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      Endothelin-1-Mediated Wave-Like [Ca 2+] i Oscillations in Intact Rabbit Inferior Vena Cava

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          Endothelin-1 (ET1) is an endogenous vasoconstrictor released by the vascular system to regulate the contractility of vascular smooth muscle cells (VSMC). It is implicated in the pathogenesis of hypertension and diabetic vasculopathy. In rabbit inferior vena cava (IVC), 10 n M ET1 induces tonic contraction mainly via type A endothelin receptor activation. Using confocal imaging of Fluo-3 loaded in thein situ VSMC within the intact IVC, we found that ET1 elicited [Ca<sup>2+</sup>]<sub>i</sub> oscillations with an average frequency of 0.31 ± 0.01 Hz. These [Ca<sup>2+</sup>]<sub>i</sub> oscillations occurred as repetitive Ca<sup>2+</sup> waves traveling along the longitudinal axis of the cells with an average velocity of 29 ± 3 µm/s. The Ca<sup>2+</sup> waves were not synchronized between neighboring VSMC nor were they propagated between them. Nifedipine (10 µ M) inhibited the tonic contraction by 27.0 ± 5.0% while SKF96365 (50 µ M) abolished the remaining contraction. In a parallel Ca<sup>2+</sup> study, nifedipine reduced the frequency of the oscillations to 0.22 ± 0.01 Hz while SKF96365 abolished the remaining [Ca<sup>2+</sup>]<sub>i</sub> oscillations. Subsequent application of 25 m M caffeine elicited no further Ca<sup>2+</sup> signal. Thus, we conclude that ET1 stimulates tonic contraction in the rabbit IVC by inducing [Ca<sup>2+</sup>]<sub>i</sub> oscillations and that stimulated Ca<sup>2+</sup> entry through both the L-type voltage-gated Ca<sup>2+</sup> channels and a nifedipine-resistant and SKF96365-sensitive pathway is crucial for the maintenance of [Ca<sup>2+</sup>]<sub>i</sub> oscillations and tonic contraction.

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          Most cited references 24

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          A novel potent vasoconstrictor peptide produced by vascular endothelial cells.

          An endothelium-derived 21-residue vasoconstrictor peptide, endothelin, has been isolated, and shown to be one of the most potent vasoconstrictors known. Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelin is an endogenous modulator of voltage-dependent ion channels. Expression of the endothelin gene is regulated by several vasoactive agents, indicating the existence of a novel cardiovascular control system.
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            Vascular endothelin in hypertension.

            Endothelins are powerful vasoconstrictor peptides that also play numerous other functions in many different organs. Endothelin-1 (ET-1) is the most abundant and important of this family of peptides in blood vessels. Production of ET-1 is increased in the endothelium and the kidney in salt-dependent models of hypertension (e.g.: DOCA-salt rats and Dahl salt-sensitive rats, in salt-loaded SHR-SP, in angiotensin II-infused and in diabetic rats). ET-1 elicits an inflammatory response by increasing oxidant stress in the vascular wall, which induces vascular remodeling and endothelial dysfunction found in the hypertensive models that exhibit an endothelin-mediated component. Endothelin receptor antagonism reduces blood pressure and vascular hypertrophic remodeling present in these hypertensive models. Patients with stage 2 hypertension have enhanced vascular expression of ET-1. Endothelin receptor antagonists lower blood pressure in hypertensive patients. They could become therapeutic agents for prevention of target organ damage in hypertension and in type 2 diabetes, chronic renal failure and congestive heart failure. Side effects of endothelin receptor blockers have prevented up to the present their development for these indications. New endothelin antagonists devoid of these side effects, or alternatively inhibitors of the endothelin converting enzymes that generate ET-1 may in the future become available to block the endothelin system. However, to date endothelin antagonists have been approved only for the treatment of primary pulmonary hypertension, a rapidly fatal condition in which the endothelin system plays an important role and endothelin antagonists exert favorable effects.
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              Acetylcholine-induced Calcium Signaling and Contraction of Airway Smooth Muscle Cells in Lung Slices

              The Ca2+ signaling and contractility of airway smooth muscle cells (SMCs) were investigated with confocal microscopy in murine lung slices (∼75-μm thick) that maintained the in situ organization of the airways and the contractility of the SMCs for at least 5 d. 10–500 nM acetylcholine (ACH) induced a contraction of the airway lumen and a transient increase in [Ca2+]i in individual SMCs that subsequently declined to initiate multiple intracellular Ca2+ oscillations. These Ca2+ oscillations spread as Ca2+ waves through the SMCs at ∼48 μm/s. The magnitude of the airway contraction, the initial Ca2+ transient, and the frequency of the subsequent Ca2+ oscillations were all concentration-dependent. In a Ca2+-free solution, ACH induced a similar Ca2+ response, except that the Ca2+ oscillations ceased after 1–1.5 min. Incubation with thapsigargin, xestospongin, or ryanodine inhibited the ACH-induced Ca2+ signaling. A comparison of airway contraction with the ACH-induced Ca2+ response of the SMCs revealed that the onset of airway contraction correlated with the initial Ca2+ transient, and that sustained airway contraction correlated with the occurrence of the Ca2+ oscillations. Buffering intracellular Ca2+ with BAPTA prohibited Ca2+ signaling and airway contraction, indicating a Ca2+-dependent pathway. Cessation of the Ca2+ oscillations, induced by ACH-esterase, halothane, or the absence of extracellular Ca2+ resulted in a relaxation of the airway. The concentration dependence of the airway contraction matched the concentration dependence of the increased frequency of the Ca2+ oscillations. These results indicate that Ca2+ oscillations, induced by ACH in murine bronchial SMCs, are generated by Ca2+ release from the SR involving IP3- and ryanodine receptors, and are required to maintain airway contraction.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 2007
                27 July 2007
                : 44
                : 6
                : 495-503
                The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, B.C., Canada
                106553 J Vasc Res 2007;44:495–503
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 42, Pages: 9
                Research Paper


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