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      Isometric Stretch Alters Vascular Reactivity of Mouse Aortic Segments

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          Abstract

          Most vaso-reactive studies in mouse aortic segments are performed in isometric conditions and at an optimal preload, which is the preload corresponding to a maximal contraction by non-receptor or receptor-mediated stimulation. In general, this optimal preload ranges from about 1.2 to 8.0 mN/mm, which according to Laplace's law roughly correlates with transmural pressures of 10–65 mmHg. For physiologic transmural pressures around 100 mmHg, preloads of 15.0 mN/mm should be implemented. The present study aimed to compare vascular reactivity of 2 mm mouse (C57Bl6) aortic segments preloaded at optimal (8.0 mN/mm) vs. (patho) physiological (10.0–32.5 mN/mm) preload. Voltage-dependent contractions of aortic segments, induced by increasing extracellular K +, and contractions by α 1-adrenergic stimulation with phenylephrine (PE) were studied at these preloads in the absence and presence of L-NAME to inhibit basal release of NO from endothelial cells (EC). In the absence of basal NO release and with higher than optimal preload, contractions evoked by depolarization or PE were attenuated, whereas in the presence of basal release of NO PE-, but not depolarization-induced contractions were preload-independent. Phasic contractions by PE, as measured in the absence of external Ca 2+, were decreased at higher than optimal preload suggestive for a lower contractile SR Ca 2+ content at physiological preload. Further, in the presence of external Ca 2+, contractions by Ca 2+ influx via voltage-dependent Ca 2+ channels were preload-independent, whereas non-selective cation channel-mediated contractions were increased. The latter contractions were very sensitive to the basal release of NO, which itself seemed to be preload-independent. Relaxation by endogenous NO (acetylcholine) of aortic segments pre-contracted with PE was preload-independent, whereas relaxation by exogenous NO (diethylamine NONOate) displayed higher sensitivity at high preload. Results indicated that stretching aortic segments to higher than optimal preload depolarizes the SMC and causes Ca 2+ unloading of the contractile SR, making them extremely sensitive to small changes in the basal release of NO from EC as can occur in hypertension or arterial stiffening.

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          Most cited references 41

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          Endothelium-derived hyperpolarising factors and associated pathways: a synopsis.

          The term endothelium-derived hyperpolarising factor (EDHF) was introduced in 1987 to describe the hypothetical factor responsible for myocyte hyperpolarisations not associated with nitric oxide (EDRF) or prostacyclin. Two broad categories of EDHF response exist. The classical EDHF pathway is blocked by apamin plus TRAM-34 but not by apamin plus iberiotoxin and is associated with endothelial cell hyperpolarisation. This follows an increase in intracellular [Ca(2+)] and the opening of endothelial SK(Ca) and IK(Ca) channels preferentially located in caveolae and in endothelial cell projections through the internal elastic lamina, respectively. In some vessels, endothelial hyperpolarisations are transmitted to myocytes through myoendothelial gap junctions without involving any EDHF. In others, the K(+) that effluxes through SK(Ca) activates myocytic and endothelial Ba(2+)-sensitive K(IR) channels leading to myocyte hyperpolarisation. K(+) effluxing through IK(Ca) activates ouabain-sensitive Na(+)/K(+)-ATPases generating further myocyte hyperpolarisation. For the classical pathway, the hyperpolarising "factor" involved is the K(+) that effluxes through endothelial K(Ca) channels. During vessel contraction, K(+) efflux through activated myocyte BK(Ca) channels generates intravascular K(+) clouds. These compromise activation of Na(+)/K(+)-ATPases and K(IR) channels by endothelium-derived K(+) and increase the importance of gap junctional electrical coupling in myocyte hyperpolarisations. The second category of EDHF pathway does not require endothelial hyperpolarisation. It involves the endothelial release of factors that include NO, HNO, H(2)O(2) and vasoactive peptides as well as prostacyclin and epoxyeicosatrienoic acids. These hyperpolarise myocytes by opening various populations of myocyte potassium channels, but predominantly BK(Ca) and/or K(ATP), which are sensitive to blockade by iberiotoxin or glibenclamide, respectively.
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            Elastic fibres and vascular structure in hypertension.

