Time‐dependent changes in Ca2+ sensitivity during phasic contraction of canine antral smooth muscle.

Ozaki, Hiroshi; Gerthoffer, William T.; Publicover, Nelson G.; Fusetani, Nobuhiro; Sanders, Kenton M.

doi:10.1113/jphysiol.1991.sp018704

Cited by 42 publications

(20 citation statements)

References 43 publications

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“…CPI-17 and Myosin Light Chain Phosphorylation-The phosphorylation status of CPI-17 and myosin light chain (MLC) in PA was determined as described previously (24). Tissue samples were collected into acetone ϩ 10% trichloroacetic acid solution at the end of each treatment described under "Results."…”

Section: Methodsmentioning

confidence: 99%

Activation of Glucose-6-phosphate Dehydrogenase Promotes Acute Hypoxic Pulmonary Artery Contraction

Gupte¹,

Rawat²,

Chettimada³

et al. 2010

Journal of Biological Chemistry

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Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to a decrease in airway O 2 tension, but the underlying mechanism is incompletely understood. We studied the contribution of glucose-6-phosphate dehydrogenase (Glc-6-PD), an important regulator of NADPH redox and production of reactive oxygen species, to the development of HPV. We found that hypoxia (95% N 2 , 5% CO 2 ) increased contraction of bovine pulmonary artery (PA) precontracted with KCl or serotonin. Depletion of extracellular glucose reduced NADPH, NADH, and HPV, substantiating the idea that glucose metabolism and Glc-6-PD play roles in the response of PA to hypoxia. Our data also show that inhibition of glycolysis and mitochondrial respiration (indicated by an increase in NAD ؉ and decrease in the ATP-to-ADP ratio) by hypoxia, or by inhibitors of pyruvate dehydrogenase or electron transport chain complexes I or III, increased generation of reactive oxygen species, which in turn activated Glc-6-PD. Inhibition of Glc-6-PD decreased Ca 2؉ sensitivity to the myofilaments and diminished Ca 2؉ -independent and -dependent myosin light chain phosphorylation otherwise increased by hypoxia. Silencing Glc-6-PD expression in PA using a targeted small interfering RNA abolished HPV and decreased extracellular Ca 2؉ -dependent PA contraction increased by hypoxia. Similarly, Glc-6-PD expression and activity were significantly reduced in lungs from Glc-6-PD mut(؊/؊) mice, and there was a corresponding reduction in HPV. Finally, regression analysis relating Glc-6-PD activity and the NADPH-to-NADP ؉ ratio to the HPV response clearly indicated a positive linear relationship between Glc-6-PD activity and HPV. Based on these findings, we propose that Glc-6-PD and NADPH redox are crucially involved in the mechanism of HPV and, in turn, may play a key role in increasing pulmonary arterial pressure, which is involved in the development of pulmonary hypertension.Pulmonary hypertension (PH) 2 is a major cause of morbidity and mortality, the incidence of which is increasing around the world. The mechanisms underlying the development of PH remain unclear, however, and current medical treatment is inadequate. That said, it has been noted that in people living at high altitude and in patients suffering from chronic obstructive pulmonary disease, the chronic reduction in inhaled O 2 induces sustained hypoxic pulmonary vasoconstriction (HPV), which eventually leads to development of PH (1, 2). HPV is a phenomenon that balances the ventilation-to-respiration quotient by constricting the pulmonary artery (PA) and redirecting blood flow in the lungs in response to local reductions in inspired pO 2 (3). Since its discovery nearly a century ago, numerous studies have been conducted to identify the mechanisms responsible for HPV. To date, however, no unifying mechanism has been identified. In 1982, McMurtry et al. (4) proposed that inhibition of glycolysis and oxidative phosphorylation mimics HPV and suggested that inhibition of the mitochondrial electron transport chain...

