Effect of celecoxib on cyclooxygenase-1-mediated prostacyclin synthesis and endothelium-dependent contraction in mouse arteries

Liu, Bin; Luo, Wei; Zhang, Yingzhan; Li, Hui; Zhu, Ningxia; Huang, Dongyang; Zhou, Yingbi

doi:10.1016/j.ejphar.2012.10.040

Cited by 10 publications

(14 citation statements)

References 41 publications

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“…It should be noted that the vasoconstrictor role of COX-2 in previous reports might be exaggerated. This is because that some of the COX-2 inhibitors used in previous studies can also inhibit COX-1-mediated endothelium-dependent contraction (22,29). In addition, our results show that PGIS expression and 6-keto-PGF 1␣ production evoked by AA or ACh are unaltered in diabetic aortas, which excludes that the decreased PGIS activity, which has been proposed to reverse the dilator activity of AA metabolism into contraction (33,54,55), is a major cause of endothelium-derived vasoconstrictor activity in diabetic mouse arteries.…”

Section: Discussionmentioning

confidence: 99%

“…The PGI2 metabolite 6-keto-PGF1␣ (with a molecular mass of 370) was determined by HPLC-mass spectroscopy (HPLC-MS), with which signals of other COX-related products [PGE2 and PGD2, molecular mass of 352; PGF2␣, molecular mass of 354; and the thromboxane A2 (TxA2) metabolite thromboxane B2, molecular mass of 370 with a longer retention time than 6-keto-PGF1␣] are separated from 6-keto-PGF1␣ and can be simultaneously monitored (23, 52) using a previously described protocol (22). Aortas were cut open and rinsed of blood components.…”

Section: Chemicals and Solutions Nmentioning

confidence: 99%

“…Aortic strips (two preweighed whole sections of the aorta for each single measurement) were incubated with PSS at 37°C for 30 min followed by exposures to PSS (1,000 l) or PSS containing ACh (10 M) or AA (10 M, 37°C) for 15 min each. The extraction of sample and standard solutions and HPLC-MS measurements were performed as previously described (22). The amount of 6-keto-PGF1␣ was calculated from the area of the signal against that of a standard curve and expressed as nanograms per milligram of wet tissue.…”

Section: Chemicals and Solutions Nmentioning

confidence: 99%

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Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

Zhu

Liu

Luo

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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. Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in noninsulin-dependent diabetic mice induced by high-fat diet and streptozotocin. Am J Physiol Heart Circ Physiol 307: H319 -H327, 2014. First published May 30, 2014 doi:10.1152/ajpheart.00022.2014.-This study tested the hypothesis that in diabetic arteries, cyclooxygenase (COX)-1 mediates endothelial prostacyclin (PGI2) synthesis, which evokes vasoconstrictor activity under the pathological condition. Non-insulin-dependent diabetes was induced to C57BL/6 mice and those with COX-1 deficiency (COX-1 Ϫ/Ϫ mice) using a high-fat diet in combination with streptozotocin injection. In vitro analyses were performed 3 mo after. Results showed that in diabetic aortas, the endothelial muscarinic receptor agonist ACh evoked an endothelium-dependent production of the PGI2 metabolite 6-keto-PGF1␣, which was abolished in COX-1 Ϫ/Ϫ mice. Meanwhile, COX-1 deficiency or COX-1 inhibition prevented vasoconstrictor activity in diabetic abdominal aortas, resulting in enhanced relaxation evoked by ACh. In a similar manner, COX-1 deficiency increased the relaxation evoked by ACh in nitric oxide synthase-inhibited diabetic renal arteries. Also, in diabetic abdominal aortas and/or renal arteries, both PGI2 and the COX substrate arachidonic acid evoked contractions similar to those of nondiabetic mice. However, the contraction to arachidonic acid, but not that to PGI2, was abolished in vessels from COX-1 Ϫ/Ϫ mice. Moreover, we found that 3 mo after streptozotocin injection, systemic blood pressure increased in diabetic C57BL/6 mice but not in diabetic COX-1 Ϫ/Ϫ mice. These results explicitly demonstrate that in the given arteries from non-insulin-dependent diabetic mice, COX-1 remains a major contributor to the endothelial PGI2 synthesis that evokes vasoconstrictor activity under the pathological condition. Also, our data suggest that COX-1 deficiency prevents or attenuates diabetic hypertension in mice, although this could be related to the loss of COX-1-mediated activities derived from both vascular and nonvascular tissues. diabetes; arachidonic acid; metabolism; thromboxane prostanoid receptors; contraction CYCLOOXYGENASE (COX

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Section: Discussionmentioning

confidence: 99%

Section: Chemicals and Solutions Nmentioning

confidence: 99%

Section: Chemicals and Solutions Nmentioning

confidence: 99%

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Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