            Blood vessels are dynamic structures composed of cells and extracellular matrix (ECM), which are in continuous cross-talk with each other. Thus, cellular changes in phenotype or in proliferation/death rate affect ECM synthesis. In turn, ECM elements not only provide the structural framework for vascular cells, but they also modulate cellular function through specific receptors. These ECM-cell interactions, together with neurotransmitters, hormones and the mechanical forces imposed by the heart, modulate the structural organization of the vascular wall. It is not surprising that pathological states related to alterations in the nervous, humoral or haemodynamic environment-such as hypertension-are associated with vascular wall remodeling, which, in the end, is deleterious for cardiovascular function. However, the question remains whether these structural alterations are simply a consequence of the disease or if there are early cellular or ECM alterations-determined either genetically or by environmental factors-that can predispose to vascular remodeling independent of hypertension. Elastic fibres might be key elements in the pathophysiology of hypertensive vascular remodeling. In addition to the well known effects of hypertension on elastic fibre fatigue and accelerated degradation, leading to loss of arterial wall resilience, recent investigations have highlighted new roles for individual components of elastic fibres and their degradation products. These elements can act as signal transducers and regulate cellular proliferation, migration, phenotype, and ECM degradation. In this paper, we review current knowledge regarding components of elastic fibres and discuss their possible pathomechanistic associations with vascular structural abnormalities and with hypertension development or progression.
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              Inhibition of basal nitric oxide synthesis increases aortic augmentation index and pulse wave velocity in vivo.

              To investigate the role of basal nitric oxide (NO) production in regulating large artery stiffness in vivo. Incremental doses of the NO synthase inhibitor L-N(G)-monomethyl arginine (LNMMA: 0.1, 0.3, 1.0 and 3.0 mg kg-1 min-1) or placebo were infused in eight healthy men. Arterial stiffness was assessed noninvasively by pulse wave analysis. Compared with placebo, infusion of LNMMA led to a dose-dependent increase in mean arterial pressure, peripheral vascular resistance, and aortic and systemic arterial stiffness. There was an accompanying reduction in heart rate and cardiac index. The highest dose of LNMMA resulted in an increase of 25% in AIx (95% confidence limits; 12, 38) and of 16 mmHg in mean arterial pressure (9, 23) compared with infusion of saline. These data indicate functional regulation of large artery stiffness in vivo by NO, and may provide new therapeutic strategies for cardiovascular risk reduction.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                16 March 2017
                2017
                : 8
                Affiliations
                1Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, University of Antwerp Antwerp, Belgium
                2Laboratory of Pharmacology, Faculty of Medicine and Health Sciences, University of Antwerp Antwerp, Belgium
                Author notes

                Edited by: Agustín Guerrero-Hernández, Center for Advanced Research, The National Polytechnic Institute, Cinvestav-IPN, Mexico

                Reviewed by: François Guerrero, University of Western Brittany, France; Michael P. Massett, Texas A&M University, USA

                *Correspondence: Paul Fransen paul.fransen@ 123456uantwerpen.be

                This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2017.00157
                5352655
                Copyright © 2017 De Moudt, Leloup, Van Hove, De Meyer and Fransen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 10, Tables: 0, Equations: 0, References: 49, Pages: 13, Words: 8866
                Funding
                Funded by: Bijzonder Onderzoeksfonds 10.13039/501100007229
                Funded by: Fonds Wetenschappelijk Onderzoek 10.13039/501100003130
                Categories
                Physiology
                Original Research

                Anatomy & Physiology

                relaxation, nitric oxide, isometric, stretch, preload, aorta, contraction

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