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Experimental Physiology Aug 2016What is the topic of this review? This report looks at the role of endothelial nitric oxide signalling in the time-of-day variation in vasoconstriction of resistance... (Review)
Review
What is the topic of this review? This report looks at the role of endothelial nitric oxide signalling in the time-of-day variation in vasoconstriction of resistance vessels. What advances does it highlight? It highlights a time-of-day variation in contraction of mesenteric arteries, characterized by a reduced contractile response to either phenylephrine or high K(+) and increased relaxation in response to acetylcholine during the active period. This time-of-day variation in contraction results from a difference in endothelial nitric oxide synthase (eNOS) signalling that correlates with levels of eNOS expression, which peak during the active period and may have far reaching physiological consequences beyond regulation of blood pressure. There is a strong time-of-day variation in the vasoconstriction in response to sympathetic stimulation that may contribute to the time-of-day variation in blood pressure, which is characterized by a dip in blood pressure during the individual's rest period when sympathetic activity is low. Vasoconstriction is known to be regulated tightly by nitric oxide signalling from the endothelial cells, so we have looked at the effect of time-of-day on levels of endothelial nitric oxide synthase (eNOS) and vascular contractility. Mesenteric arteries isolated from the nocturnal rat exhibit a time-of-day variation in their contractile response to α1 -adrenoreceptor and muscarinic activation, which is characterized by a reduced vasoconstriction in response to phenylephrine and enhanced vasodilatation in response to acetylcholine during the rat's active period at night. An increase in eNOS signalling during the active period is responsible for this time-of-day difference in response to phenylephrine and acetylcholine and correlates with the large increase in eNOS expression (mRNA and protein) during the active period, possibly driven by the presence of a functioning peripheral circadian clock. This increase in eNOS signalling may function to limit the increase in peripheral resistance and therefore blood pressure during the increased sympathetic activity.
Topics: Animals; Blood Pressure; Endothelium, Vascular; Humans; Mesenteric Arteries; Nitric Oxide Synthase Type III; Signal Transduction; Vasoconstriction
PubMed: 27474265
DOI: 10.1113/EP085780 -
Journal of Neuroengineering and... May 2018Electrical vasoconstriction is a promising approach to control blood pressure or restrict bleeding in non-compressible wounds. We explore the neural and non-neural...
BACKGROUND
Electrical vasoconstriction is a promising approach to control blood pressure or restrict bleeding in non-compressible wounds. We explore the neural and non-neural pathways of electrical vasoconstriction in-vivo.
METHODS
Charge-balanced, asymmetric pulses were delivered through a pair of metal disc electrodes. Vasoconstriction was assessed by measuring the diameter of rat saphenous vessels stimulated with low-voltage (20 V, 1 ms) and high-voltage (150 V, 10 μs) stimuli at 10 Hz for 5 min. Activation pathways were explored by topical application of a specific neural agonist (phenylephrine, alpha-1 receptor), a non-specific agonist (KCl) and neural inhibitors (phenoxybenzamine, 25 mg/ml; guanethidine, 1 mg/ml). Acute tissue damage was assessed with a membrane permeability (live-dead) fluorescent assay. The Joule heating in tissue was estimated using COMSOL Multiphysics modeling.
RESULTS
During stimulation, arteries constricted to 41 ± 8% and 37 ± 6% of their pre-stimulus diameter with low- and high-voltage stimuli, while veins constricted to 80 ± 18% and 40 ± 11%, respectively. In arteries, despite similar extent of constriction, the recovery time was very different: about 30 s for low-voltage and 10 min for high-voltage stimuli. Neural inhibitors significantly reduced low-voltage arterial constriction, but did not affect high-voltage arterial or venous constriction, indicating that high-voltage stimuli activate non-neural vasoconstriction pathways. Adrenergic pathways predominantly controlled low-voltage arterial but not venous constriction, which may involve a purinergic pathway. Viability staining confirmed that stimuli were below the electroporation threshold. Modeling indicates that heating of the blood vessels during stimulation (< 0.2 °C) is too low to cause vasoconstriction.
CONCLUSIONS
We demonstrate that low-voltage stimuli induce reversible vasoconstriction through neural pathways, while high-voltage stimuli activate non-neural pathways, likely in addition to neural stimulation. Different stimuli providing precise control over the extent of arterial and venous constriction as well as relaxation rate could be used to control bleeding, perfusion or blood pressure.
