Milrinone

Milrinone is a PDE3 inhibitor, and also an inotrope and vasodilator.

Signaling Pathways >> Metabolic Enzyme/Protease >> Phosphodiesterase (PDE)

Research Areas >> Cardiovascular Disease

Milrinone (1 µM) increases PKA activity in hypoxic myocytes to normoxic levels. Milrinone (50 nM) normalizes TP receptor sensitivity in hypoxic myocytes by restoring PKA-mediated regulatory TP receptor phosphorylation[1]. Milrinone significantly reduces NE-induced vasoconstriction, attenuating both NE sensitivity and maximal tension generation. Inhibition of ATP-sensitive K+ channels or voltage-gated K+ channels do not prevent the milrinone-induced attenuation of NE responses[4].

Milrinone (1 μg/kg/min, i.v.) significantly reduces PAP, PVR (−18.96 ± 1.7%), and LAP (−26.03 ± 2.3%) in congestive heart failure (CHF) rats. Milrinone (1 mg/mL, inhalation) results in a near-maximal reduction of PAP without significant effects on AP, decreases pulmonary artery pressure similarly in a larger collective of CHF rats. Milrinone inhalation selectively increases cAMP but not cGMP plasma concentrations in both groups. Repeated milrinone inhalations even reduce lung wet/dry weight ratio[2]. Milrinone (49.5 μg) largely shifts the ESPVR upwards and significantly increases end-systolic pressure (ESP(0.08)) and the systolic pressure-volume area (PVA(0.08)) at a mid-range LV volume (0.08 mL/g myocardium). Milrinone also slightly decreases LV ESP(ESV) and decreased Ea[3].

In juvenile rats of 100 ± 8 g body weight (bw), CHF is induced by supracoronary aortic banding. In brief, rats are anesthetized by intraperitoneal injection of ketamine (87 mg/kg bw) and xylazine (13 mg/kg bw). Rats are placed in the supine position, the chest wall is shaved, and a left thoracotomy is performed in the third intercostal space during ventilation with 100% O2. The ascending aorta is freed from connective tissue and partially occluded by implantation of a titanium clip with a defined internal diameter of 0.8 mm. After surgical closure of the thorax, the rats are allowed to recover from anesthesia. For postoperative analgesia, rats receive 250 mg/kg bw of metamizole intramuscularly immediately after the operation and on the first postoperative day. Sham-operated rats serve as controls. After recovery from anesthesia, the animals are placed in cages with free access to water and standard laboratory diet. For inhalation, milrinone (0.2-5 mg/mL) or NaCl (0.9%) are nebulized using an ultrasonic nebulizer and inhaled for 3 min at identical peak inspiratory pressures as used throughout the experiment. A 3-min nebulization of 1 mg/mL milrinone results in vaporization of 14 μg of the phosphodiesterase-3 inhibitor as determined by microgravimetry. Therefore, the respective dose of 39 μg/kg is analog to inhaled doses in human studies. For intravenous delivery, milrinone (initial bolus of 2-10 μg/kg, followed by 0.2-1 μg/kg/min) or equivalent volumes of NaCl (0.9%; initial bolus of 1.6 mL/kg, followed by 10 μL/kg/h) are administered by an infusion pump for 10 min.

[1]. Santhosh KT, et al. Milrinone attenuates thromboxane receptor-mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes. Br J Pharmacol. 2011 Jul;163(6):1223-36.

[2]. Hentschel T, et al. Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure. Anesthesiology. 2007 Jan;106(1):124-31.

[3]. Kishi T, et al. Effects of milrinone on left ventricular end-systolic pressure-volume relationship of rat hearts in situ. Clin Exp Pharmacol Physiol. 2001 Sep;28(9):737-42.

[4]. Taylor MS, et al. Effect of milrinone on small mesenteric artery vasoconstriction: role of K(+) channels. Am J Physiol. 1999 Jul;277(1 Pt 1):G69-78.

3-Isobutyl-1-methylxanthine | rolipram | PF-04957325 | AN-2728 | GLPG1690 | BAY-60-7550 | Icariin | Ibudilast | PF-8380 | TAK-063 | Dipyridamole | Cilostazol | GSK256066 | Cialis | Pentoxifylline

MOLECULAR FORMULA :

C12-H9-N3-O

MOLECULAR WEIGHT :

211.24

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 :

91 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

58 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 27,652,1996

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

73 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

137 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

62 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 27,652,1996

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

79 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

>25 mg/kg

TOXIC EFFECTS :

Behavioral - somnolence (general depressed activity) Cardiac - other changes Lungs, Thorax, or Respiration - fibrosis, focal (pneumoconiosis)

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: 21,2891,1993

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

40 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rabbit

DOSE/DURATION :

44400 ug/kg

TOXIC EFFECTS :

Behavioral - ataxia Cardiac - cardiomyopathy including infarction Lungs, Thorax, or Respiration - dyspnea

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

4550 mg/kg/13W-I

TOXIC EFFECTS :

Behavioral - muscle weakness Gastrointestinal - changes in structure or function of salivary glands

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

11375 mg/kg/65W-I

TOXIC EFFECTS :

Related to Chronic Data - death

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

1200 mg/kg/30D-I

TOXIC EFFECTS :

Cardiac - cardiomyopathy including infarction Kidney, Ureter, Bladder - changes in bladder weight Related to Chronic Data - death

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

14560 mg/kg/1Y-I

TOXIC EFFECTS :

Blood - pigmented or nucleated red blood cells Nutritional and Gross Metabolic - other changes

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

910 mg/kg/13W-I

TOXIC EFFECTS :

Cardiac - cardiomyopathy including infarction Cardiac - pulse rate increase, without fall in BP Cardiac - changes in heart weight

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

60 mg/kg/2W-I

TOXIC EFFECTS :

Cardiac - cardiomyopathy including infarction Cardiac - EKG changes not diagnostic of specified effects Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases

REFERENCE :

NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

455 mg/kg/13W-I

TOXIC EFFECTS :

Lungs, Thorax, or Respiration - fibrosis, focal (pneumoconiosis)

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: 21,2891,1993