Dose-response effects of milrinone on hemodynamics of newborn pigs with hypoxia-reoxygenation

Joynt, Chloë; Bigam, David L.; Charrois, Gregory J.R.; Jewell, Laurence D.; Korbutt, Gregory S.; Cheung, Po-Yin

doi:10.1007/s00134-008-1060-5

Cited by 18 publications

(18 citation statements)

References 34 publications

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“…Milrinone, a phosphodiesterase (PDE)‐3 inhibitor, is an inotrope and vasodilator, increasing cellular cAMP and improving hypoxic pulmonary haemodynamics (Joynt et al ., 2008; Lakshminrusimha et al ., 2009). Studies on the functional effects of milrinone have recently focused on prostanoid receptors, as milrinone attenuates inflammatory lung injury (Bueltmann et al ., 2009), potentiates the anti‐remodelling effect of PGI 2 on hypoxic artery (Phillips et al ., 2005) and enhances relaxation to PGI 2 in PPHN (Lakshminrusimha et al ., 2009).…”

Section: Introductionmentioning

confidence: 99%

Milrinone attenuates thromboxane receptor‐mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes

Santhosh

Elkhateeb

Nolette

et al. 2011

British J Pharmacology

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Keywordspersistent pulmonary hypertension of the newborn; hypoxia; prostanoid; prostacyclin; phosphodiesterase inhibitor ---------------------------------------------------------------- BACKGROUND AND PURPOSENeonatal pulmonary hypertension (PPHN) is characterized by pulmonary vasoconstriction, due in part to dysregulation of the thromboxane prostanoid (TP) receptor. Hypoxia induces TP receptor-mediated hyperresponsiveness, whereas serine phosphorylation mediates desensitization of TP receptors. We hypothesized that prostacyclin (IP) receptor activity induces TP receptor phosphorylation and decreases ligand affinity; that TP receptor sensitization in hypoxic myocytes is due to IP receptor inactivation; and that this would be reversible by the cAMP-specific phosphodiesterase inhibitor milrinone. EXPERIMENTAL APPROACHWe examined functional regulation of TP receptors by serine phosphorylation and effects of IP receptor stimulation and protein kinase A (PKA) activity on TP receptor sensitivity in myocytes from neonatal porcine resistance pulmonary arteries after 72 h hypoxia in vitro. Ca 2+ response curves to U46619 (TP receptor agonist) were determined in hypoxic and normoxic myocytes incubated with or without iloprost (IP receptor agonist), forskolin (adenylyl cyclase activator), H8 (PKA inhibitor) or milrinone. TP and IP receptor saturation binding kinetics were measured in presence of iloprost or 8-bromo-cAMP. KEY RESULTSLigand affinity for TP receptors was normalized in vitro by IP receptor signalling intermediates. However, IP receptor affinity was compromised in hypoxic myocytes, decreasing cAMP production. Milrinone normalized TP receptor sensitivity in hypoxic myocytes by restoring PKA-mediated regulatory TP receptor phosphorylation. CONCLUSIONS AND IMPLICATIONSTP receptor sensitivity and EC50 for TP receptor agonists was regulated by PKA, as TP receptor serine phosphorylation by PKA down-regulated Ca 2+ mobilization. Hypoxia decreased IP receptor activity and cAMP generation, inducing TP receptor hyperresponsiveness, which was reversed by milrinone. AbbreviationsEP, prostaglandin E receptor; IP, prostacyclin receptor; IP3, inositol-1,4,5-trisphosphate; NECA, adenosine-5′-N-ethylcarboxamide; PDE, phosphodiesterase; PKA, protein kinase A; TP, thromboxane receptor

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Section: Introductionmentioning

confidence: 99%

Milrinone attenuates thromboxane receptor‐mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes

Santhosh

Elkhateeb

Nolette

et al. 2011

British J Pharmacology

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“…The changes in mesenteric blood flow are related to the changes in regional vascular resistance, and at least in part to the concomitant changes in the cardiac output. The dose-dependent effect of milrinone on cardiac output in this study has been recently reported (18). The relationship between blood pressure, cardiac output, and intestinal perfusion during H-R is still not well defined (7,8,23,24).…”

Section: Discussionmentioning

confidence: 88%

“…Stability was defined as a hemodynamic measurement change T less than 10% over 20 min, pH 7.35 to 7.45, PaO 2 of 60 to 100 mmHg, and PaCO 2 of 35 to 45 mmHg. Normocapnic alveolar hypoxia was initiated with the inhalation of a mixture of oxygen and nitrogen gas to obtain an inspired oxygen concentration of 0.10 to 0.15 and PaO 2 of 20 to 40 mmHg for 2 h. Previous studies have determined that this degree of hypoxemia in this piglet model will produce a clinical asphyxia with severe metabolic acidosis, systemic hypotension, and a decrease in pulmonary blood flow to 40% of baseline (17,18). Piglets were then reoxygenated with 100% oxygen for 1 h and a further 3 h of 21% oxygen.…”

Section: H-r and Treatment Proceduresmentioning

confidence: 99%

Intestinal Hemodynamic Effects of Milrinone in Asphyxiated Newborn Pigs After Reoxygenation With 100% Oxygen

