The Effects of the Heat Shock Protein 90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin, Cannabinoid Agonist WIN 55,212-2, and Nitric Oxide Synthase Inhibitor Nω-Nitro-L-Arginine Methyl Ester Hydrochloride on the Serotonin and Dry Skin-Induced Itch

2021 ◽  
pp. 1-10
Author(s):  
Zeynep Gizem Todurga Seven ◽  
Fatma Kubra Tombulturk ◽  
Selim Gokdemir ◽  
Sibel Ozyazgan
Keyword(s):  
Nitric Oxide ◽  
Heat Shock ◽  
Methyl Ester ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Ester Hydrochloride ◽  
Methyl Ester Hydrochloride ◽  
Synthase Inhibitor ◽  
Cannabinoid Agonist ◽  
Antipruritic Effect

<b><i>Introduction:</i></b> In many types of itch, the interaction between immune system cells, keratinocytes, and sensory nerves involved in the transmission of itch is quite complex. Especially for patients with chronic itching, current treatments are insufficient, and their quality of life deteriorates significantly. <b><i>Objective:</i></b> In this study, we aimed to investigate the role of the heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), cannabinoid agonist WIN 55,212-2, and nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME) in pruritus. <b><i>Methods:</i></b> We created a serotonin (5-HT)-induced (50 μg/μL/mouse, i.d.) acute and acetone-ether-water (AEW)-induced chronic itching models. 17-AAG (1, 3, and 5 mg/kg, intraperitoneally [i.p.]), WIN 55,212-2 (1 mg/kg, i.p.), and L-NAME (1 mg/kg, i.p.) were applied to Balb/c mice. <b><i>Results:</i></b> We found that 17-AAG suppressed the scratches of mice, depending on the dose. The itch behavior was reduced by WIN 55,212-2, but L-NAME showed no antipruritic effect at the administered dose. The combined application of these agents in both pruritus models showed synergism in terms of the antipruritic effect. Our results showed that NO did not play a role in the antipruritic effect of WIN 55,212-2 and 17-AAG. Increased plasma IgE levels with AEW treatment decreased with the administration of 17-AAG (5 mg/kg, i.p.) and WIN 55,212-2. <b><i>Conclusion:</i></b> These results demonstrate that Hsp90 may play a role in the peripheral pathway of pruritus, and cannabinoid agonists and Hsp90 inhibitors can be used together in the treatment of pruritus.

Nitric oxide and β-adrenergic agonist-induced bronchial arterial vasodilation

1997 ◽  
Vol 82 (2) ◽  
pp. 686-692 ◽  
Author(s):  
Nirmal B. Charan ◽  
Shane R. Johnson ◽  
S. Lakshminarayan ◽  
William H. Thompson ◽  
Paula Carvalho
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Methyl Ester ◽  
No Synthase ◽  
Ester Hydrochloride ◽  
Methyl Ester Hydrochloride ◽  
Adrenergic Agonist ◽  
Flow Probe ◽  
Cyclic Monophosphate ◽  
Synthase Inhibitor

Charan, Nirmal B., Shane R. Johnson, S. Lakshminarayan, William H. Thompson, and Paula Carvalho. Nitric oxide and β-adrenergic agonist-induced bronchial arterial vasodilation. J. Appl. Physiol. 82(2): 686–692, 1997.—In anesthetized sheep, we measured bronchial blood flow (Q˙br) by an ultrasonic flow probe to investigate the interaction between inhaled nitric oxide (NO; 100 parts/million) given for 5 min and 5 ml of aerosolized isoetharine (1.49 × 10−2 M concentration). NO and isoetharine increased Q˙br from 26.5 ± 6.5 to 39.1 (SE) ± 10.6 and 39.7 ± 10.7 ml/min, respectively ( n = 5). Administration of NO immediately after isoetharine further increasedQ˙br to 57.3 ± 15.1 ml/min. NO synthase inhibitor N ω-nitro-l-arginine methyl ester hydrochloride (l-NAME; 30 mg/kg, in 20 ml saline given iv) decreased Q˙br to 14.6 ± 2.6 ml/min. NO given three times alternately with isoetharine progressively increased Q˙br from 14.6 ± 2.6 to 74.3 ± 17.0 ml/min, suggesting that NO and isoetharine potentiate vasodilator effects of each other. In three other sheep, afterl-NAME, three sequential doses of isoetharine increased Q˙br from 10.2 ± 3.4 to 11.5 ± 5.7, 11.7 ± 4.7, and 13.3 ± 5.7 ml/min, respectively, indicating that effects of isoetharine are predominantly mediated through synthesis of NO. When this was followed by three sequential administrations of NO, Q˙br increased by 146, 172, and 185%, respectively. Thus in the bronchial circulation there seems to be a close interaction between adenosine 3′,5′-cyclic monophosphate- and guanosine 3′,5′-cyclic monophosphate-mediated vasodilatation.

