β₁-Adrenoreceptor activation contributes to ischemia-reperfusion damage as well as playing a role in ischemic preconditioning

Abstract

Protein kinase A (PKA) activation has been implicated in early-phase ischemic preconditioning. We recently found that during ischemia PKA activation causes inactivation of cytochrome- c oxidase (CcO) and contributes to myocardial damage due to ischemia-reperfusion. It may be that β-adrenergic stimulation during ischemia via endogenous catecholamine release activates PKA. Thus β-adrenergic stimulation may mediate both myocardial protection and damage during ischemia. The present studies were designed to determine the role of the β1-adrenergic receptor (β1-AR) in myocardial ischemic damage and ischemic preconditioning. Langendorff-perfused rabbit hearts underwent 30-min ischemia by anterior coronary artery ligation followed by 2-h reperfusion. Occlusion-reperfusion damage was evaluated by delineating the nonperfused volume of myocardium at risk and volume of myocardial necrosis after 2-h reperfusion. In some hearts ischemic preconditioning was accomplished by two 5-min episodes of global low-flow ischemia separated by 10 min before coronary occlusion-reperfusion. Orthogonal electrocardiograms were recorded, and coronary flow was monitored by a drip count. Three hearts from each experimental group were used to determine mitochondrial CcO and aconitase activities. Two-hour reperfusion after occlusion caused an additional decrease in CcO activity vs. that after 30-min occlusion alone. Blocking the β1-AR during occlusion-reperfusion reversed CcO activity depression and preserved myocardium at risk for necrosis. Similarly, mitochondrial aconitase activity exhibited a parallel response after occlusion-reperfusion as well as for the other interventions. Furthermore, classic ischemic preconditioning had no effect on CcO depression. However, blocking the β1-AR during preconditioning eliminated the cardioprotection. If the β1-AR was blocked after preconditioning, the myocardium was preserved. Interestingly, in both of the latter cases the depression in CcO activity was reversed. Thus the β1-AR plays a dual role in myocardial ischemic damage. Our findings may lead to therapeutic strategies for preserving myocardium at risk for infarction, especially in coronary reperfusion intervention.

Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures

“…Later reports proposed ␣ (68, 214)-and ␤ (193,209)adrenoceptor activation as a putative trigger of ischemic preconditioning, based on the findings that receptor blockade abrogated ischemic preconditioning-induced cardioprotection. However, there were contradictory findings.…”

“…In search of effective receptor subtypes, Tsuchida et al showed the direct involvement of ␣ 1b -adrenoceptor in ischemic preconditioning (214), but studies using transgenic mice support cardioprotection by ␣ 1a rather than by ␣ 1b (160). On the other hand, the ␤ 2 -adrenoceptor is reported to confer cardioprotection in ischemic preconditioning (209), whereas preischemic ␤ 1 -activation could be an alternative (193).…”

“…For example, sustained transgenic activation of ␣ 1b -adrenoceptor did not elicit cardioprotection (160), whereas temporal blockade during the preconditioning period protected the myocardium (68,214). Also, ␤ 1 -adrenoceptor activation is reported to be beneficial during the preconditioning period but deleterious after reperfusion (193).…”

Myocardial ischemia-reperfusion and cardioprotection: a study with microdialysis in a porcine model

“…However, it is indicated that beta-1 adrenergic signalling is not essential for ischemic preconditioning (Iliodromitis 2004, Lange 2006. It is possible that the beta-1 adrenergic receptors have a dual role as a potential participant in the mediation of ischemic damage as well as in preconditioning (Spear 2007), dependent on the timing of activation or inhibition. It may be of clinical interest, and concern, whether betablockers have a protective effect or a potential to block the protection offered by other agents.…”

Landiolol does not enhance the effect of ischemic preconditioning in isolated rat hearts

“…Mieno and his colleagues [7] found that activation of the b2-adrenergic receptor plays a pivotal role in generating the protective effect of ischemic preconditioning in rat hearts. Spear et al [8] found that the b1-adrenergic receptor plays a dual role in myocardial ischemic damage: it contributes to ischemiareperfusion damage as well as playing a role in ischemic preconditioning.…”