unit (“dialysis-unit-SBP”) with risk of mortality. Here we explored the relationship between SBP with cardiovascular (CVD) events, which has important treatment implications but has not been well-elucidated. Among 383 HD participants enrolled in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study, multivariable splines and Cox models were used to study the association between SBP and adjudicated CVD events (heart failure, myocardial infarction, ischemic stroke, peripheral artery disease), controlling for differences in demographics, CVD risk factors and dialysis parameters. Dialysis-unit-SBP and out-of-dialysis-unit-SBP were modestly correlated (r=0.34, p

Carotid bodies play a critical role in protecting against hypoxemia, and their activation increases sympathetic activity, arterial pressure, and ventilation, responses opposed by acute stimulation of the baroreflex. Although chemoreceptor hypersensitivity is associated with sympathetically mediated hypertension, the mechanisms involved and their significance in the pathogenesis of hypertension remain unclear. We investigated the chronic interactions of these reflexes in dogs with sympathetically mediated, obesity-induced hypertension based on the hypothesis that hypoxemia and tonic activation of carotid chemoreceptors may be associated with obesity. After 5 weeks on a high-fat diet, the animals experienced a 35% to 40% weight gain and increases in arterial pressure from 106±3 to 123±3 mm Hg and respiratory rate from 8±1 to 12±1 breaths/min along with hypoxemia (arterial partial pressure of oxygen=81±3 mm Hg) but eucapnia. During 7 days of carotid baroreflex activation by electric stimulation of the carotid sinus, tachypnea was attenuated, and hypertension was abolished before these variables returned to prestimulation values during a recovery period. After subsequent denervation of the carotid sinus region, respiratory rate decreased transiently in association with further sustained reductions in arterial partial pressure of oxygen (to 65±2 mm Hg) and substantial hypercapnia. Moreover, the severity of hypertension was attenuated from 125±2 to 116±3 mm Hg (45%–50% reduction). These findings suggest that hypoxemia may account for sustained stimulation of peripheral chemoreceptors in obesity and that this activation leads to compensatory increases in ventilation and central sympathetic outflow that contributes to neurogenically mediated hypertension. Furthermore, the excitatory effects of chemoreceptor hyperactivity are abolished by chronic activation of the carotid baroreflex.

Impaired baroreflex control of heart rate (BRS) and attendant risk for cardiac arrhythmias are associated with sympathetically-mediated obesity hypertension. Since both global and renal-specific sympathoinhibition have sustained antihypertensive effects in obesity, we compared BRS in obese dogs subjected to 7 days of electrical baroreflex activation (BA) and, after recovery (REC), to bilateral surgical renal denervation (RDX). After control (C) measurements and 4 weeks of high fat diet, fat intake was reduced (RF) to maintain a body weight increase of ∼ 50%, which led to an increase in mean arterial pressure (MAP) from 100±2 to 117±3 mmHg and heart rate (HR) from 86±3 to 130±4 bpm. Obesity hypertension was associated with decreased sensitivity of 24h spontaneous BRS (determined by the sequence technique from daily beat-to-beat time series) and pulse interval (PI) variability (24h SD). While both BA and RDX abolished hypertension, only BA diminished tachycardia and normalized BRS, consequently improving HR variability. Short-term systolic blood pressure variability (5 min SD) also decreased with high fat feeding and was restored to control upon reduction of fat intake (RF) during established obesity hypertension, suggesting a vasoplegic effect of fat. These data suggest that in addition to the antihypertensive effects of sympathoinhibition, BA corrects cardiac baroreflex dysfunction in obesity hypertension, presumably by enhancing cardiac vagal activity. This in turn markedly improves depressed HR variability, a known risk factor for cardiac arrhythmic events.