Milrinone (Synonyms: WIN 47,203)

Animal experiment:

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.

References:

[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.