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Journal of Physiology and Pharmacology... Feb 2016The genomic action of aldosterone has already been known to the scientific community and is well-documented to a satisfactory degree. However, the existence of rapid,... (Review)
Review
The genomic action of aldosterone has already been known to the scientific community and is well-documented to a satisfactory degree. However, the existence of rapid, non-genomic aldosterone actions has repeatedly been proven. These actions are apparent to a lot of tissues, among which the cardiac tissue, with the cardiac cells being responsible for the secretion of endogenous aldosterone. In the genomic pathway, the connection between the hormone and its receptor results increased reabsorption of sodium and water and excretion of potassium. Thus, the genomic procedure reacts indirectly on cardiovascular system by altering the blood pressure. New studies have shed light on unknown aspects of the non-genomic mechanism, which is sometimes performed by means of mineralocorticoid receptor (MR), while others through an MR-independent pathway. It is believed that aldosterone exerts its non-genomic action with the help of a different receptor, probably a G protein coupled receptor. A possible target is protein kinase C (PKC), and PKCε is postulated increase the permeability of the membrane of the cardiac cells to sodium, resulting in delayed repolarization and prolongation of action potential. These findings totally agree with and account for the serendipitous finding of our laboratory, that there is a positive correlation between plasma aldosterone levels and left ventricle (LV) contraction duration. Also, aldosterone has been proven to exacerbate the oxidative stress and induce vasoconstriction by acting on the vascular resistance and the cardiac output. Finally, this article deals with the role of aldosterone in cardiac fibrosis and the latest aspects of aldosterone actions on the heart muscle as well as providing a historical overview of the landmarks pertaining aldosterone's research.
Topics: Aldosterone; Animals; Heart Ventricles; Humans; Myocardium; Receptors, Mineralocorticoid; Vascular Resistance; Vasoconstriction
PubMed: 27010892
DOI: No ID Found -
American Journal of Physiology. Heart... May 2022Pulmonary hypertension (PH) is a serious disease characterized by various degrees of pulmonary vasoconstriction and progressive fibroproliferative remodeling and... (Review)
Review
Pulmonary hypertension (PH) is a serious disease characterized by various degrees of pulmonary vasoconstriction and progressive fibroproliferative remodeling and inflammation of the pulmonary arterioles that lead to increased pulmonary vascular resistance, right ventricular hypertrophy, and failure. Pulmonary vascular tone is regulated by a balance between vasoconstrictor and vasodilator mediators, and a shift in this balance to vasoconstriction is an important component of PH pathology, Therefore, the mainstay of current pharmacological therapies centers on pulmonary vasodilation methodologies that either enhance vasodilator mechanisms such as the NO-cGMP and prostacyclin-cAMP pathways and/or inhibit vasoconstrictor mechanisms such as the endothelin-1, cytosolic Ca, and Rho-kinase pathways. However, in addition to the increased vascular tone, many patients have a "fixed" component in their disease that involves altered biology of various cells in the pulmonary vascular wall, excessive pulmonary artery remodeling, and perivascular fibrosis and inflammation. Pulmonary arterial smooth muscle cell (PASMC) phenotypic switch from a contractile to a synthetic and proliferative phenotype is an important factor in pulmonary artery remodeling. Although current vasodilator therapies also have some antiproliferative effects on PASMCs, they are not universally successful in halting PH progression and increasing survival. Mild acidification and other novel approaches that aim to reverse the resident pulmonary vascular pathology and structural remodeling and restore a contractile PASMC phenotype could ameliorate vascular remodeling and enhance the responsiveness of PH to vasodilator therapies.
Topics: Cell Proliferation; Humans; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; Vascular Remodeling; Vasoconstriction
PubMed: 35213243
DOI: 10.1152/ajpheart.00021.2022 -
Experimental Physiology Aug 2021What is the central question of this study? Sympathetically mediated vasoconstriction is preserved during hypoxaemia in humans, but our understanding of vascular control...
NEW FINDINGS
What is the central question of this study? Sympathetically mediated vasoconstriction is preserved during hypoxaemia in humans, but our understanding of vascular control comes from predominantly male cohorts. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not? What is the main finding and its importance? Sympathetically mediated vasoconstriction is preserved or even enhanced during steady-state hypoxia in young men, and the peripheral vascular response to sympathetic activation during hypoxaemia is attenuated in young women. These data advance our understanding of sex-related differences in hypoxic vascular control.
