Chronic β 1 -adrenoceptor blockade impairs ischaemic tolerance and preconditioning in murine myocardium

Abstract

β-adrenoceptor antagonists are commonly used in ischaemic heart disease (IHD) patients, yet may impair signalling and efficacy of ‘cardioprotective’ interventions. We assessed effects of chronic β1-adrenoceptor antagonism on myocardial resistance to ischemia-reperfusion (IR) injury and the ability of cardioprotective interventions [classic ischaemic preconditioning (IPC); novel sustained ligand-activated preconditioning (SLP)] to reduce IR injury in murine hearts. Young male C57Bl/6 mice were untreated or received atenolol (0.5 g/l in drinking water) for 4 weeks. Subsequently two cardioprotective stimuli were evaluated: morphine pellets implanted (to induce SLP, controls received placebo) 5 days prior to Langendorff heart perfusion, and IPC in perfused hearts (3 × 1.5 min ischemia/2 min reperfusion). Atenolol significantly reduced in vivo heart rate. Untreated control hearts exhibited substantial left ventricular dysfunction (~50% pressure development recovery, ~20 mmHg diastolic pressure rise) with significant release of lactate dehydrogenase (LDH, tissue injury indicator) after 25 min ischemia/45 min reperfusion. Contractile dysfunction and elevated LDH were reduced >50% with IPC and SLP. While atenolol treatment did not modify baseline contractile function, post-ischaemic function was significantly depressed compared to untreated hearts. Atenolol pre-treatment abolished beneficial effects of IPC, whereas SLP protection was preserved. These data indicate that chronic β1-adrenoceptor blockade can exert negative effects on functional IR tolerance and negate conventional IPC (implicating β1-adrenoceptors in IR injury and IPC signalling). However, novel morphine-induced SLP is resistant to inhibition by β1-adrenoceptor antagonism.

Sevoflurane, Propofol and Carvedilol Block Myocardial Protection by Limb Remote Ischemic Preconditioning

“…A brief treatment of short-acting BB, esmolol, also attenuated the effects of ischemic preconditioning in rabbit hearts [14]. In addition, beta-adrenergic blockade with atenolol abrogated the beneficial effects of preconditioning in isolated mouse hearts [44]. However, retrospective analyses of clinical studies showed no impact of BB on RIPC-induced cardioprotection in patients undergoing CABG surgery [45].…”

Opioid receptors and cardioprotection – ‘opioidergic conditioning’ of the heart

“…Opioidergic SLP also augments protection via acute adenosine receptor activation (Peart et al ., ) and caveolin‐3 overexpression (See Hoe et al ., ). Importantly, SLP is effective in aged (Peart and Gross, ) and diabetic myocardium (See Hoe et al ., ) refractory to conventional protective stimuli, and also retains efficacy following 4 weeks of β‐adrenoceptor blockade whereas ischaemic preconditioning is lost under these conditions (See Hoe et al ., ).…”

“…The α‐adrenoceptor also influences cardioprotection, with evidence of impaired preconditioning in patients treated with the α‐adrenoceptor selective phentolamine (Tomai et al ., ). Our pilot data indicate that chronic (28 day) treatment with the β 1 ‐antagonist atenolol impairs intrinsic ischaemic tolerance and negates preconditioning‐dependent protection in murine tissue (See Hoe et al ., ). Nonetheless, protection via sustained opioid treatment appears resistant to these inhibitory effects.…”

Hurdles to Cardioprotection in the Critically Ill

“…The role of β-agonism in cardioprotection is controversial, with many studies reporting protective and deleterious actions of both β 1 - [303,304,305,306,307] and β 2 -adrenoceptors [306,307,308,309,310] (β 1 - and β 2 -Ars, respectively) in the context of myocardial IRI. β-agonism that promotes Gs-PKA pathway activation is typically associated with myocardial damage, and activation of the Gi-ERK pathway is prosurvival; however, there are exceptions to this rule [305,308].…”

“…β-agonism that promotes Gs-PKA pathway activation is typically associated with myocardial damage, and activation of the Gi-ERK pathway is prosurvival; however, there are exceptions to this rule [305,308]. These mixed effects may reflect cardiac vs. extra-cardiac responses of β-ARs, variances in drug selectivity for β-AR subtype, and non-specific actions of β-AR responses [303]. Interestingly, a unique cardioprotective phenomenon termed sustained ligand-activated preconditioning (SLP) induces potent tolerance to IRI through regulation of the β 2 -AR-Gα s -PKA signaling pathway [308].…”