Effect of preischemic β-adrenoceptor stimulation on postischemic contractile dysfunction

Aims: Short periods of preischemic beta-adrenoceptor stimulation protect hearts against postischemic left ventricular dysfunction. It was the aim of this study to decide whether this procedure mimics ischemic preconditioning by the generation of preischemic hemodynamic and energetic stress or whether it represents an endogenous phenomenon and to investigate the influence of age and hypertension. Main methods: Isolated rat hearts were investigated ex vivo by Langendorff perfusion and exposed to an established ischemia/reperfusion protocol (45 min no-flow ischemia and 90 min reperfusion). Left ventricular developed pressure (LVDP), rate pressure product, and +/- dP/dt were analyzed. Key findings: Isoprenaline concentration dependently increased LVDP up to 40 +/- 15 mm Hg (approximately EC50 of 9.9 +/- 0.5 nM). Isoprenaline given prior to ischemia attenuated the subsequent postischemic ventricular dysfunction (approximately EC50 of 1.4 +/- 0.2 pM). However, concentrations high enough to improve LVDP in normoxic hearts did not improve postischemic recovery albeit a significant reduction of hypercontraction-induced cell damage. The effect on functional recovery was attenuated by atenolol, H89, and wortmannin suggesting that beta-adrenoceptor stimulation, protein kinase A, and PI 3-kinase activation are involved. The effect was conserved in hearts from 13 month old rats but lost in age-matched spontaneously hypertensive rats. Significance: The study identifies preischemic beta-adrenoceptor stimulation as a pharmacological preconditioning protocol that does not simply mimic classical ischemic preconditioning by induction of hemodynamic or energetic stress prior to a prolonged ischemic period. The observed loss of effectiveness in hypertensives may contribute to the reduced ischemic tolerance of hypertensives. (C) 2009 Elsevier Inc. All rights reserved.