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1.
Role of Rho in Salt-Sensitive Hypertension.
Kawarazaki, W, Fujita, T
International journal of molecular sciences. 2021;(6)
Abstract
A high amount of salt in the diet increases blood pressure (BP) and leads to salt-sensitive hypertension in individuals with impaired renal sodium excretion. Small guanosine triphosphatase (GTP)ase Rho and Rac, activated by salt intake, play important roles in the pathogenesis of salt-sensitive hypertension as key switches of intracellular signaling. Focusing on Rho, high salt intake in the central nervous system increases sodium concentrations of cerebrospinal fluid in salt-sensitive subjects via Rho/Rho kinase and renin-angiotensin system activation and causes increased brain salt sensitivity and sympathetic nerve outflow in BP control centers. In vascular smooth muscle cells, Rho-guanine nucleotide exchange factors and Rho determine sensitivity to vasoconstrictors such as angiotensin II (Ang II), and facilitate vasoconstriction via G-protein and Wnt pathways, leading to increased vascular resistance, including in the renal arteries, in salt-sensitive subjects with high salt intake. In the vascular endothelium, Rho/Rho kinase inhibits nitric oxide (NO) production and function, and high salt amounts further augment Rho activity via asymmetric dimethylarginine, an endogenous inhibitor of NO synthetase, causing aberrant relaxation and increased vascular tone. Rho-associated mechanisms are deeply involved in the development of salt-sensitive hypertension, and their further elucidation can help in developing effective protection and new therapies.
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2.
A Paradoxical Vasodilatory Nutraceutical Intervention for Prevention and Attenuation of Migraine-A Hypothetical Review.
Chaliha, DR, Vaccarezza, M, Takechi, R, Lam, V, Visser, E, Drummond, P, Mamo, JCL
Nutrients. 2020;(8)
Abstract
Studies suggest that migraine pain has a vascular component. The prevailing dogma is that peripheral vasoconstriction activates baroreceptors in central, large arteries. Dilatation of central vessels stimulates nociceptors and induces cortical spreading depression. Studies investigating nitric oxide (NO) donors support the indicated hypothesis that pain is amplified when acutely administered. In this review, we provide an alternate hypothesis which, if substantiated, may provide therapeutic opportunities for attenuating migraine frequency and severity. We suggest that in migraines, heightened sympathetic tone results in progressive central microvascular constriction. Suboptimal parenchymal blood flow, we suggest, activates nociceptors and triggers headache pain onset. Administration of NO donors could paradoxically promote constriction of the microvasculature as a consequence of larger upstream central artery vasodilatation. Inhibitors of NO production are reported to alleviate migraine pain. We describe how constriction of larger upstream arteries, induced by NO synthesis inhibitors, may result in a compensatory dilatory response of the microvasculature. The restoration of central capillary blood flow may be the primary mechanism for pain relief. Attenuating the propensity for central capillary constriction and promoting a more dilatory phenotype may reduce frequency and severity of migraines. Here, we propose consideration of two dietary nutraceuticals for reducing migraine risk: L-arginine and aged garlic extracts.
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3.
[Role of Ca2+ in hypoxic pulmonary vasoconstriction].
Wei, G, Cheng, Y, Huang, Y, He, Q
Zhonghua wei zhong bing ji jiu yi xue. 2019;(5):647-649
Abstract
In acute hypoxia, pulmonary vascular will contract and divert blood to better ventilated area to optimize ventilation/perfusion matching, which is known as hypoxic pulmonary vasoconstriction (HPV). In chronic hypoxia, irreversible pulmonary vascular remodeling can be induced, characterized by pulmonary artery middle smooth muscle cells and the outer fiber cell hyperplasia in luminal stenosis and pulmonary artery hypertension (PAH) eventually. Furthermore, PAH can cause increased ventricular afterload, and right heart failure in severe cases. Pulmonary artery smooth muscle cell (PASMC) elevated Ca2+ concentration is one of the most important factors of its contractions, proliferation and migration. Recent studies on Ca2+ promoting in HPV were summarized in order to provide evidence for clinical prevention of hypoxia and therapeutic PAH.
