Mechanisms of nitric oxide generation from nitroglycerin and endogenous sources during hypoxia <i>in vivo</i>

Agvald, Per; Adding, Christofer; Artlich, A.; Persson, Mats A. A.; Gustafsson, Lars E.

doi:10.1038/sj.bjp.0704489

Cited by 50 publications

(48 citation statements)

References 48 publications

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“…These results suggest that hypoxic enhancement of Ca 2ϩ sensitivity in IPA was due to hypoxic inhibition of NO production or activity in smooth muscle. Consistent with this possibility, all three NOS isoforms (neuronal, inducible, and endothelial) have been detected in PASMC (12, 17, 49, 67, 71, 76, 78 -80), and hypoxic inhibition of NO production or its transduction pathways has been reported in isolated pulmonary arteries (19,28,55,63) and isolated (1,7,9,11,20,24,29,44) and intact (1,13,60) lungs.…”

Section: Discussionsupporting

confidence: 52%

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

Weigand

Shimoda

Sylvester

2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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(37,40,48,51,52,54,56,62,72,77,82). The increased [Ca 2ϩ ] i leads in turn to calmodulin-dependent activation of myosin light chain (MLC) kinase (MLCK), MLCK-dependent phosphorylation of the 20-kDa regulatory MLC (P-MLC 20 ), P-MLC 20 -dependent activation of the actin-myosin interaction, and PASMC contraction (38,42,74,75,83 ] i during the slowly developing phase 2 contraction (52). Endothelial denudation did not alter the [Ca 2ϩ ] i response to hypoxia but abolished phase 2 contraction (51). These results suggest that phase 2 contraction resulted from an increase in PASMC Ca 2ϩ sensitivity and that this sensitization was due to release of factors from endothelial cells, rather than direct effects of hypoxia on smooth muscle. The identities of these factors remain unknown; however, antagonists of endothelin-1 (ET-1) had no effect on phase 2 HPV in endothelium-intact IPA, suggesting that ET-1 played no role (51). Although the nitric oxide/guanylate cyclase/protein kinase G (NO/GC/PKG) transduction pathway can alter Ca 2ϩ sensitivity in pulmonary arteries (27, 57), its effect on Ca 2ϩ sensitivity during acute hypoxia has not been examined.Consistent with endothelium dependence, hypoxia did not change steady-state isometric force achieved during normoxia at [Ca 2ϩ ] i ϭ 3-1,000 nM in endothelium-denuded rat extrapulmonary arteries permeabilized with ␤-escin and exposed to phorbol-12,13-dibutyrate, a protein kinase C activator, at 30°C (58); however, an effect of hypoxia may have been precluded in these experiments by use of proximal pulmonary arteries, which have weak contractile responses to hypoxia (39,40,61,65); phorbol-12,13-dibutyrate, which enhances Ca 2ϩ sensitivity on its own (30, 59); and low temperature, which inhibits HPV (4,21,36). Hypoxia also did not alter the relation between increases in [Ca 2ϩ ] i and decreases in cell length induced by the Ca 2ϩ ionophore 4-bromo-A-23187 in freshly isolated porcine distal PASMC at 37°C (62); however, since these cells were variably attached to glass coverslips, uneven loading among cells and the absence of isotonic conditions may have obscured possible effects of hypoxia.Many stimuli increase myofilament Ca 2ϩ sensitivity by decreasing activity of MLC phosphatase (MLCP), the enzyme responsible for dephosphorylation and inactivation of P-MLC 20 . Decreased MLCP activity leads to [Ca 2ϩ ] i -independent increases in P-MLC 20 concentration ([P-MLC 20 ]), actin-myosin interaction, and contraction (66), and can be achieved by upregulation of signals causing MLCP inhibition, such as those generated by Rho kinase (31, 66), or downregulation of signals causing MLCP activation, such as those generated by NO/GC/PKG (35,66). Among these possibilities, Rho kinase has been the most studied in PASMC during hypoxia.

