diazoxide

Diazoxide is an ATP-sensitive potassium channel activator ; can be used to treat hyperinsulinism.

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> Membrane Transporter/Ion Channel >> Potassium Channel

Research Areas >> Cardiovascular Disease

Diazoxide has a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Diazoxide has powerful protective properties against cardiac ischemia[1].Diazoxide could protect NSC-34 neurons against the main sources of neurodegenerative damage. Diazoxide increases Nrf2 nuclear translocation in NSC-34 motoneurons and prevents endogenous oxidative damage[2].

Diazoxide attenuates postresuscitation brain injury, protects mitochondrial function, inhibits brain cell apoptosis, and activates the PKC pathway by opening mitoKATP channels[3]. Treatment with diazoxide in wild-type mice decreases intraocular pressure (IOP) by 21.5±3.2% with an absolute IOP reduction of 3.9 ± 0.6 mm Hg[4].

Diazoxide is dissolved in DMSO to prepare 50 mM stock solution. NSC-34 cells are allowed to differentiate for 8 weeks under reduced serum conditions and then seeded in 24-well plates. Glutamate is dissolved in culture medium and added to cultures at concentration of 10 μM for 24 h. Cell treatment with 100 µM diazoxide starts 2 h before glutamate exposure. Cell viability is measured by the MTT assay[2].

Rats: Adult male Sprague-Dawley rats with induced cerebral ischemia (n=10 per group) receive an intraperitoneal injection of 0.1% DMSO (1 mL; vehicle group), diazoxide (10 mg/kg; DZ group), or diazoxide (10 mg/kg) plus 5-hydroxydecanoate (5 mg/kg; DZ + 5-HD group) 30 min after CPR. The control group (sham group, n=5) undergoes sham operation, without cardiac arrest. Mitochondrial respiratory control rate (RCR) is determined. Brain cell apoptosis is assessed using TUNEL staining. Expression of Bcl-2, Bax, and protein kinase C epsilon (PKCε) in the cerebral cortex is determined by Western blotting and immunohistochemistry[3]. Mouse: Diazoxide is prepared by diluting a 100 mM stock solution in 10% polyethoxylated castor oil in PBS. In C57BL/6 wild-type and Kir6.2(−/−) mice, a 5 μL drop of 5 mM diazoxide is topically administered to one eye of each mouse while the fellow control eye received vehicle (DMSO and 10% polyethoxylated castor oil in the same proportion as the treated eye). IOP is measured daily at 1 hour, 4 hours, and 23 hours following treatment. Treatment with diazoxide and vehicle is continued daily for 14 consecutive days[4].

[1]. Coetzee WA, et al. Multiplicity of effectors of the cardioprotective agent, diazoxide. Pharmacol Ther. 2013 Nov;140(2):167-75.

[2]. Virgili N, et al. K(ATP) channel opener diazoxide prevents neurodegeneration: a new mechanism of action viaantioxidative pathway activation. PLoS One. 2013 Sep 11;8(9):e75189.

[3]. Wu H, et al. Diazoxide Attenuates Postresuscitation Brain Injury in a Rat Model of Asphyxial Cardiac Arrest by Opening Mitochondrial ATP-Sensitive Potassium Channels. Biomed Res Int. 2016;2016:1253842.

[4]. Chowdhury UR, et al. ATP-sensitive potassium (K(ATP)) channel openers diazoxide and nicorandil lower intraocular pressure in vivo. Invest Ophthalmol Vis Sci. 2013 Jul 22;54(7):4892-9.

Nigericin sodium salt | Senicapoc | E-4031 | 4-AMINOPYRIDINE | Ginsenoside Rg3 | TRAM-34 | Dofetilide | PAP-1 | Minoxidil | Flufenamic Acid | Flupirtine maleate | NS-1619 | Endoxifen (Z-isomer hydrochloride) | NS309 | Quinine

MOLECULAR FORMULA :

C8-H7-Cl-N2-O2-S

MOLECULAR WEIGHT :

230.68

WISWESSER LINE NOTATION :

T66 BSWM ENJ D1 IG

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

980 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

AIPTAK Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- Volume(issue)/page/year: 143,446,1963

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

510 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

AIPTAK Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- Volume(issue)/page/year: 143,446,1963

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

444 mg/kg

TOXIC EFFECTS :

Vascular - BP lowering not characterized in autonomic section

REFERENCE :

JPETAB Journal of Pharmacology and Experimental Therapeutics. (Williams & Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- Volume(issue)/page/year: 136,344,1962

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

326 mg/kg

TOXIC EFFECTS :

Vascular - BP lowering not characterized in autonomic section

REFERENCE :

JPETAB Journal of Pharmacology and Experimental Therapeutics. (Williams & Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- Volume(issue)/page/year: 136,344,1962

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

228 mg/kg

TOXIC EFFECTS :

Vascular - BP lowering not characterized in autonomic section

REFERENCE :

JPETAB Journal of Pharmacology and Experimental Therapeutics. (Williams & Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- Volume(issue)/page/year: 136,344,1962 ** REPRODUCTIVE DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

65 mg/kg

SEX/DURATION :

female 110-114 day(s) after conception

TOXIC EFFECTS :

Reproductive - Effects on Embryo or Fetus - other effects to embryo

REFERENCE :

JCNDBK Journal of Clinical Pharmacology and New Drugs. (Stamford, CT) V.11-13, 1971-73. For publisher information, see JCPCBR. Volume(issue)/page/year: 11,206,1971 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X7114 No. of Facilities: 63 (estimated) No. of Industries: 1 No. of Occupations: 3 No. of Employees: 612 (estimated) No. of Female Employees: 395 (estimated)