(−)Doxazosin is a necessary component for the hypotensive effect of (±)doxazosin during long-term administration in conscious rats

Zhao, Jing; Kong, Dezhi; Li, Qing; Yaqin, Zhen; Wang, Miao; Zhao, Yan; Wang, Dong-kai; Ren, Lei-Ming

doi:10.1038/aps.2013.154

Cited by 6 publications

(3 citation statements)

References 22 publications

(27 reference statements)

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“…NA is a neurotransmitter released from sympathetic nerve endings that activate α 1 -adrenoceptors on the cell membrane of vascular smooth muscle to produce vasoconstriction, and activates β 2 -adrenoceptors to produce vasodilation. In in vitro experiments, both the neuronal uptake and the nonneuronal uptake of NA also significantly affected NA-induced vasoconstriction [16,[24][25][26] . Whether LE affected the neuronal uptake and nonneuronal uptake of NA is unknown, and the activation of α 2 -adrenoceptors and β 2 -adrenoceptors by NA was not ruled out in the study by Lee et al [23] .…”

Section: Discussionmentioning

confidence: 99%

Differential effects of short- and long-term bupivacaine treatment on α1-adrenoceptor-mediated contraction of isolated rat aorta rings and the reversal effect of lipid emulsion

Guo

Zhang

et al. 2015

Acta Pharmacol Sin

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Aim: Arterial function is significantly influenced by bupivacaine at both clinically relevant concentrations and toxic concentrations, but the underlying mechanisms are not fully understood. In the present study we investigated the role of α 1 -adrenoceptors in bupivacaine effects on isolated rat aortas. Methods: Isolated aortic rings were prepared from rats and suspended in an organ bath. Phenylephrine (Phe)-induced vasoconstriction and acetylcholine (ACh)-induced vasodilation were recorded through an isometric force transducer connected to a data acquisition system. Results: Administration of bupivacaine (30-300 μmol/L) produced mild vasoconstriction, and this response declined with repeated administrations. Treatment of the aortic rings with bupivacaine (3-30 μmol/L) for 20 min enhanced Phe-induced vasoconstriction, while treatment for 40 min suppressed Phe-induced vasoconstriction. Both the short-and long-term bupivacaine treatment suppressed ACh-induced vasodilation. Incubation of the aortic rings with 0.2%-0.6% lipid emulsion (LE) for 100 min significantly increased the pD 2 and E max values of Phe-induced vasoconstriction, and incubation with 0.4% LE for 100 min reversed the inhibition of bupivacaine on vasoconstriction induced by Phe (30 μmol/L). In contrast, incubation with LE suppressed ACh-induced vasodilation, even at a lower concentration and with a 5-min incubation. Conclusion: Bupivacaine exerts dual effects on α 1 -adrenoceptor-mediated vasoconstriction of isolated rat aortic rings: short-term treatment enhances the response, while long-term treatment inhibits it; the inhibition may be reversed via long-term incubation with LE.

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Section: Discussionmentioning

confidence: 99%

Differential effects of short- and long-term bupivacaine treatment on α1-adrenoceptor-mediated contraction of isolated rat aorta rings and the reversal effect of lipid emulsion

Guo

Zhang

et al. 2015

Acta Pharmacol Sin

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“…In healthy individuals, a single oral dose of 1 mg DOXA resulted in peak plasma concentrations of 7.6 ng/ml at 3.6 hours, while hypertensive patients achieved 76 ng/ml within 2-3 hours with an 8 mg dose [ 34 ]. A pharmacokinetic study in non-fasted rodents has reported that after a single oral administration of 8 mg/kg DOXA, the plasma concentration was at 200 ng/ml at 2 h [ 36 ]. Therefore, we estimate that when 5 mg/kg DOXA used in our in vivo experiments was orally administered to mice as a single dose, peak plasma concentrations could be achieved at approximately 125 to 187.5 ng/ml.…”

Section: Discussionmentioning

confidence: 99%

Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR

Kim,

Park,

Park

et al. 2023

J Exp Clin Cancer Res

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Background Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3rd-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC. Methods The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA. Results DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44high/CD24low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function. Conclusions Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.

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“…Forty rats were randomly divided into five experimental groups (n = 8 each) as follows: Group 1 (control), Group 2 (sham operated), Group 3 (IR injury only), Group 4 (rats received doxazosin, 8 mg/kg), Group 5 (rats received dapagliflozin 10 mg/kg) . Drugs were given by oral gavage for 3 successive days prior to IR injury and 2 hours before euthanasia.…”

Section: Methodsmentioning

confidence: 99%

Doxazosin down‐regulates sodium‐glucose cotransporter‐2 and exerts a renoprotective effect in rat models of acute renal injury

Rezq

Nasr

Shaheen

et al. 2019

Basic Clin Pharma Tox

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Sodium-glucose cotransporter-2 (SGLT2) is known to be involved in the progression of acute renal injury (ARI) and is regulated by different mediators in the kidneys including extracellular signal-regulated kinase (ERK), hypoxia-inducible factor 1 alpha (HIF1α) and prostaglandin E2 (PGE2). In the present study, we investigated the possible protective effect of doxazosin on renal ischaemia/reperfusion (IR) and glycerol-induced ARI by determining its effect on SGLT2 via modifying ERK-HIF1α pathway and/or PGE2. Rats were divided into control, sham or IR where the rats received the vehicle, doxazosin (8 mg/kg) or the SGLT2 inhibitor, dapagliflozin (10 mg/kg) for 3 days followed by 45 minutes bilateral renal ischaemia then 24 hours reperfusion. Another group of rats received the vehicle, doxazosin or dapagliflozin for three days followed by injection of 50% glycerol (8 mL/kg, IM) or saline. Kidney function tests, systolic blood pressure (SBP), oxidative stress markers (malondialdehyde [MDA] and NADPH oxidase), nitric oxide (NO), inducible nitric oxide synthase (iNOS), HIF1α, ERK phosphorylation and PGE2 levels were determined.Additionally, renal sections were used for immunological expression of SGLT2. ARI rats showed significantly increased SBP; worsened kidney function tests; increased oxidative stress, iNOS, NO, HIF1α levels; and decreased PGE2 and ERK phosphorylation along with up-regulated SGLT2. Doxazosin treatment protected against the kidney damage and attenuated the associated biochemical changes. Doxazosin has a direct renoprotective effect possibly by down-regulating SGLT2. K E Y W O R D Sacute renal injury, extracellular signal-regulated kinase, hypoxia-inducible factor 1, prostaglandin E2, sodium-glucose cotransporter 2 414 | REZQ Et al.

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(−)Doxazosin is a necessary component for the hypotensive effect of (±)doxazosin during long-term administration in conscious rats

Cited by 6 publications

References 22 publications

Differential effects of short- and long-term bupivacaine treatment on α1-adrenoceptor-mediated contraction of isolated rat aorta rings and the reversal effect of lipid emulsion

Differential effects of short- and long-term bupivacaine treatment on α1-adrenoceptor-mediated contraction of isolated rat aorta rings and the reversal effect of lipid emulsion

Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR

Doxazosin down‐regulates sodium‐glucose cotransporter‐2 and exerts a renoprotective effect in rat models of acute renal injury

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