Zhu

Liu

Luo

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…In addition, while mice are commonly used as models to study human diseases, such as hypertension, the exact role of PGI 2 synthesis in their renal arteries still remains to be clearly elucidated. Moreover, there is considerable inconsistency regarding the role of each of the two COX isoforms in regulating vasomotor reactions, including those of renal vasculature (6,8,12,17,27,29,34,35,37,38,40), possibly in part due to the use of isoform-selective COX inhibitors that might have effects independent of their intended targets (2,3,20,26).Therefore, the aim of this study was to determine whether PGI 2 evokes contraction in mouse renal arteries and, if so, how TP and/or IP receptors function in the vessel. In addition, experiments were performed to determine how the genetic deficiency of COX-1 (COX-1 Ϫ/Ϫ ) influences on the in vitro PGI 2 synthesis and/or vasomotor reaction.…”

mentioning

confidence: 99%

A vasoconstrictor role for cyclooxygenase-1-mediated prostacyclin synthesis in mouse renal arteries

Liu

Zhang

Zhu

et al. 2013

American Journal of Physiology-Renal Physiology

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This study was to determine whether prostacyclin [prostaglandin I 2 (PGI2)] evokes mouse renal vasoconstriction and, if so, the underlying mechanism(s) and how its synthesis via cyclooxygenase-1 (COX-1) influences local vasomotor reaction. Experiments were performed on vessels from C57BL/6 mice and/or those with COX-1 deficiency (COX-1 Ϫ/Ϫ ). Results showed that in renal arteries PGI2 evoked contraction more potently than in carotid arteries, where COX-1 is suggested to mediate prominent endothelium-dependent contraction. A similar result was observed with the thromboxane-prostanoid (TP) receptor agonist U46619. However, in renal arteries TP receptor antagonism, which inhibited the contraction, did not result in any relaxation in response to PGI2. Moreover, we noted that the endothelial muscarinic receptor agonist ACh evoked an increase in the production of the PGI2 metabolite 6-keto-PGF1␣, which was prevented by endothelial denudation or COX-1 Ϫ/Ϫ . Interestingly, COX-1 Ϫ/Ϫ was further found to abolish a force development that was sensitive to TP receptor antagonism and result in enhanced relaxation evoked by ACh following NO synthase inhibition. Also, in renal arteries the COX substrate arachidonic acid evoked a vasoconstrictor response, which was again abolished by COX-1 Ϫ/Ϫ . Meanwhile, nonselective COX inhibition did not show any effect in vessels from COX-1 Ϫ/Ϫ mice. Thus, in mouse renal arteries, high expression of TP receptors together with little functional involvement from the vasodilator PGI 2 receptors results in a potent vasoconstrictor effect evoked by PGI2. Also, our data imply that endogenous COX-1-mediated PGI2 synthesis leads to vasoconstrictor activity and this could be an integral part of endothelium-derived mechanisms in regulating local renal vascular function. arachidonic acid; TP receptors; contraction; IP receptors; vasodilation CYCLOOXYGENASE (COX), which exists in COX-1 and -2 isoforms, metabolizes arachidonic acid (AA) to produce various vasoactive prostanoids. Among them, prostacyclin [prostaglandin I 2 (PGI 2 )] is the major product generated in the endothelium, acting on the PGI 2 (IP) receptors on medial smooth muscle to mediate vasodilatation and protect vessels from the development of disease (4,25,33). Decreased production of endothelial PGI 2 synthesis has been suggested to cause increased incidence of cardiovascular events (8,12,40). On the other hand, studies also indicate that the endothelial COX-mediated metabolism generates vasoconstrictor products that act on thromboxane-prostanoid (TP) receptors to mediate vasoconstriction (9,14,16,28,30,32,43). Interestingly, PGI 2 can also activate smooth muscle TP receptors (11,21,22,36,38). This has been explained by an excessive production of PGI 2 and/or dysfunction of IP receptors found in conditions such as hypertension (11,36,38). Moreover, both TP and IP receptors may concomitantly modulate the vasomotor reaction to PGI 2 ; hence, in vessels with limited functional IP receptors the process of PGI 2 synthesis itself is suggeste...

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“…It lacks any platelet aggregation inhibitory activity as seen with some other COX inhibitors [119]. Clinical and research literature routinely call celecoxib “COX-2 selective” and this is relatively so but to our reading of the data celecoxib inhibits COX-1 to some degree [120-123 vide infra]. Shortly after clinical introduction to clinical practice in symptomatic treatment of pain, anti-cancer effects were noted both empirically and by theoretical reasoning [124].…”

Section: Introductionmentioning

confidence: 99%

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

Kast¹,

2014

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CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs- aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

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Effect of celecoxib on cyclooxygenase-1-mediated prostacyclin synthesis and endothelium-dependent contraction in mouse arteries

Cited by 10 publications

References 41 publications

Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

A vasoconstrictor role for cyclooxygenase-1-mediated prostacyclin synthesis in mouse renal arteries

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

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