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4.
How is the human umbilical artery regulated?
Lorigo, M, Mariana, M, Feiteiro, J, Cairrao, E
The journal of obstetrics and gynaecology research. 2018;(7):1193-1201
Abstract
The purpose of this review is to present an update of the main mechanisms involved in the physiological regulation of contraction and relaxation of the human umbilical artery (HUA) smooth muscle cells. A literature review was performed based on the analysis of papers available on PubMed. The most important and relevant studies regarding the regulation of the HUA are presented in this article. The vascular smooth muscle is a highly specialized structure, whose main function is to regulate the vascular tonus. This is controlled by a balance between the cellular signaling pathways that mediate contraction and relaxation. The cells responsible for the contractile property of this muscle are the smooth muscle cells (SMC), and an excellent source of these cells is the HUA, involved in fetoplacental circulation. Since the umbilical blood vessels are not innervated, the HUA tonus is modulated by vasoactive substances that regulate the contractile process. The main vasoactive substances that induce contraction are serotonin, histamine, thromboxane, bradykinin, endothelin 1 and prostaglandin F2α, that are linked to the activation of proteins Gq and Gi/0 . On the other hand, the main vasorelaxation mechanisms are the activation of adenyl and guanil cyclases, potassium channels and the inhibition of calcium channels. The SMC from the HUA allow the study of different cellular mechanisms and their functions. Therefore, these cells are an important tool to study the mechanisms regulating the contractility of this artery, allowing to detect potential therapeutic targets to treat HUA disorders (gestational hypertension and pre-eclampsia).
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5.
Hypoxic Pulmonary Vasoconstriction: From Molecular Mechanisms to Medicine.
Dunham-Snary, KJ, Wu, D, Sykes, EA, Thakrar, A, Parlow, LRG, Mewburn, JD, Parlow, JL, Archer, SL
Chest. 2017;(1):181-192
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Abstract
Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). In the nonventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis, which optimizes systemic Po2 without altering pulmonary artery pressure (PAP). In single-lung anesthesia, HPV reduces blood flow to the nonventilated lung, thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PAP, and initiates PH. Exaggerated or heterogeneous HPV contributes to high-altitude pulmonary edema. Conversely, impaired HPV, whether due to disease (eg, COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1α and can promote abnormal metabolism and cell proliferation. The resulting pseudohypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen sensing are important in human health and disease.
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6.
Review of the Ongoing Story of Appetite Suppressants, Serotonin Pathway, and Pulmonary Vascular Disease.
Bazan, IS, Fares, WH
The American journal of cardiology. 2016;(10):1691-1696
Abstract
Obesity is pandemic in the Western Hemisphere, especially in the United States (US) and is associated with morbidity and mortality. Recent data show that a large proportion of the US population is at least overweight and almost 2 in 5 Americans are obese. This ongoing trend of increasing obesity rates has led to a thriving market for anorexigens. Despite the health benefits of weight loss, several anorexigens had devastating side effects including pulmonary vascular disease which manifests as the clinical syndrome of pulmonary arterial hypertension (PAH). PAH is an incurable and fatal disease and is characterized by vascular constriction, hypertrophy, and proliferation that over time lead to right-sided cardiac failure. Over the past few decades, several weight loss medications have been associated with the development of PAH, possibly caused by an increase in systemic serotonin levels, resulting in vasoconstriction of the pulmonary arteries and initiating a cascade of pathologic vascular remodeling leading to vascular fibrosis. Once sufficient evidence for the association of these drugs with PAH or other related pathologies was found, many were removed from the market. However, there are other appetite suppressants still currently on the market (whether Food and Drug Administration-approved or "dietary supplements") that have to some extent similar mechanisms of action to those associated with PAH but lack robust enough data to prove or disprove an association. The serotonin pathway seems to be repeatedly implicated. In conclusion, given that PAH is a progressive and debilitating disease, it is important to highlight possible risk factors that could be avoided.
