Levcromakalim

LevCromakalim is an ATP-sensitive K+ channel (KATP) activator.

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

Research Areas >> Cardiovascular Disease

K+ channel[1]

LevCromakalim (Cromakalim) inhibits spontaneous contractions completely in a glibenclamide-sensitive manner. LevCromakalim (5 µM) inhibits spontaneous contractions, which are recovered by glibenclamide. LevCromakalim (1, 5 and 10 µM) inhibits phasic contractions to 34±21.1%, 20.1±20.0% and 0% of the control (n=5, respectively; P<0.05). Glibenclamide reverses the inhibition of spontaneous isometric contractions caused by LevCromakalim (5 µM) to 84±1.5% of the control (n=5; P<0.05). LevCromakalim (20 and 100 µM) also inhibits oxytocin (OXT) (10 nM)-induced phasic contractions to 34±21.4% and 14±12.6% of the control (n=6 and 4, respectively; P<0.05). Glibenclamide reverses the inhibition of spontaneous isometric contractions by LevCromakalim (100 µM) to 79±3.5% of the control (n=4; P<0.05). Tonic contraction by OXT is also suppressed by Cromakalim in a glibenclamide-sensitive manner[2].The function of the KATP channels is examined with the specific channel opener LevCromakalim (Cromakalim). LevCromakalim induces dose-dependent relaxation in both the young and old mesenteric artery (MAs); and there is no difference in relaxation with age. However, the relaxation is markedly reduced in response to the high-salt (HS) diet in the old MAs (P<0.05). Maximum dilations to LevCromakalim (10-4 M) are 97 ± 3% in the young MAs versus 98 ± 1% in the young salt arteries, while dilations are 99±0.7% in the old MAs when compared with 85 ± 5% in the old salt arteries (P<0.05)[3].

LevCromakalim (Cromakalim) is dissolved in 10% DMSO and Krebs solution[3]. The endothelium-dependent relaxation is tested by performing concentration-response experiments with acetylcholine (ACh; 10 nM-10 μM). Typically, MAs are exposed to each dose of ACh for at least 6 minutes and maximal responses are determined. Function of the KATP channels are examined with 10 µM of glibenclamide (a selective KATP channel inhibitor) and LevCromakalim (Cromakalim) (10 nM to 100 μM), a KATP channel opener. The addition of glibenclamide to the arterial bath 10 minutes prior to ACh does not alter passive maximum internal diameters of any MAs in our groups.The vessel diameter changes are presented as percentages (%) of dilation of the preconstricted vessels, calculated[3].

[1]. Matsumoto T, et al. Tunicamycin-Induced Alterations in the Vasorelaxant Response in Organ-Cultured Superior Mesenteric Arteries of Rats. Biol Pharm Bull. 2016;39(9):1475-81.

[2]. Hong SH, et al. Regulation of myometrial contraction by ATP-sensitive potassium (KATP) channel via activation of SUR2B and Kir 6.2 in mouse. J Vet Med Sci. 2016 Aug 1;78(7):1153-9.

[3]. Whidden MA, Altered potassium ATP channel signaling in mesenteric arteries of old high salt-fed rats. J Exerc Nutrition Biochem. 2016 Jun;20(2):58-64.

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MOLECULAR FORMULA :

C16-H18-N2-O3

MOLECULAR WEIGHT :

286.36

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>2500 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Behavioral - ataxia Lungs, Thorax, or Respiration - dyspnea

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 22(Suppl 7),S1425,1994

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>4 mg/kg

TOXIC EFFECTS :

Lungs, Thorax, or Respiration - respiratory stimulation

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 22(Suppl 7),S1425,1994

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>750 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Lungs, Thorax, or Respiration - respiratory depression Nutritional and Gross Metabolic - body temperature decrease

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 22(Suppl 7),S1425,1994

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

>4 mg/kg

TOXIC EFFECTS :

Behavioral - convulsions or effect on seizure threshold Behavioral - coma Lungs, Thorax, or Respiration - respiratory stimulation

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 22(Suppl 7),S1425,1994 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

273 mg/kg/13W-C

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - changes in circulation Liver - changes in liver weight Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol)

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 22(Suppl 7),S1425,1994

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

110 mg/kg/52W-C

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - changes in circulation Cardiac - changes in heart weight Related to Chronic Data - changes in ovarian weight

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 22(Suppl 7),S1425,1994

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

18 mg/kg/13W-I

TOXIC EFFECTS :

Endocrine - changes in adrenal weight Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 22(Suppl 7),S1425,1994

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

37 mg/kg/52W-I

TOXIC EFFECTS :

Endocrine - changes in adrenal weight

REFERENCE :

YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 22(Suppl 7),S1425,1994