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Section: Methodsmentioning

confidence: 99%

Activation of Glucose-6-phosphate Dehydrogenase Promotes Acute Hypoxic Pulmonary Artery Contraction

Gupte¹,

Rawat²,

Chettimada³

et al. 2010

Journal of Biological Chemistry

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“…Although these cells are driven by non-neuronal pacemakers to generate spontaneous electrical and mechanical activities, contractile strength and co-ordination between regions is regulated by transmitters released from enteric nerves, circulating hormones, and locally released paracrine substances (see Sanders & Smith, 1989 (Himpens, Matthjis & Somlyo, 1989;Ozaki et al 1991). Changes in the Ca2+-force relationship during contraction and relaxation are thought to be due to relatively rapid changes in the sensitivity of the contractile system to Ca2+ (Somlyo et al 1989; Karaki, 1990).…”

Section: Discussionmentioning

confidence: 99%

“…Muscle strips to be loaded with fura-2 were incubated in phosphate-free KRB solution containing 10 /M fura-2 acetoxymethyl ester (fura-2 AM) and 0-025% (v/v) (Konishi, Olson, Hollingworth & Baylor, 1988) and small oscillatory changes in R340/380 and muscle tension could still be observed after treatment with 20 /zM ionomycin for 20 min, as described by Ozaki, Gerthoffer, Publicover, Fusetani & Sanders (1991) ACh (1 /M) were measured before and after the fura-2 loading protocol (see above). The amplitudes of contractile responses were not significantly affected by the fura-2 loading procedure (data not shown), suggesting that the intracellular concentration of fura-2 necessary to resolve Ca2+ transients did not affect normal excitation-contraction coupling in these muscles.…”

Section: Methodsmentioning

confidence: 99%

Sensitization of the contractile system of canine colonic smooth muscle by agonists and phorbol ester.

Sato

Leposavic

Publicover

et al. 1994

The Journal of Physiology

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“…However, it is also well known that the relationship between the extent of the [Ca 2+ ] i elevation and the strength of the developed tension varies depending on the stimulus. 5,8,9 In general, receptor-mediated contractile stimuli produce more tension for a given elevation of [Ca 2+ ] i than membrane depolarization alone. [10][11][12][13] The Ca…”

Section: Introductionmentioning

confidence: 99%

Calcium Sensitization Mechanisms in Gastrointestinal Smooth Muscles

Perrino

2016

J Neurogastroenterol Motil

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An increase in intracellular Ca2+ is the primary trigger of contraction of gastrointestinal (GI) smooth muscles. However, increasing the Ca 2+ sensitivity of the myofilaments by elevating myosin light chain phosphorylation also plays an essential role. Inhibiting myosin light chain phosphatase activity with protein kinase C-potentiated phosphatase inhibitor protein-17 kDa (CPI-17) and myosin phosphatase targeting subunit 1 (MYPT1) phosphorylation is considered to be the primary mechanism underlying myofilament Ca 2+ sensitization. The relative importance of Ca 2+ sensitization mechanisms to the diverse patterns of GI motility is likely related to the varied functional roles of GI smooth muscles. Increases in CPI-17 and MYPT1 phosphorylation in response to agonist stimulation regulate myosin light chain phosphatase activity in phasic, tonic, and sphincteric GI smooth muscles. Recent evidence suggests that MYPT1 phosphorylation may also contribute to force generation by reorganization of the actin cytoskeleton. The mechanisms responsible for maintaining constitutive CPI-17 and MYPT1 phosphorylation in GI smooth muscles are still largely unknown. The characteristics of the cell-types comprising the neuroeffector junction lead to fundamental differences between the effects of exogenous agonists and endogenous neurotransmitters on Ca 2+ sensitization mechanisms. The contribution of various cell-types within the tunica muscularis to the motor responses of GI organs to neurotransmission must be considered when determining the mechanisms by which Ca 2+ sensitization pathways are activated. The signaling pathways regulating Ca 2+ sensitization may provide novel therapeutic strategies for controlling GI motility. This article will provide an overview of the current understanding of the biochemical basis for the regulation of Ca

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Time‐dependent changes in Ca2+ sensitivity during phasic contraction of canine antral smooth muscle.

Cited by 42 publications

References 43 publications

Activation of Glucose-6-phosphate Dehydrogenase Promotes Acute Hypoxic Pulmonary Artery Contraction

Activation of Glucose-6-phosphate Dehydrogenase Promotes Acute Hypoxic Pulmonary Artery Contraction

Sensitization of the contractile system of canine colonic smooth muscle by agonists and phorbol ester.

Calcium Sensitization Mechanisms in Gastrointestinal Smooth Muscles

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