Joynt¹,

Bigam²,

Charrois

et al. 2009

Shock

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Neonatal asphyxia can result in poor perfusion, vasoconstriction, and decreased oxygen delivery in the intestine. Milrinone increases myocardial contractility and causes peripheral vasodilatation. We examined the dose-response of milrinone on the intestinal circulation, oxygen metabolism, and injury in a newborn piglet model of asphyxia-reoxygenation. Piglets (aged 1-3 days, weighing 1.5-2.3 kg) were acutely instrumented to measure superior mesenteric artery (SMA) flow and oxygen delivery. After stabilization, hypoxia (inspired oxygen concentration, 0.08-0.15) was induced for 2 h followed by reoxygenation with 100% O2 for 1 h then 21% O2 for 3 h. At 2 h of reoxygenation, saline or milrinone infusion at doses of 0.25, 0.5, or 0.75 microg/kg per min was given for 2 h in a blinded randomized fashion (n = 7 per group). Hemodynamic and oxygen transport parameters were analyzed at predefined time points. Intestinal tissue lactate concentrations, plasma milrinone levels, and intestinal glutathione redox status were determined at the end of the experiment. In the intestinal tract, milrinone significantly increased SMA flow and oxygen delivery while decreasing vascular resistance at a dose of 0.75 microg/kg per min (P < 0.05, ANOVA). A modest increase in SMA flow and oxygen delivery was found with milrinone at 0.5 microg/kg per min. Plasma milrinone levels correlated with SMA flow and vascular resistance (r = 0.5 and r = -0.6, respectively, P < 0.05). Intestinal lactate concentrations and histopathology were not significantly different among groups. Oxidized glutathione correlated with SMA vascular resistance and negatively with milrinone levels (r = 0.6 and r = -0.5, P < 0.05). When used to treat shock in a newborn model of asphyxia-reoxygenation, milrinone dose-dependently increases SMA flow and oxygen delivery with a significantly decreased SMA vascular resistance at higher doses.

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“…The experimentation has been previously described [8,21] . Briefly, inhalational anesthesia was used initially using isoflurane, which was substituted by a combination of intravenous midazolam (0.1-0.2 mg/kg/h) for sedation and fentanyl (5-50 g/ kg/h) for analgesia after vascular access was established.…”

Section: Anesthesia and Surgical Instrumentationmentioning

confidence: 99%

“…At 2 h of reoxygenation, when low cardiac output and hypotension predictably developed [8,21] , the piglets received either placebo (D 5 W) or levosimendan as a bolus over 10 min followed by continuous infusion at the corresponding dosage for a total of 2 h of treatment.…”

Section: H-r and Treatmentmentioning

confidence: 99%

Differential Hemodynamic Effects of Levosimendan in a Porcine Model of Neonatal Hypoxia-Reoxygenation

et al. 2011

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Background: Neonatal asphyxia can be complicated by myocardial dysfunction with secondary alterations in pulmonary and regional hemodynamics. Levosimendan is a calcium-sensitizing inotrope that may support cardiac output, but little is known regarding its differential hemodynamic effects in asphyxiated neonates. Methods: Mixed breed piglets (1–4 days old, weight 1.6–2.3 kg) were acutely instrumented. Normocapnic alveolar hypoxia (10–15% oxygen) was induced for 2 h, followed by reoxygenation with 100% (1 h) and then 21% oxygen (3 h). At 2 h of reoxygenation, after volume loading (Ringer’s lactate 10 ml/kg), either levosimendan (0.1 or 0.2 µg/kg/min) or D₅W (placebo) was infused for 2 h in a blinded, block-randomized fashion (n = 7–8/group). The systemic, pulmonary and regional (carotid, superior mesenteric and renal) hemodynamics were compared. Results: At 0.1 and 0.2 µg/kg/min, levosimendan significantly increased cardiac output (121 and 123% of pretreatment, respectively) and heart rate, and decreased systemic vascular resistance without causing hypotension. Pulmonary arterial pressure and estimated pulmonary vascular resistance were significantly increased from pretreatment baseline in 0.1 but not 0.2 µg/kg/min levosimendan. Levosimendan infusion had no effects on regional hemodynamics. Myocardial efficiency but not oxygen consumption increased with 0.1 µg/kg/min levosimendan without significant effects on plasma troponin and myocardial lactate levels. Conclusions: In newborn piglets following hypoxia-reoxygenation injury, levosimendan improves cardiac output but has no marked effects in carotid, superior mesenteric and renal perfusion. It appears that various doses of levosimendan increase the cardiac output through different mechanisms. Further investigations are needed to examine the effectiveness of levosimendan as a cardiovascular supportive therapy either alone or in conjunction with other inotropes in asphyxiated neonates.

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Dose-response effects of milrinone on hemodynamics of newborn pigs with hypoxia-reoxygenation

Abstract: When used to treat shock in newborn piglets with hypoxia-reoxygenation, milrinone improved cardiac output and carotid flow while maintaining systemic blood pressure. Pulmonary hypertension was not aggravated. Further studies are needed to confirm these findings in asphyxiated neonates.

Cited by 18 publications

References 34 publications

Milrinone attenuates thromboxane receptor‐mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes

Milrinone attenuates thromboxane receptor‐mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes

Intestinal Hemodynamic Effects of Milrinone in Asphyxiated Newborn Pigs After Reoxygenation With 100% Oxygen

Differential Hemodynamic Effects of Levosimendan in a Porcine Model of Neonatal Hypoxia-Reoxygenation

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