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7.
Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction.
Sommer, N, Strielkov, I, Pak, O, Weissmann, N
The European respiratory journal. 2016;(1):288-303
Abstract
Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The oxygen sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulated in vivo by the endothelium. While factors such as nitric oxide modulate HPV, reactive oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact oxygen sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCs via direct or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV.
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8.
Pharmacological strategies to prevent contrast-induced acute kidney injury.
Pattharanitima, P, Tasanarong, A
BioMed research international. 2014;:236930
Abstract
Contrast-induced acute kidney injury (CI-AKI) is the most common iatrogenic cause of acute kidney injury after intravenous contrast media administration. In general, the incidence of CI-AKI is low in patients with normal renal function. However, the rate is remarkably elevated in patients with preexisting chronic kidney disease, diabetes mellitus, old age, high volume of contrast agent, congestive heart failure, hypotension, anemia, use of nephrotoxic drug, and volume depletion. Consequently, CI-AKI particularly in high risk patients contributes to extended hospitalizations and increases long-term morbidity and mortality. The pathogenesis of CI-AKI involves at least three mechanisms; contrast agents induce renal vasoconstriction, increase of oxygen free radicals through oxidative stress, and direct tubular toxicity. Several strategies to prevent CI-AKI have been evaluated in experimental studies and clinical trials. At present, intravascular volume expansion with either isotonic saline or sodium bicarbonate solutions has provided more consistent positive results and was recommended in the prevention of CI-AKI. However, the proportion of patients with risk still develops CI-AKI. This review critically evaluated the current evidence for pharmacological strategies to prevent CI-AKI in patients with a risk of developing CI-AKI.
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9.
Autonomic nervous system dysfunction: implication in sickle cell disease.
Connes, P, Coates, TD
Comptes rendus biologies. 2013;(3):142-7
Abstract
Sickle cell disease is an inherited hemoglobinopathy caused by a single amino acid substitution in the β chain of hemoglobin that causes the hemoglobin to polymerize in the deoxy state. The resulting rigid, sickle-shaped red cells obstruct blood flow causing hemolytic anemia, tissue damage, and premature death. Hemolysis is continual. However, acute exacerbations of sickling called vaso-occlusive crises (VOC) resulting in severe pain occur, often requiring hospitalization. Blood rheology, adhesion of cellular elements of blood to vascular endothelium, inflammation, and activation of coagulation decrease microvascular flow and increase likelihood of VOC. What triggers the transition from steady state to VOC is unknown. This review discusses the interaction of blood rheological factors and the role that autonomic nervous system (ANS) induced vasoconstriction may have in triggering crisis as well as the mechanism of ANS dysfunction in SCD.
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10.
Scorpion venoms, kidney and potassium.
Angsanakul, J, Sitprija, V
Toxicon : official journal of the International Society on Toxinology. 2013;:81-7
Abstract
Scorpion venoms cause renal injury by the interaction of renal ischemia due to intense renal vasoconstriction and inflammatory reactions due to proinflammatory cytokines and mediators. Renal vasoconstriction is not only induced by catecholamine storm but also by angiotensin II and the direct action of venom on vascular ion channels. Increased aldosterone also contributes to hypertension. Blocking of renal tubular K channels decreases renal K excretion and increases serum K level which increases aldosterone release. Hyperaldosteronism increases K excretion mostly through ROMK2 and ROMK3 unblocked by the venom. The presence of angiotensin converting enzyme inhibitor in some scorpion species can increase serum K. Therefore, there are both K increasing and K decreasing effects in renal K excretion. Serum K in scorpionism is the net result of the two opposing effects. Hyperkalemia is therefore inconsistent.