ABSTRACT
Activation of the sympathetic nervous system causes vasoconstriction and a reduction in peripheral blood flow. Sympathetically mediated vasoconstriction may be attenuated during systemic hypoxia to maintain oxygen delivery; however, in predominantly male participants sympathetically mediated vasoconstriction is preserved or even enhanced during hypoxaemia. Given the potential for sex-specific differences in hypoxic vascular control, prior results are limited in application. We tested the hypothesis that young women attenuate sympathetically mediated vasoconstriction during steady-state hypoxaemia, whereas men do not. Healthy young men (n = 13, 25 ± 4 years) and women (n = 11, 24 ± 4 years) completed two trials consisting of a 2-min cold pressor test (CPT, a well-established sympathoexcitatory stimulus) during baseline normoxia and steady-state hypoxaemia. Beat-to-beat blood pressure (finger photoplethysmography) and forearm blood flow (venous occlusion plethysmography) were measured continuously. Total and forearm vascular conductance (TVC and FVC, respectfully) were calculated. A change (Δ) in TVC and FVC from steady-state during the last 1 min of CPT was calculated and differences between normoxia and systemic hypoxia were assessed. In men, the reduction in TVC during CPT was greater during hypoxia compared to normoxia (ΔTVC, P = 0.02), whereas ΔTVC did not differ between conditions in women (P = 0.49). In men, ΔFVC did not differ between normoxia and hypoxia (P = 0.92). In women, the reduction in FVC during CPT was attenuated during hypoxia (ΔFVC, P < 0.01). We confirm sympathetically mediated vasoconstriction is preserved or enhanced during hypoxaemia in young men, whereas peripheral vascular responsiveness to sympathetic activation during hypoxaemia is attenuated in young women. The results advance our understanding of sex-related differences in hypoxic vascular control.
Topics: Blood Pressure; Female; Forearm; Humans; Hypoxia; Male; Regional Blood Flow; Sex Characteristics; Sympathetic Nervous System; Vasoconstriction
PubMed: 34187092
DOI: 10.1113/EP089461 -
Physiological Reports Feb 2016Exercise training (ET) increases sympathetic vasoconstrictor responsiveness and enhances contraction-mediated inhibition of sympathetic vasoconstriction (i.e.,...
Exercise training (ET) increases sympathetic vasoconstrictor responsiveness and enhances contraction-mediated inhibition of sympathetic vasoconstriction (i.e., sympatholysis) through a nitric oxide (NO)-dependent mechanism. Changes in α2-adrenoreceptor vasoconstriction mediate a portion of these training adaptations, however the contribution of other postsynaptic receptors remains to be determined. Therefore, the purpose of this study was to investigate the effect of ET on α1-adrenoreceptor-mediated vasoconstriction in resting and contracting muscle. It was hypothesized that α1-adrenoreceptor-mediated sympatholysis would be enhanced following ET. Male Sprague Dawley rats were randomized to sedentary (S; n = 12) or heavy-intensity treadmill ET (n = 11) groups. Subsequently, rats were anesthetized and instrumented for lumbar sympathetic chain stimulation and measurement of femoral vascular conductance (FVC) at rest and during muscle contraction. The percentage change in FVC in response to sympathetic stimulation was measured in control, α1-adrenoreceptor blockade (Prazosin; 20 μg, IV), and combined α1 and NO synthase (NOS) blockade (l-NAME; 5 mg·kg(-1) IV) conditions. Sympathetic vasoconstrictor responsiveness was increased (P < 0.05) in ET compared to S rats at low, but not high (P > 0.05) stimulation frequencies at rest (S: 2 Hz: -25 ± 4%; 5 Hz: -45 ± 5 %; ET: 2 Hz: -35 ± 7%, 5 Hz: -52 ± 7%), whereas sympathetic vasoconstrictor responsiveness was not different (P > 0.05) between groups during contraction (S: 2 Hz: -11 ± 8%; 5 Hz: -26 ± 11%; ET: 2 Hz: -10 ± 7%, 5 Hz: -27 ± 12%). Prazosin blunted (P < 0.05) vasoconstrictor responsiveness in S and ET rats at rest and during contraction, and abolished group differences in vasoconstrictor responsiveness. Subsequent NOS blockade increased vasoconstrictor responses (P < 0.05) in S at rest and during contraction, whereas in ET vasoconstriction was increased (P < 0.05) in response to sympathetic stimulation at 2 Hz at rest and unchanged (P > 0.05) during contraction. ET enhanced (P < 0.05) sympatholysis, however the training-mediated improvements in sympatholysis were abolished by α1-adrenoreceptor blockade. Subsequent NOS inhibition did not alter (P > 0.05) sympatholysis in S or ET rats. In conclusion, ET augmented α1-adrenoreceptor-mediated vasoconstriction in resting skeletal muscle and enhanced α1-adrenoreceptor-mediated sympatholysis. Furthermore, these data suggest that NO is not required to inhibit α2-adrenoreceptor- and nonadrenoreceptor-mediated vasoconstriction during exercise.