Nitric oxide preconditioning regulates endothelial monolayer integrity via the heat shock protein 90-soluble guanylate cyclase pathway

2007 ◽  
Vol 292 (2) ◽  
pp. H893-H903 ◽  
Author(s):  
Galina N. Antonova ◽  
Connie M. Snead ◽  
Alexander S. Antonov ◽  
Christiana Dimitropoulou ◽  
Richard C. Venema ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Cell Injury ◽  
Soluble Guanylate Cyclase ◽  
Heat Shock Protein 90 ◽  
Protective Effects ◽  
No Donor ◽  
Spermine Nonoate

Large (pathological) amounts of nitric oxide (NO) induce cell injury, whereas low (physiological) NO concentrations often ameliorate cell injury. We tested the hypotheses that pretreatment of endothelial cells with low concentrations of NO (preconditioning) would prevent injury induced by high NO concentrations. Apoptosis, induced in bovine aortic endothelial cells (BAECs) by exposing them to either 4 mM sodium nitroprusside (SNP) or 0.5 mM N-(2-aminoethyl)- N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) for 8 h, was abolished by 24-h pretreatment with either 100 μM SNP, 10 μM spermine NONOate, or 100 μM 8-bromo-cGMP (8-Br-cGMP). Repair of BAECs following wounding, measured as the recovery rate of transendothelial electrical resistance, was delayed by 8-h exposure to 4 mM SNP, and this delay was significantly attenuated by 24-h pretreatment with 100 μM SNP. NO preconditioning produced increased association and expression of soluble guanyl cyclase (sGC) and heat shock protein 90 (HSP90). The protective effect of NO preconditioning, but not the injurious effect of 4 mM SNP, was abolished by either a sGC activity inhibitor 1H-[1,2,4]oxadiazolo-[4,3- a]quinoxalin-1-one (ODQ) or a HSP90 binding inhibitor (radicicol) and was mimicked by 8-Br-cGMP. We conclude that preconditioning with a low dose of NO donor accelerates repair and maintains endothelial integrity via a mechanism that includes the HSP90/sGC pathway. HSP90/sGC may thus play a role in the protective effects of NO-generating drugs from injurious stimuli.

scholarly journals Heat Shock Protein 90 Mediates the Balance of Nitric Oxide and Superoxide Anion from Endothelial Nitric-oxide Synthase

2001 ◽  
Vol 276 (21) ◽  
pp. 17621-17624 ◽  
Author(s):  
Kirkwood A. Pritchard ◽  
Allan W. Ackerman ◽  
Eric R. Gross ◽  
David W. Stepp ◽  
Yang Shi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heat Shock ◽  
Nitric Oxide Synthase ◽  
Heat Shock Protein ◽  
Endothelial Nitric Oxide Synthase ◽  
Superoxide Anion ◽  
Heat Shock Protein 90 ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Role of heat shock protein 90 in bradykinin-stimulated endothelial nitric oxide release

2000 ◽  
Vol 35 (3) ◽  
pp. 165-170 ◽  
Author(s):  
M.Brennan Harris ◽  
Hong Ju ◽  
Virginia J. Venema ◽  
Michele Blackstone ◽  
Richard C. Venema
Keyword(s):  
Nitric Oxide ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 90 ◽  
Nitric Oxide Release ◽  
Endothelial Nitric Oxide

Heat shock protein 90 modulates endothelial nitric oxide synthase activity and vascular reactivity in the newborn piglet pulmonary circulation

2007 ◽  
Vol 292 (6) ◽  
pp. L1515-L1525 ◽  
Author(s):  
Judy L. Aschner ◽  
Susan L. Foster ◽  
Mark Kaplowitz ◽  
Yongmei Zhang ◽  
Heng Zeng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Heat Shock ◽  
Nitric Oxide Synthase ◽  
Heat Shock Protein ◽  
Pulmonary Circulation ◽  
Endothelial Nitric Oxide Synthase ◽  
Vascular Reactivity ◽  
Heat Shock Protein 90 ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Heat shock protein 90 (Hsp90) binding to endothelial nitric oxide synthase (eNOS) is an important step in eNOS activation. The conformational state of bound Hsp90 determines whether eNOS produces nitric oxide (NO) or superoxide (O2•−). We determined the effects of the Hsp90 antagonists geldanamycin (GA) and radicicol (RA) on basal and ACh-stimulated changes in vessel diameter, cGMP production, and Hsp90:eNOS coimmunoprecipitation in piglet resistance level pulmonary arteries (PRA). In perfused piglet lungs, we evaluated the effects of GA and RA on ACh-stimulated changes in pulmonary arterial pressure (Ppa) and perfusate accumulation of stable NO metabolites (NOx−). The effects of GA and RA on ACh-stimulated O2•− generation was investigated in cultured pulmonary microvascular endothelial cells (PMVEC) by dihydroethidine (DHE) oxidation and confocal microscopy. Hsp90 inhibition with GA or RA reduced ACh-mediated dilation, abolished the ACh-stimulated increase in cGMP, and reduced eNOS:Hsp90 coprecipitation. GA and RA also inhibited the ACh-mediated changes in Ppa and NOx− accumulation rates in perfused lungs. ACh increased the rate of DHE oxidation in PMVEC pretreated with GA and RA but not in untreated cells. The cell-permeable superoxide dismutase mimetic M40401 reversed GA-mediated inhibition of ACh-induced dilation in PRA. We conclude that Hsp90 is a modulator of eNOS activity and vascular reactivity in the newborn piglet pulmonary circulation. Uncoupling of eNOS with GA or RA inhibits ACh-mediated dilation by a mechanism that involves O2•− generation.

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