title: Phenylephrine postconditioning increases myocardial injury: are alpha-1 sympathomimetic agonist cardioprotective?
abstract: OBJECTIVE
  We studied effects of phenylephrine (PHE) on postischemic functional recovery and myocardial injury in an ischemia-reperfusion (I-R) experimental model.
  
  
  METHODS
  Rat hearts were Langendorff-perfused and subjected to 30 min zero-flow ischemia (I) and 60 min reperfusion (R). During R PHE was added at doses of 1 μM (n = 10) and 50 μM (n = 12). Hearts (n = 14) subjected to 30 and 60 min of I-R served as controls. Contractile function was assessed by left ventricular developed pressure (LVDP) and the rate of increase and decrease of LVDP; apoptosis by fluorescent imaging targeting activated caspase-3, while myocardial injury by lactate dehydrogenase (LDH) released during R. Activation of kinases was measured at 5, 15, and 60 min of R using western blotting.
  
  
  RESULTS
  PHE did not improve postischemic contractile function. PHE increased LDH release (IU/g); 102 ± 10.4 (Mean ± standard error of mean) control versus 148 ± 14.8 PHE (1), and 145.3 ± 11 PHE (50) hearts, (P < 0.05). PHE markedly increased apoptosis. Molecular analysis showed no effect of PHE on the activation of proapoptotic c-Jun N-terminal kinase signaling; a differential pattern of p38 mitogen activated protein kinase (MAPK) activation was found depending on the PHE dose used. With 1 μM PHE, p-p38/total-p38 MAPK levels at R were markedly increased, indicating its detrimental effect. With PHE 50 μM, no further changes in p38 MAPK were seen. Activation of Akt kinase was decreased implying involvement of different mechanisms in this response.
  
  
  CONCLUSIONS
  PHE administration during reperfusion does not improve postischemic recovery due to exacerbation of myocardial necrosis and apoptosis. This finding may be of clinical and therapeutic relevance.
authors.affiliation: Department of Pharmacology, University of Athens, 11527 Goudi, Athens, Greece.
authors.forename: Iordanis
authors.initials: I
authors.lastname: Mourouzis
authors.forename: Theodosios
authors.initials: T
authors.lastname: Saranteas
authors.forename: Heidi
authors.initials: H
authors.lastname: Ligeret
authors.forename: Christophe
authors.initials: C
authors.lastname: Portal
authors.forename: Philippos
authors.initials: P
authors.lastname: Perimenis
authors.forename: Constantinos
authors.initials: C
authors.lastname: Pantos
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002316:Cardiotonic Agents; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D002316:Cardiotonic Agents; D010656:Phenylephrine