Topics: Adrenergic alpha-1 Receptor Antagonists; Animals; Enzyme Inhibitors; Male; Muscle Contraction; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Physical Conditioning, Animal; Prazosin; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Rest; Sympathetic Nervous System; Vasoconstriction
PubMed: 26869686
DOI: 10.14814/phy2.12707 -
Autonomic Neuroscience : Basic &... Nov 2017We review the information that has been provided by optical imaging experiments directed at understanding the role and effects of sympathetic nerve activity (SNA) in the... (Review)
Review
We review the information that has been provided by optical imaging experiments directed at understanding the role and effects of sympathetic nerve activity (SNA) in the functioning of blood vessels. Earlier studies utilized electric field stimulation of nerve terminals (EFS) in isolated arteries and vascular tissues (ex vivo) to elicit SNA, but more recently, imaging studies have been conducted in vivo, enabling the study of SNA in truly physiological conditions. Ex vivo: In vascular smooth muscle cells (VSMC) of isolated arteries, the three sympathetic neurotransmitters, norepinephrine (NE), ATP and neuropeptide Y (NPY), elicit or modulate distinct patterns of Ca signaling, as revealed by confocal imaging of exogenous fluorescent Ca indicators. Purinergic junctional Ca transients (jCaTs) arise from Ca influx during excitatory junction potentials (eJPs), and are associated with the initial neurogenic contraction. Adrenergic Ca waves and oscillations cause contraction while SNA-induced endothelial Ca 'pulsars' cause relaxation. In vivo: optical biosensor mice, which express genetically encoded Ca indicators (GECI's) specifically in smooth muscle, combined with non-invasive imaging techniques has enabled imaging SNA-induced Ca signaling and arterial diameter in vivo. SNA induces Ca oscillations in intact arteries. [Ca] of arterial smooth muscle cells increased in hypertension, in association with increased SNA. High resolution imaging has revealed local sympathetic, neurogenic Ca signaling within smooth muscle and endothelial cells of the vasculature. The ongoing development of in vivo imaging together with an expanding availability of different biosensor animals promises to enable the further assessment of SNA and its effects in the vasculature of living animals.
Topics: Animals; Calcium; Calcium Signaling; Humans; Muscle, Smooth, Vascular; Neurogenesis; Sympathetic Nervous System; Vasoconstriction
PubMed: 28781164
DOI: 10.1016/j.autneu.2017.07.007 -
Hypertension (Dallas, Tex. : 1979) Aug 2020Increased arterial stiffness and vascular remodeling precede and are consequences of hypertension. They also contribute to the development and progression of...
Increased arterial stiffness and vascular remodeling precede and are consequences of hypertension. They also contribute to the development and progression of life-threatening cardiovascular diseases. Yet, there are currently no agents specifically aimed at preventing or treating arterial stiffening and remodeling. Previous research indicates that vascular smooth muscle actin polymerization participates in the initial stages of arterial stiffening and remodeling and that LIMK (LIM kinase) promotes F-actin formation and stabilization via cofilin phosphorylation and consequent inactivation. Herein, we hypothesize that LIMK inhibition is able to prevent vasoconstriction- and hypertension-associated arterial stiffening and inward remodeling. We found that small visceral arteries isolated from hypertensive subjects are stiffer and have greater cofilin phosphorylation than those from nonhypertensives. We also show that LIMK inhibition prevents arterial stiffening and inward remodeling in isolated human small visceral arteries exposed to prolonged vasoconstriction. Using cultured vascular smooth muscle cells, we determined that LIMK inhibition prevents vasoconstrictor agonists from increasing cofilin phosphorylation, F-actin volume, and cell cortex stiffness. We further show that localized LIMK inhibition prevents arteriolar inward remodeling in hypertensive mice. This indicates that hypertension is associated with increased vascular smooth muscle cofilin phosphorylation, cytoskeletal stress fiber formation, and heightened arterial stiffness. Our data further suggest that pharmacological inhibition of LIMK prevents vasoconstriction-induced arterial stiffening, in part, via reductions in vascular smooth muscle F-actin content and cellular stiffness. Accordingly, LIMK inhibition should represent a promising therapeutic means to stop the progression of arterial stiffening and remodeling in hypertension.