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Section: Discussionsupporting

confidence: 52%

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

Weigand

Shimoda

Sylvester

2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Our in vitro studies showed that incubation in the presence of GTN increased the sensitivity to doxorubicin and paclitaxel in cells exposed to hypoxia but not in cells at 20% O 2 . It has been reported that the biotransformation of GTN is increased under hypoxic conditions (19,41). Therefore, GTN may represent an important and useful agent for selectively targeting the more malignant hypoxic cells.…”

Section: Discussionmentioning

confidence: 99%

Chemosensitization of Cancer In vitro and In vivo by Nitric Oxide Signaling

Frederiksen¹,

Sullivan²,

Maxwell³

et al. 2007

Clinical Cancer Research

123

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Purpose: Hypoxia contributes to drug resistance in solid cancers, and studies have revealed that low concentrations of nitric oxide (NO) mimetics attenuate hypoxia-induced drug resistance in tumor cells in vitro. Classic NO signaling involves activation of soluble guanylyl cyclase, generation of cyclic GMP (cGMP), and activation of cGMP-dependent protein kinase. Here, we determined whether chemosensitization by NO mimetics requires cGMP-dependent signaling and whether low concentrations of NO mimetics can chemosensitize tumors in vivo. Experimental Design: Survival of human prostate and breast cancer cells was assessed by clonogenic assays following exposure to chemotherapeutic agents. The effect of NO mimetics on tumor chemosensitivity in vivo was determined using a mouse xenograft model of human prostate cancer. Drug efflux in vitro was assessed by measuring intracellular doxorubicin-associated fluorescence. Results: Low concentrations of the NO mimetics glyceryl trinitrate (GTN) and isosorbide dinitrate attenuated hypoxia-induced resistance to doxorubicin and paclitaxel. Similar to hypoxiainduced drug resistance, inhibition of various components of the NO signaling pathway increased resistance to doxorubicin, whereas activation of the pathway with 8-bromo-cGMP attenuated hypoxia-induced resistance. Drug efflux was unaffected by hypoxia and inhibitors of drug efflux did not significantly attenuate hypoxia-induced chemoresistance. Compared with mice treated with doxorubicin alone, tumor growth was decreased in mice treated with doxorubicin and a transdermal GTN patch. The presence of GTN and GTN metabolites in plasma samples was confirmed by gas chromatography. Conclusion: Tumor hypoxia induces resistance to anticancer drugs by interfering with endogenous NO signaling and reactivation of NO signaling represents a novel approach to enhance chemotherapy.

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“…1,2 This idea is based on reports, both in vitro and in vivo, [3][4][5][6][7] that suggest that exposure to GTN leads to the formation of NO. However, in most of these studies, NO was observed only when GTN concentrations considerably exceeded the plasma levels reached during clinical dosing, whereas a number of further reports question the direct formation of NO.…”

mentioning

confidence: 99%

Discrepancies Between Nitroglycerin and NO-Releasing Drugs on Mitochondrial Oxygen Consumption, Vasoactivity, and the Release of NO

Núñez

Víctor

Tur

et al. 2005

Circulation Research

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Abstract-It has been generally acknowledged that the actions of glyceryl trinitrate (GTN) are a result of its bioconversion into NO. However, recent observations have thrown this idea into doubt, with many studies demonstrating that NO is present only when there are high concentrations of GTN. We have explored this discrepancy by developing a new approach that uses confocal microscopy to directly detect NO. Intracellular levels of NO in the rat aortic vascular wall have been compared with those present after incubation with 3 different NO donors (DETA-NO, 3-morpholinosydnonimine, and S-nitroso-N-acetylpenicillamine), endothelial activation with acetylcholine, or administration of GTN. We have also evaluated the relaxant effects of these treatments on isolated rings of aorta following activation of the enzyme soluble guanylyl cyclase and their inhibitory action on mitochondrial respiration, which is an index of the interaction of NO with the enzyme of the electron transport chain cytochrome C oxidase. In the case of the various NO donors and acetylcholine, we detected a concentration-dependent relationship in the intensity of vascular relaxation and degree of NO fluorescence and an increase in the

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Mechanisms of nitric oxide generation from nitroglycerin and endogenous sources during hypoxia in vivo

Cited by 50 publications

References 48 publications

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

Enhancement of myofilament calcium sensitivity by acute hypoxia in rat distal pulmonary arteries

Chemosensitization of Cancer In vitro and In vivo by Nitric Oxide Signaling

Discrepancies Between Nitroglycerin and NO-Releasing Drugs on Mitochondrial Oxygen Consumption, Vasoactivity, and the Release of NO

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