Topics: Animals; Electric Stimulation; Male; Rats; Rats, Long-Evans; Saphenous Vein; Vasoconstriction
PubMed: 29843762
DOI: 10.1186/s12984-018-0390-y -
Frontiers in Immunology 2022Anaphylaxis is a systemic hypersensitivity reaction that can be life threatening. Mechanistically, it results from the immune activation and release of a variety of... (Review)
Review
UNLABELLED
Anaphylaxis is a systemic hypersensitivity reaction that can be life threatening. Mechanistically, it results from the immune activation and release of a variety of mediators that give rise to the signs and symptoms of this pathological event. For years, most of the research in anaphylaxis has focused on the contribution of the immune component. However, approaches that shed light on the participation of other cellular and molecular agents are necessary. Among them, the vascular niche receives the various signals (e.g., histamine) that elicit the range of anaphylactic events. Cardiovascular manifestations such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and cardiac alterations are crucial in the pathophysiology of anaphylaxis and are highly involved to the development of the most severe cases. Specifically, the endothelium, vascular smooth muscle cells, and their molecular signaling outcomes play an essential role downstream of the immune reaction. Therefore, in this review, we synthesized the vascular changes observed during anaphylaxis as well as its cellular and molecular components. As the risk of anaphylaxis exists both in clinical procedures and in routine life, increasing our knowledge of the vascular physiology and their molecular mechanism will enable us to improve the clinical management and how to treat or prevent anaphylaxis.
KEY MESSAGE
Anaphylaxis, the most severe allergic reaction, involves a variety of immune and non-immune molecular signals that give rise to its pathophysiological manifestations. Importantly, the vascular system is engaged in processes relevant to anaphylactic events such as increased vascular permeability, vasodilation, hypotension, vasoconstriction, and decreased cardiac output. The novelty of this review focuses on the fact that new studies will greatly improve the understanding of anaphylaxis when viewed from a vascular molecular angle and specifically from the endothelium. This knowledge will improve therapeutic options to treat or prevent anaphylaxis.
Topics: Anaphylaxis; Histamine; Humans; Hypotension; Vasoconstriction; Vasodilation
PubMed: 35371072
DOI: 10.3389/fimmu.2022.836222 -
Experimental Physiology Aug 2019What is the topic of this review? This review presents an update and synthesis of normal mechanisms of human cutaneous vasoconstriction in response to cold stress. It... (Review)
Review
NEW FINDINGS
What is the topic of this review? This review presents an update and synthesis of normal mechanisms of human cutaneous vasoconstriction in response to cold stress. It then discusses conditions in which cutaneous vasoconstrictor responses are excessive or insufficient and cases in which cold-induced vasoconstrictor responses become counter to maintaining thermal and haemodynamic homeostasis. What advances does it highlight? The review highlights our current understanding of the mechanisms that mediate alterations in cold-induced cutaneous vasoconstriction in pathology and environmental extremes, which has important clinical implications for preventing cold- and cardiovascular-related deaths.
ABSTRACT
In humans, cold-induced peripheral vasoconstriction is an essential element of body temperature regulation. Given that the thermoregulatory system responds rapidly to changes in skin temperature, sympathetically mediated cutaneous vasoconstriction represents a crucial 'first line of defense' against excessive reduction in body temperature. Sympathetic noradrenergic vasoconstrictor nerves cause a rapid decrease in skin blood flow, thus increasing the insulative capacity of the skin and decreasing heat loss from the body. Small changes in the activity of these nerves are also responsible for the subtle changes in skin blood flow that occur with normal daily activities or minor changes in environmental temperature. With ageing, hypertension and other conditions, the cutaneous reflex vasoconstrictor response can become excessive or insufficient. Healthy older adults have impaired reflex vasoconstriction, which may result in an impaired ability to defend body temperature in some circumstances. Hypertension is associated with augmented vasoconstriction, which could have pathological implications for left ventricular afterload in individuals already at risk for cardiovascular events. Finally, in some cases, the reflex vasoconstrictor response becomes distinctly counterproductive to its own goals of maintaining cardiovascular and thermoregulatory homeostasis. Examples include Raynaud's phenomenon, in which exaggerated vasoconstriction can produce ischaemia in the periphery, and the cutaneous vasoconstrictor response to therapeutic body cooling in severe hyperthermia, which can limit the heat exchange necessary to prevent serious heat illness.