Topics: Adult; Animals; Arteries; Coronary Vessels; Female; Humans; Hypertension; Lim Kinases; Male; Mice; Mice, Transgenic; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein Kinase Inhibitors; Signal Transduction; Vascular Remodeling; Vascular Stiffness; Vasoconstriction
PubMed: 32594801
DOI: 10.1161/HYPERTENSIONAHA.120.15203 -
Journal of Applied Physiology... Aug 2019Mechanical ventilation (MV) is a life-saving intervention, yet with prolonged MV (i.e., ≥6 h) there are time-dependent reductions in diaphragm blood flow and an...
Mechanical ventilation (MV) is a life-saving intervention, yet with prolonged MV (i.e., ≥6 h) there are time-dependent reductions in diaphragm blood flow and an impaired hyperemic response of unknown origin. Female Sprague-Dawley rats (4-8 mo, = 118) were randomized into two groups; spontaneous breathing (SB) and 6-h (prolonged) MV. After MV or SB, vasodilation (flow-induced, endothelium-dependent and -independent agonists) and constriction (myogenic and α-adrenergic) responses were measured in first-order (1A) diaphragm resistance arterioles in vitro, and endothelial nitric oxide synthase (eNOS) mRNA expression was quantified. Following prolonged MV, there was a significant reduction in diaphragm arteriolar flow-induced (SB, 34.7 ± 3.8% vs. MV, 22.6 ± 2.0%; ≤ 0.05), endothelium-dependent (via acetylcholine; SB, 64.3 ± 2.1% vs. MV, 36.4 ± 2.3%; ≤ 0.05) and -independent (via sodium nitroprusside; SB, 65.0 ± 3.1% vs. MV, 46.0 ± 4.6%; ≤ 0.05) vasodilation. Compared with SB, there was reduced eNOS mRNA expression ( ≤ 0.05). Prolonged MV diminished phenylephrine-induced vasoconstriction (SB, 37.3 ± 6.7% vs. MV, 19.0 ± 1.9%; ≤ 0.05) but did not alter myogenic or passive pressure responses. The severe reductions in diaphragmatic blood flow at rest and during contractions, with prolonged MV, are associated with diaphragm vascular dysfunction which occurs through both endothelium-dependent and endothelium-independent mechanisms. Following prolonged mechanical ventilation, vascular alterations occur through both endothelium-dependent and -independent pathways. This is the first study, to our knowledge, demonstrating that diaphragm arteriolar dysfunction occurs consequent to prolonged mechanical ventilation and likely contributes to the severe reductions in diaphragmatic blood flow and weaning difficulties.
Topics: Acetylcholine; Animals; Arterioles; Diaphragm; Female; Muscle Contraction; Nitric Oxide Synthase Type III; Nitroprusside; Phenylephrine; Rats; Rats, Sprague-Dawley; Respiration, Artificial; Vascular Resistance; Vasoconstriction; Vasodilation
PubMed: 31161883
DOI: 10.1152/japplphysiol.00189.2019 -
Communications Biology Sep 2022Human and animal studies have reported widespread reductions in cerebral blood flow associated with chronic cocaine exposures. However, the molecular and cellular...
Human and animal studies have reported widespread reductions in cerebral blood flow associated with chronic cocaine exposures. However, the molecular and cellular mechanisms underlying cerebral blood flow reductions are not well understood. Here, by combining a multimodal imaging platform with a genetically encoded calcium indicator, we simultaneously measured the effects of acute cocaine on neuronal and astrocytic activity, tissue oxygenation, hemodynamics and vascular diameter changes in the mouse cerebral cortex. Our results showed that cocaine constricted blood vessels (measured by vessel diameter Φ changes), decreasing cerebral total blood volume (HbT) and temporally reducing tissue oxygenation. Cellular imaging showed that the mean astrocytic Ca dependent fluorescence [Formula: see text] increase in response to cocaine was weaker but longer lasting than the mean neuronal Ca dependent fluorescence [Formula: see text] changes. Interestingly, while cocaine-induced [Formula: see text] increase was temporally correlated with tissue oxygenation change, the [Formula: see text] elevation after cocaine was in temporal correspondence with the long-lasting decrease in arterial blood volumes. To determine whether the temporal association between astrocytic activation and cocaine induced vasoconstriction reflected a causal association we inhibited astrocytic Ca using GFAP-DREADD(Gi). Inhibition of astrocytes attenuated the vasoconstriction resulting from cocaine, providing evidence that astrocytes play a critical role in cocaine's vasoconstrictive effects in the brain. These results indicate that neurons and astrocytes play different roles in mediating neurovascular coupling in response to cocaine. Our findings implicate neuronal activation as the main driver of the short-lasting reduction in tissue oxygenation and astrocyte long-lasting activation as the driver of the persistent vasoconstriction with cocaine. Understanding the cellular and vascular interaction induced by cocaine will be helpful for future putative treatments to reduce cerebrovascular pathology from cocaine use.
