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      Smooth muscle gap-junctions allow propagation of intercellular Ca 2+ waves and vasoconstriction due to Ca 2+ based action potentials in rat mesenteric resistance arteries

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          Graphical abstract


          • In rat mesenteric resistance arteries (MA), smooth muscle (SMC) gap junctions enable intercellular Ca 2+ waves and vasoconstriction.
          • Simultaneous block of K + channels and activation of L-type VGCCs triggered SMC action potentials and propagating intercellular Ca 2+ waves.
          • Ca 2+ spread was spike-like in appearance, of constant speed at 2.6 ± 0.3 mm s −1 and associated with vasoconstriction spread at 2.5 ± 0.3 mm s −1.
          • The ability of arteries to spread intercellular Ca 2+ waves and phasic contractions was independent of the endothelium.
          • Propagation but not the generation of Ca 2+ spikes was reversibly inhibited by the gap junction blocker 18β-glycyrrhetinic acid (18β–GA).


          The role of vascular gap junctions in the conduction of intercellular Ca 2+ and vasoconstriction along small resistance arteries is not entirely understood. Some depolarizing agents trigger conducted vasoconstriction while others only evoke a local depolarization. Here we use a novel technique to investigate the temporal and spatial relationship between intercellular Ca 2+ signals generated by smooth muscle action potentials (APs) and vasoconstriction in mesenteric resistance arteries (MA). Pulses of exogenous KCl to depolarize the downstream end (T1) of a 3 mm long artery increased intracellular Ca 2+ associated with vasoconstriction. The spatial spread and amplitude of both depended on the duration of the pulse, with only a restricted non-conducting vasoconstriction to a 1 s pulse. While blocking smooth muscle cell (SMC) K + channels with TEA and activating L-type voltage-gated Ca 2+ channels (VGCCs) with BayK 8644 spread was dramatically facilitated, so the 1 s pulse evoked intercellular Ca 2+ waves and vasoconstriction that spread along an entire artery segment 3000 μm long. Ca 2+ waves spread as nifedipine-sensitive Ca 2+ spikes due to SMC action potentials, and evoked vasoconstriction. Both intercellular Ca 2+ and vasoconstriction spread at circa 3 mm s −1 and were independent of the endothelium. The spread but not the generation of Ca 2+ spikes was reversibly blocked by the gap junction inhibitor 18β-GA. Thus, smooth muscle gap junctions enable depolarization to spread along resistance arteries, and once regenerative Ca 2+-based APs occur, spread along the entire length of an artery followed by widespread vasoconstriction.

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          Most cited references 43

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          Principles and standards for reporting animal experiments in The Journal of Physiology and Experimental Physiology.

           David Grundy (2015)
          The Journal of Physiology and Experimental Physiology have always used UK legislation as the basis of their policy on ethical standards in experiments on non-human animals. However, for international journals with authors, editors and referees from outside the UK the policy can lack transparency and is sometimes cumbersome, requiring the intervention of a Senior Ethics Reviewer or advice from external experts familiar with UK legislation. The journals have therefore decided to set out detailed guidelines for how authors should report experimental procedures that involve animals. As well as helping authors, this new clarity will facilitate the review process and decision making where there are questions regarding animal ethics.
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            Incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat is suggestive of a role in endothelium-derived hyperpolarizing factor-mediated responses.

            Although the chemical nature of endothelium-derived hyperpolarizing factor (EDHF) remains elusive, electrophysiological evidence exists for electrical communication between smooth muscle cells and endothelial cells suggesting that electrotonic propagation of hyperpolarization may explain the failure to identify a single chemical factor as EDHF. Anatomical evidence for myoendothelial gap junctions, or the sites of electrical coupling, is, however, rare. In the present study, serial-section electron microscopy and reconstruction techniques have been used to examine the incidence of myoendothelial gap junctions in the proximal and distal mesenteric arteries of the rat where EDHF responses have been reported to vary. Myoendothelial gap junctions were found to be very small in the mesenteric arteries, the majority being <100 nm in diameter. In addition, they were significantly more common in the distal compared with the proximal regions of this arterial bed. Pentalaminar gap junctions between adjacent endothelial cells were much larger and were common in both proximal and distal mesenteric arteries. These latter junctions were frequently found near the myoendothelial gap junctions. These results provide the first evidence for the presence of sites for electrical communication between endothelial cells and smooth muscle cells in the mesenteric vascular bed. Furthermore, the relative incidence of these sites suggests that there may be a relationship between the activity of EDHF and the presence of myoendothelial gap junctions.
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              Role of interstitial cells and gap junctions in the transmission of spontaneous Ca2+ signals in detrusor smooth muscles of the guinea-pig urinary bladder.

              To investigate mechanisms underlying the transmission of spontaneous Ca2+ signals in the bladder, changes in intracellular concentrations of Ca2+ ([Ca2+]i) were visualized in isolated detrusor smooth muscle bundles of the guinea-pig urinary bladder loaded with a fluorescent Ca2+ indicator, fura-PE3 or fluo-4. Spontaneous increases in [Ca2+]i (Ca2+ transients) preferentially originated along the boundary of muscle bundles and then spread to the other boundary (Ca2+ waves). The synchronicity of Ca2+ waves across the bundles was disrupted by 18beta-glycyrrhetinic acid (18beta-GA, 40 microm), carbenoxolone (30 microm) or 2-aminoethoxydiphenylborate (2-APB, 50-100 microm), while CPA (10 microm), ryanodine (100 microm), xestospongin C (3 microm) and U-73122 (10 microm) had no effect. Intracellular recordings using two independent microelectrodes demonstrated that 2-APB (100 microm) blocked electrical coupling between detrusor smooth muscle cells. Nifedipine (10 microm) but not nominal Ca2+-free solution diminished the synchronicity of Ca2+ waves before preventing their generation. Staining for c-kit identified interstitial cells (IC) located along both boundaries of muscle bundles. IC were also scattered amongst smooth muscle cells and were more dominantly distributed in connective tissue between muscle bundles. IC generated nifedipine-resistant spontaneous Ca2+ transients, which occurred independently of those of smooth muscles. In conclusion, the propagation of Ca2+ transients in the bladder appears to be exclusively mediated by the spread of action potentials through gap junctions being facilitated by the regenerative nature of L-type Ca2+ channels, without significant contribution of intracellular Ca2+ stores. IC in the bladder may modulate the transmission of Ca2+ transients originating from smooth muscle cells rather than being the pacemaker of spontaneous activity.

                Author and article information

                Cell Calcium
                Cell Calcium
                Cell Calcium
                1 November 2018
                November 2018
                : 75
                : 21-29
                [a ]Department of Cellular and Molecular Physiology and Gastroenterology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK
                [b ]Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
                Author notes
                [* ]Corresponding author. Present address: Department of Cellular and molecular Physiology and Gastroenterology, Institute of Translational Medicine, University of Liverpool, Crown street, Liverpool, L69 3BX, UK. burdyga@
                © 2018 The Authors

                This is an open access article under the CC BY license (



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