EXPERIMENTAL STUDY
urocortin promotes hemodynamic and bioenergetic recovery and improves cell survival in the isolated rat heart exposed to ischemia/reperfusion
Tiziano M. Scarabelli, MD*,*,
Evasio Pasini, MD ,
Anastasis Stephanou, PhD*,
Laura Comini, MSc,
Salvatore Curello, MD ,
Riccardo Raddino, MD,
Roberto Ferrari, MD, PhD,
Richard Knight, MD, PhD and
David S. Latchman, PhD, DSc*
* Medical Molecular Biology Unit, Institute of Child Health and Great Ormond Street Hospital, University College London, London, United Kingdom
Cardiovascular Pathophysiology Research Centre, S. Maugeri Foundation IRCCS, University of Ferrara, Ferrara, Italy
Cardiology Department, University of Brescia, Brescia, Italy
Department of Cystic Fibrosis, National Heart and Lung Institute, Imperial College London, London, United Kingdom
Manuscript received September 11, 2001;
revised manuscript received March 27, 2002,
accepted April 5, 2002.
* Reprint requests and correspondence: Dr. Tiziano M. Scarabelli, Medical Molecular Biology Unit, Institute of Child Health and Great Ormond Street Hospital, University College London, London, WC1H 9DQ, United Kingdom.
t.scarabelli{at}ich.ucl.ac.uk
OBJECTIVES: This study evaluates the hemodynamic, bioenergetic and cytoprotective effects of urocortin (Ucn) in the isolated rat heart exposed to ischemia (I)/reperfusion (R).
BACKGROUND: We have previously demonstrated that administration of exogenous Ucn reduces infarct size in ischemic-reperfused rat hearts.
METHODS: Urocortin 10–8M was added to the perfusate before I, before I and during R, and during R alone in the isolated pulsed rat heart exposed to 35 min I followed by 60 min R.
RESULTS: Partial to complete recovery of diastolic pressure and developed pressure was seen irrespective of when Ucn was perfused. In particular, beneficial effects are observed when Ucn is only given during R. Urocortin given only before I, and before I and over R, although not during R alone, also produces significant recovery of high-energy phosphate pools. In each group, improvement in ventricular function is associated with reduction both in myocardial damage, assessed by creatine phosphokinase release, and in endothelial cell and cardiomyocyte apoptosis, assessed by caspase 3 activity and fluorescent-based terminal deoxynucleotidyl transferase mediated nick end labelling enhanced with counterstains. These improvements in ventricular performance, bioenergetics and cell survival are not secondary to any inotropic effects of Ucn.
CONCLUSIONS: This is the first report to show enhanced cardiac function induced by Ucn during I/R. Because the cytoprotective and functional benefits are still produced when Ucn is given only at R, these data suggest that Ucn may be useful clinically in the management of myocardial infarction.
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Abbreviations and Acronyms
| | ATP | | adenosine triphosphate | | BS | | buffer solution | | CF | | coronary flow | | CM | | cardiomyocyte | | CPK | | creatine phosphokinase | | C3 | | caspase 3 | | dP | | diastolic pressure | | DP | | developed pressure | | EC | | endothelial cell | | I/R | | ischemia/reperfusion | | TUNEL | | terminal deoxynucleotidyl transferase mediated nick end labelling | | Ucn | | urocortin |
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