Topics: Animals; Astrocytes; Cerebrovascular Circulation; Cocaine; Cocaine-Related Disorders; Humans; Mice; Vasoconstriction
PubMed: 36097038
DOI: 10.1038/s42003-022-03877-w -
Journal of Cellular and Molecular... Aug 2023Allogeneic blood vessels are regarded as one of the best natural substitutes for diseased blood vessels due to their good vascular compliance and histocompatibility....
Allogeneic blood vessels are regarded as one of the best natural substitutes for diseased blood vessels due to their good vascular compliance and histocompatibility. Since the supply and demand of allograft blood vessels do not always match in time and space, a good preservation scheme for isolated blood vessels is essential. The abdominal aortas of 110 male Sprague-Dawley (SD) rats were randomly divided into three groups, including cold storage group (4°C) (CSG), frozen storage group (FSG) and ambient storage group (25 ± 2°C) (ASG). Seven time points of preservation for 1, 3, 5, 7, 14, 30 and 90 days were set for detection. The changes in vascular physiological function were evaluated by MTT test and vasoconstriction ability detection, and the changes in vascular wall structure were evaluated by the tension tolerance test and pathological staining. The vascular function of CSG was better than FSG within first the 7 days, but the result was opposite since the 14th day. The vascular wall structure, collagen and elastic fibres of vessels, in CSG, showed oedema within 30 days, and continuous disintegration and rupture at 90 days. The vessel wall structure of FSG remained intact within 90 days. The tensile strength of the vessels in CSG was better than that in FSG within 5 days, and there was no statistical difference between the two groups between the 7th and 30th day, and then, the FSG was higher than CSG on the 90th day. Both cold storage and frozen storage could be applied as safe and effective preservation schemes for isolated rat artery within first 30 days. Cold storage is recommended when the storage time is <14 days, and then, frozen storage is better.
Topics: Rats; Male; Animals; Endothelium, Vascular; Rats, Sprague-Dawley; Vasoconstriction; Cryopreservation; Aorta, Abdominal
PubMed: 37357501
DOI: 10.1111/jcmm.17822 -
Basic & Clinical Pharmacology &... Aug 2020Adenosine monophosphate-activated protein kinase (AMPK), expressed/present ubiquitously in the body, contributes to metabolic regulation. In the vasculature, activation... (Review)
Review
Adenosine monophosphate-activated protein kinase (AMPK), expressed/present ubiquitously in the body, contributes to metabolic regulation. In the vasculature, activation of AMPK is associated with several beneficial biological effects including enhancement of vasodilatation, reduction of oxidative stress and inhibition of inflammatory reactions. The vascular protective effects of certain anti-diabetic (metformin and sitagliptin) or lipid-lowering (simvastatin and fenofibrate) therapeutic agents, of active components of Chinese medicinal herbs (resveratrol and berberine) and of pharmacological agents (AICAR, A769662 and PT1) have been attributed to the activation of AMPK (in endothelial cells, vascular smooth muscle cells and/or perivascular adipocytes), independently of changes in the metabolic profile (eg glucose tolerance and/or plasma lipoprotein levels), leading to improved endothelium-derived nitric oxide-mediated vasodilatation and attenuated endothelium-derived cyclooxygenase-dependent vasoconstriction. By contrast, endothelial AMPK activation with pharmacological agents or by genetic modification is associated with reduced endothelium-dependent relaxations in small blood vessels and elevated systolic blood pressure. Indeed, AMPK activators inhibit endothelium-dependent hyperpolarization (EDH)-type relaxations in superior mesenteric arteries, partly by inhibiting endothelial calcium-activated potassium channel signalling. Therefore, AMPK activation is not necessarily beneficial in terms of endothelial function. The contribution of endothelial AMPK in the regulation of vascular tone, in particular in the microvasculature where EDH plays a more important role, remains to be characterized.
Topics: AMP-Activated Protein Kinases; Animals; Diabetes Mellitus; Endothelium, Vascular; Humans; Hypoglycemic Agents; Muscle, Smooth, Vascular; Nitric Oxide; Potassium Channels; Signal Transduction; Vasoconstriction; Vasodilation
PubMed: 31671245
DOI: 10.1111/bcpt.13357