Topics: Body Temperature Regulation; Cardiovascular System; Cold Temperature; Homeostasis; Humans; Hypertension; Skin; Skin Temperature; Vasoconstriction
PubMed: 31045297
DOI: 10.1113/EP087718 -
Science Signaling Nov 2023Humans and mice with mutations in and manifest hallmarks of cerebral small vessel disease (cSVD). Mice with a missense mutation in at amino acid 1344 () exhibit...
Humans and mice with mutations in and manifest hallmarks of cerebral small vessel disease (cSVD). Mice with a missense mutation in at amino acid 1344 () exhibit age-dependent intracerebral hemorrhages (ICHs) and brain lesions. Here, we report that this pathology was associated with the loss of myogenic vasoconstriction, an intrinsic vascular response essential for the autoregulation of cerebral blood flow. Electrophysiological analyses showed that the loss of myogenic constriction resulted from blunted pressure-induced smooth muscle cell (SMC) membrane depolarization. Furthermore, we found that dysregulation of membrane potential was associated with impaired Ca-dependent activation of large-conductance Ca-activated K (BK) and transient receptor potential melastatin 4 (TRPM4) cation channels linked to disruptions in sarcoplasmic reticulum (SR) Ca signaling. mutations impair protein folding, which can cause SR stress. Treating mice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins and alleviates SR stress, restored SR Ca signaling, maintained BK and TRPM4 channel activity, prevented loss of myogenic tone, and reduced ICHs. We conclude that alterations in SR Ca handling that impair ion channel activity result in dysregulation of SMC membrane potential and loss of myogenic tone and contribute to age-related cSVD in mice.
Topics: Mice; Animals; Humans; Signal Transduction; Ion Transport; Vasoconstriction; TRPM Cation Channels; Collagen Type IV
PubMed: 37963192
DOI: 10.1126/scisignal.adi3966 -
Journal of Applied Physiology... Dec 2015The human pulmonary vasculature vasoconstricts in response to a reduction in alveolar oxygen tension, a phenomenon termed hypoxic pulmonary vasoconstriction (HPV). This... (Review)
Review
The human pulmonary vasculature vasoconstricts in response to a reduction in alveolar oxygen tension, a phenomenon termed hypoxic pulmonary vasoconstriction (HPV). This review describes the time course of this behavior, which occurs in distinct phases, and then explores the importance for HPV of the hypoxia-inducible factor (HIF) pathway. Next, the HIF-hydroxylase enzymes that act as molecular oxygen sensors within the HIF pathway are discussed. These enzymes are particularly sensitive to intracellular iron availability, which confers iron-sensing properties on the HIF pathway. Human studies of iron chelation and supplementation are then reviewed. These demonstrate that the iron sensitivity of the HIF pathway evident from in vitro experiments is relevant to human pulmonary vascular physiology. Next, the importance of iron status in high-altitude illness and chronic cardiopulmonary disease is explored, and the therapeutic potential of intravenous iron discussed. The review concludes by highlighting some further complexities that arise from interactions between the HIF pathway and other intracellular iron-sensing mechanisms.
Topics: Altitude Sickness; Animals; Humans; Hypoxia; Iron; Oxygen Consumption; Pulmonary Circulation; Vasoconstriction
PubMed: 26066825
DOI: 10.1152/japplphysiol.00179.2015 -
American Journal of Physiology. Heart... Feb 2017Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, which is composed... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors, which is composed of three members encoded by distinct genes: PPARα, PPARβ/δ, and PPARγ. The biological actions of PPARα and PPARγ and their potential as a cardiovascular therapeutic target have been extensively reviewed, whereas the biological actions of PPARβ/δ and its effectiveness as a therapeutic target in the treatment of hypertension remain less investigated. Preclinical studies suggest that pharmacological PPARβ/δ activation induces antihypertensive effects in direct [spontaneously hypertensive rat (SHR), ANG II, and DOCA-salt] and indirect (dyslipemic and gestational) models of hypertension, associated with end-organ damage protection. This review summarizes mechanistic insights into the antihypertensive effects of PPARβ/δ activators, including molecular and functional mechanisms. Pharmacological PPARβ/δ activation induces genomic actions including the increase of regulators of G protein-coupled signaling (RGS), acute nongenomic vasodilator effects, as well as the ability to improve the endothelial dysfunction, reduce vascular inflammation, vasoconstrictor responses, and sympathetic outflow from central nervous system. Evidence from clinical trials is also examined. These preclinical and clinical outcomes of PPARβ/δ ligands may provide a basis for the development of therapies in combating hypertension.
