Nebulized phosphodiesterase III inhibitor during warm ischemia attenuates pulmonary ischemia-reperfusion injury.

Abstract

BACKGROUND:

The control of warm ischemia-reperfusion injury is crucial in managing donors after cardiac death for lung transplantation. We focused on transalveolar administration as a drug-delivery route for such donors. Milrinone is a phosphodiesterase 3 inhibitor that inhibits the breakdown of cyclic adenosine monophosphate and selectively relaxes smooth muscle. We hypothesized that nebulized milrinone would mitigate warm ischemia-reperfusion injury of lung.

METHODS:

This study was conducted with an isolated rat lung perfusion model. Lungs were excised, exposed to 55-minute ischemia at 37 degrees C, and reperfused for 60 minutes. During ischemia, nebulized milrinone (n = 6) or saline (n = 6) was inhaled. Lungs were continuously perfused without ischemia as a sham group (n = 6). Airway resistance, pulmonary vascular resistance, pulmonary compliance, weight gain and blood gas were measured. Adenine nucleotide levels and apoptosis were investigated in the reperfused lungs.

RESULTS:

Milrinone nebulization decreased post-ischemic pulmonary vascular resistance (0.98 +/- 0.05 and 1.74 +/- 0.17 cm H(2)O/ml.min at 60 minutes of reperfusion in the milrinone and control groups, respectively [p < 0.01]). It did not alter cyclic adenosine monophosphate levels, but it did elevate adenosine triphosphate levels (9.87 +/- 0.38 and 6.91 +/- 0.45 in the milrinone and control groups, respectively [p < 0.01]) and suppressed apoptosis (3.83 +/- 0.91 and 46.17 +/- 3.39 of mean apoptotic cell numbers in the milrinone and control groups, respectively [p < 0.01]).

CONCLUSIONS:

Milrinone nebulization decreased post-ischemic pulmonary vascular resistance, elevated adenosine triphosphate levels, and suppressed apoptosis. Nebulized milrinone has some protective effects against warm ischemia.

• Authors: Jitian Zhang, Fengshi Chen, Xiangdong Zhao, Akihiro Aoyama, Toshihiro Okamoto, Takuji Fujinaga, Tsuyoshi Shoji, Hiroaki Sakai, Youbin Cui, Toru Bando, Hiroshi Date
• Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation (J Heart Lung Transplant) Vol. 28 Issue 1 Pg. 79-84 (Jan 2009) ISSN: 1557-3117 [Electronic] United States
• PMID: 19134535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aerosols
• Phosphodiesterase 3 Inhibitors
• Phosphodiesterase Inhibitors
• DNA Nucleotidylexotransferase
• Milrinone

Topics

• Aerosols
• Animals
• DNA Nucleotidylexotransferase (metabolism)
• In Situ Nick-End Labeling
• Lung (drug effects, physiology)
• Lung Transplantation (adverse effects, physiology)
• Male
• Milrinone (administration & dosage, therapeutic use)
• Models, Animal
• Nebulizers and Vaporizers
• Phosphodiesterase 3 Inhibitors
• Phosphodiesterase Inhibitors (administration & dosage, therapeutic use)
• Postoperative Complications (prevention & control)
• Rats
• Reperfusion Injury (prevention & control)
• Vascular Resistance (drug effects)