α1-Adrenoceptors during simulated ischemia and reoxygenation of the human myocardium: Effect of the dose and time of administration

AbstractObjective: We sought to investigate the effect of α1-adrenoceptor activity on the ischemic and reoxygenated human myocardium. Methods: Right atrial appendages (n = 6 per group) obtained during elective cardiac operations were sliced and stabilized in normoxic normothermic buffer solution for 30 minutes and then subjected to 90 minutes of simulated ischemia, followed by 120 minutes of reoxygenation. In study 1 the dose responses to the α1-adrenoceptor agonist phenylephrine (0.01, 0.1, 1, 10, and 100 μmol/L) and to the α1-adrenoceptor antagonist prazosin (0.1, 1, 10, and 100 μmol/L) when administered for 10 minutes before ischemia, during ischemia, and during reoxygenation were examined. The influence of the time of administration (ie, before ischemia, during ischemia, or during reoxygenation) of phenylephrine (0.1 μmol/L) and prazosin (10 μmol/L) was then investigated in study 2. In study 3 the effect of the combined administration of phenylephrine given before ischemia and prazosin given during ischemia was investigated. In study 4 the protective effect of phenylephrine given before ischemia (for 10 minutes or for 5 minutes with a 5-minute washout period) was compared with that of ischemic preconditioning (5 minutes of ischemia and 5 minutes of reoxygenation). At the end of each protocol, the leakage of creatine kinase (in units per gram of wet weight) and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide to insoluble formazan dye (in millimoles per gram of wet weight) were measured. Results: Phenylephrine is maximally beneficial at 0.1 and 1 μmol/L (creatinine kinase, 0.97 ± 0.06 and 0.95 ± 0.03 U/g, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 153.0 ± 7.8 and 156.2 ± 6.7 mmol/g, respectively) compared with ischemic control (creatine kinase, 1.87 ± 0.03 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 108.5 ± 6.8 mmol/g; P <.05) but prazosin is detrimental at concentrations above 10 μmol/L (creatine kinase, 5.22 ± 0.29 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 69.8 ± 2.9 mmol/g; P <.05 vs ischemic control). In addition, phenylephrine (0.1 μmol/L) is protective when given before ischemia (creatine kinase, 2.06 ± 0.21 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 148.5 ± 4.5 mmol/g; P <.05 vs ischemic control) but is detrimental when given during ischemia alone (creatine kinase, 4.49 ± 0.98 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 70.5 ± 6.1 mmol/g; P <.05 vs ischemic control) and has no significant effect during reoxygenation. In contrast, prazosin (10 μmol/L) is beneficial when given during ischemia alone (creatine kinase, 1.34 ± 0.10 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 148.5 ± 4.5 mmol/g; P <.05 vs ischemic control), is detrimental when given during reoxygenation alone (creatine kinase, 1.5 ± 0.16 U/g; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 85.0 ± 4.7 mmol/g; P <.05 vs ischemic control), and has no effect when given before ischemia. The use of phenylephrine before ischemia alone is as protective as prazosin given during ischemia alone, but the combination of the two drugs does not cause additional benefit. Interestingly, the protection afforded by phenylephrine when given before ischemia is similar to that obtained with ischemic preconditioning. Conclusions: In the human myocardium activation of α1-adrenoceptors before ischemia is protective but is detrimental during ischemia, whereas blockade of α1-adrenoceptors is beneficial during ischemia but detrimental during reoxygenation. The degree of protection achieved by activation of the α1-adrenoceptors before ischemia is similar to that obtained with blockade of α1-adrenoceptors during ischemia and that of ischemic preconditioning.J Thorac Cardiovasc Surg 2001;122:103-1