Topics: Animals; Antihypertensive Agents; Blood Pressure; Endothelium, Vascular; Fatty Acids; Gene Expression Regulation; Humans; Hypertension; Inflammation; PPAR delta; PPAR-beta; Phenoxyacetates; RGS Proteins; Rats; Rats, Inbred SHR; Sympathetic Nervous System; Thiazoles; Vasoconstriction; Vasodilation
PubMed: 27881385
DOI: 10.1152/ajpheart.00155.2016 -
Cells May 2024Norbormide (NRB) is a -selective toxicant, which was serendipitously discovered in 1964 and formerly marketed as an eco-friendly rodenticide that was deemed harmless to... (Review)
Review
Norbormide (NRB) is a -selective toxicant, which was serendipitously discovered in 1964 and formerly marketed as an eco-friendly rodenticide that was deemed harmless to non- species. However, due to inconsistent efficacy and the emergence of second-generation anticoagulants, its usage declined, with registration lapsing in 2003. NRBs' lethal action in rats entails irreversible vasoconstriction of peripheral arteries, likely inducing cardiac damage: however, the precise chain of events leading to fatality and the target organs involved remain elusive. This unique contractile effect is exclusive to rat arteries and is induced solely by the endo isomers of NRB, hinting at a specific receptor involvement. Understanding NRB's mechanism of action is crucial for developing species-selective toxicants as alternatives to the broad-spectrum ones currently in use. Recent research efforts have focused on elucidating its cellular mechanisms and sites of action using novel NRB derivatives. The key findings are as follows: NRB selectively opens the rat mitochondrial permeability transition pore, which may be a factor that contributes to its lethal effect; it inhibits rat vascular K channels, which potentially controls its -selective vasoconstricting activity; and it possesses intracellular binding sites in both sensitive and insensitive cells, as revealed by fluorescent derivatives. These studies have led to the development of a prodrug with enhanced pharmacokinetic and toxicological profiles, which is currently undergoing registration as a novel efficacious eco-sustainable -selective toxicant. The NRB-fluorescent derivatives also show promise as non-toxic probes for intracellular organelle labelling. This review documents in more detail these developments and their implications.
Topics: Animals; Rats; Rodenticides; Humans; Vasoconstriction; Mitochondrial Permeability Transition Pore
PubMed: 38727324
DOI: 10.3390/cells13090788 -
Anaesthesia Nov 2015During and after cardiac surgery with cardiopulmonary bypass, high concentrations of oxygen are routinely administered, with the intention of preventing cellular... (Review)
Review
During and after cardiac surgery with cardiopulmonary bypass, high concentrations of oxygen are routinely administered, with the intention of preventing cellular hypoxia. We systematically reviewed the literature addressing the effects of arterial hyperoxia. Extensive evidence from pre-clinical experiments and clinical studies in other patient groups suggests predominant harm, caused by oxidative stress, vasoconstriction, perfusion heterogeneity and myocardial injury. Whether these alterations are temporary and benign, or actually affect clinical outcome, remains to be demonstrated. In nine clinical cardiac surgical studies in low-risk patients, higher oxygen targets tended to compromise cardiovascular function, but did not affect clinical outcome. No data about potential beneficial effects of hyperoxia, such as reduction of gas micro-emboli or post-cardiac surgery infections, were reported. Current evidence is insufficient to specify optimal oxygen targets. Nevertheless, the safety of supraphysiological oxygen suppletion is unproven. Randomised studies with a variety of oxygen targets and inclusion of high-risk patients are needed to identify optimal oxygen targets during and after cardiac surgery.
Topics: Cardiac Surgical Procedures; Cardiopulmonary Bypass; Heart; Humans; Hyperoxia; Inflammation; Oxidative Stress; Oxygen; Postoperative Period; Vasoconstriction
PubMed: 26348878
DOI: 10.1111/anae.13218 -
American Journal of Physiology. Heart... Jul 2022
Topics: Female; Humans; Pregnancy; Radial Artery; Uterus; Vasoconstriction
PubMed: 35594068
DOI: 10.1152/ajpheart.00227.2022