Heart Protection by Combination Therapy with Esmolol and Milrinone at Late-Ischemia and Early Reperfusion

Abstract

IntroductionThe present study determined whether late-ischemia/early reperfusion therapy with the β1-adrenergic receptor (AR) blocker esmolol and phosphodiesterase III inhibitor milrinone reduced left ventricular (LV) myocardial infarct size (IS).Methods and ResultsIn an ischemia/reperfusion rat model (30-min ischemia/4-hr reperfusion), esmolol, milrinone or esmolol + milrinone were intravenous (IV) infused over 10 min (from the last 5min of ischemia to the first 5min of reperfusion). LV-IS were 48.9 ± 8.9%, 41.5 ± 5.4%, 25.8 ± 7.7% and 16.8 ± 7.3% for saline, esmolol, milrinone, and esmolol + milrinone, respectively (n = 12/group). Esmolol + milrinone further reduced LV-IS compared with esmolol or milrinone alone (p < 0.05). LV-IS-reduction induced by esmolol + milrinone was eliminated in the presence of protein kinase A-(PKA)-inhibitor (Rp-cAMPS) or Akt-inhibitor (AKT 1/2 kinase inhibitor). In mixed rat ventricular cardiomyocyte cultures, intra-ischemic application of esmolol, milrinone or esmolol + milrinone reduced myocyte death rates by 5.5%, 13.3%, and 16.8%, respectively, compared with saline (p < 0.01). This cell protective effect by esmolol + milrinone was abrogated in the presence of PKA-inhibitor or Akt-inhibitor. Esmolol, milrinone or esmolol + milrinone increased myocardial PKA activity by 22%, 28% and 59%, respectively, compared with saline (n = 6, p < 0.01). No non-specific adverse effect of Rp-cAMPS on myocytes was identified in a purified myocyte preparation during hypoxia/re-oxygenation. Antiapoptotic pathways were assessed by measuring myocardial phosphorylated Akt (pAkt) levels combined with terminal dUTP nick-end labelling staining analysis. Ten minutes following infusion of esmolol, milrinone or esmolol + milrinone, there were 1.7-, 2.7-, and 6-fold increase in tissue pAkt levels, respectively. This esmolol + milrinone induced pAkt activation was abolished in the presence of PKA inhibitor. Esmolol, milrinone and esmolol + milrinone reduced myocyte apoptosis rates by 22%, 37% and 60%, respectively, compared with saline (p < 0.01).ConclusionsLate-ischemia/early reperfusion therapy with esmolol + milrinone additively reduces LV-IS associated with robust activation of myocardial PKA and subsequent Akt-antiapoptotic pathway.

Milrinone-induced postconditioning reduces hepatic ischemia-reperfusion injury in rats: the roles of phosphatidylinositol 3-kinase and nitric oxide

“…Previous studies showed that milrinone administration stimulated immediate accumulation of cAMP and elevation of PKA in the liver tissue, and pretreatment with a PKA inhibitor prevented milrinone-induced PreC [14,15]. In heart, milrinone-induced PostC also increased myocardial PKA activity and Akt phosphorylation, and reduced myocardial infarct size and myocyte apoptosis [16]. Thus, it is possible that milrinone-induced hepatic PostC is associated with the activation of PKA and the PI3K/Akt-dependent pathway.…”

“…Second, we did not measure systemic hemodynamics such as blood pressure and heart rate in this study. It has been shown that milrinone treatment (50 µg/kg) before liver ischemia [15], or after myocardial ischemia [16] did not affect systemic hemodynamics. In another study, wortmannin or L-NAME administered 5 min before reperfusion also did not affect systemic hemodynamics in myocardial infarction models [29].…”

“…It has been reported that milrinone has PreC properties against hepatic IR injury via cAMP/PKA activation [14,15]. Milrinone-induced heart PostC is associated with the activation of PKA/Akt-dependent anti-apoptotic signaling [16]. Furthermore, studies have shown that cardioprotection is associated with NO production following Akt-mediated eNOS activation [17,18].…”

Hemodynamic Treatment Aimed to Reduce Catecholamine Toxicity in Patients Suffering from Septic Shock: An Observational Single Center Study

“…In view of differences in cAMP-independent actions and compartimentation of cAMPmediated signaling [49], the combined application of milrinone and metoprolol may bear potential benefits on myocardial function [8,14,49,55]. To date, combination therapy of ßblocker and phosphodiesterase inhibitor has been used either as a bridge to ß-blocker therapy in patients with severe heart failure or as a twitch instead of dobutamine for the cardiac patient dependent on inotropic support and started on ß-blocker therapy [56].In the latter patients, chronic ß-adrenergic stress causes adrenergic desensitization thereby blunting the inotropic response in particular to dobutamine but also to milrinone [57].…”

Sustained release of milrinone delivered via microparticles in a rodent model of myocardial infarction

“…Group II received a bolus intravenous tail vein injection of milrinone (50 mg/kg in 250 mL) slowly over 10 minutes. 14,15 Finally, group III received an intravenous tail vein injection of milrinone prepared in PLGA-MPs in an equivalent dose and volume as in group II. The reason for using empty MPs as a control was to ensure that these particles per se had no effect on cardiac function or other inadvertent toxicity.…”