Delayed myocardial preconditioning by alpha1-adrenoceptors involves inhibition of apoptosis.
OBJECTIVE:Previous studies have demonstrated that alpha1-adrenoceptor activation increases myocardial resistance to ischemic injury 24 hours later. Here we tested the hypothesis that delayed protection is associated with limited infarction and involves altered expression of pro-apoptotic and/or anti-apoptotic proteins. METHODS:Rabbits were treated with phenylephrine or an equivalent volume of vehicle (n = 6 per group). Twenty-four hours after pretreatment, isolated hearts were perfused with a bovine erythrocyte suspension in modified Krebs solution, subjected to 45 minutes of global ischemia (37 C), and reperfused for 120 minutes. Infarct size was determined by triphenyltetrazolium chloride staining. Apoptosis was quantified by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling. Left ventricular tissue from separate groups of animals (n = 5 per group), 24 hours after pretreatment with phenylephrine or vehicle but without ischemia and reperfusion, was analyzed by Western blotting for content of the anti-apoptotic protein, bclx, and pro-apoptotic protein, bax. RESULTS:Isolated hearts after phenylephrine pretreatment had increased end-reperfusion developed pressures (56.8 +/- 4.9 vs 36.2 +/- 3.9 mm Hg for vehicle, P =.008) and decreased elevated end-diastolic pressures (26.7 +/- 4.5 vs 42.3 +/- 5.0 mm Hg for vehicle, P =.04). Phenylephrine pretreatment abrogated infarction (9.9 +/- 2.4% vs 42.6 +/- 6.3% for vehicle, P =.002) and reduced the number of apoptotic nuclei (24 +/- 4.8 vs 51 +/- 4.6 for vehicle, P = .038). Analysis by Western blotting showed that the ratio of bclx to bax protein increased in phenylephrine-pretreated hearts (2.65 +/- 0.5 vs 1.0 +/- 0.1 for vehicle, P =.008). CONCLUSION:Delayed myocardial protection to infarction mediated by alpha1-adrenoceptor activation involves an increased bclx/bax ratio, thereby limiting apoptotic cell death.
Baghelai, K; Graham, LJ; Wechsler, AS; Jakoi, ER
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