The nondepolarizing, normokalemic cardioplegia formulation adenosine-lidocaine (adenocaine) exerts anti-neutrophil effects by synergistic actions of its components

ObjectiveA new strategy of normothermic cardioplegia based on the combination of adenosine and lidocaine (adenocaine; Hibernation Therapeutics Global Ltd, Kilquade, Ireland) achieves nondepolarized arrest at normokalemia. Both adenosine and lidocaine independently inhibit neutrophil (polymorphonuclear neutrophil; PMN) activity. However, whether adenocaine exerts greater anti-inflammatory effects is not known. We tested the hypothesis that adenocaine synergistically attenuates PMN functions.MethodsSuperoxide anion (O2−) generation: Isolated porcine PMNs were primed with cytochalasin B (5 μg/mL) and activated by N-formylmethionyl-leucyl-phenylalanine (100 nM). O2− release was quantified using lucigenin-enhanced chemiluminescence. Data were expressed as percent of stimulated control.ResultsBoth adenosine and lidocaine alone inhibited O2− production in a dose-dependent manner (adenosine reduced to 67% ± 8.4% and 21% ± 2.2% of maximal stimulation at 0.1 and 10 μmol/L, respectively, lidocaine reduced to 57.9% ± 18.6% and 28% ± 5% at 10 and 100 μmol/L, respectively). Adenocaine further reduced O2− generation in a synergistic manner. In addition, adenosine alone (0.1–10 μmol/L) inhibited O2− generation in primed but not activated PMNs, whereas lidocaine alone (1–100 μmol/L) inhibited O2− release in both primed and activated PMNs. Adenocaine further reduced O2− generation because of inhibition of both priming and activation stages. Both adenosine and lidocaine alone and adenocaine comparably inhibited platelet activating factor–induced CD11 b/c surface expression on PMNs (flow cytometry), but adenocaine further suppressed both CD18 expression (to 47.4% ± 9.7%) and PMN adherence (to 47.2% ± 4.3%) compared with adenosine and lidocaine alone. Transmigration of calcein-acetyoxymethyl–labeled PMNs through transwells seeded with cultured coronary artery endothelial cells was reduced comparably by adenosine (to 80.1% ± 6.7%) and adenocaine (67.3% ± 9.6%).ConclusionsAdenocaine suppresses multiple PMN functions including O2− generation, adhesion molecule expression, PMN adherence, and transmigration. In addition to inducing nondepolarized arrest, adenocaine cardioplegia may exert cardioprotection by inhibiting PMN-mediated inflammatory responses

Adenosine, lidocaine and Mg^2+ improves cardiac and pulmonary function, induces reversible hypotension and exerts anti-inflammatory effects in an endotoxemic porcine model

Introduction The combination of Adenosine (A), lidocaine (L) and Mg^2+ (M) (ALM) has demonstrated cardioprotective and resuscitative properties in models of cardiac arrest and hemorrhagic shock. This study evaluates whether ALM also demonstrates organ protective properties in an endotoxemic porcine model. Methods Pigs (37 to 42 kg) were randomized into: 1) Control (n = 8) or 2) ALM (n = 8) followed by lipopolysaccharide infusion (1 μg∙kg^-1∙h^-1) for five hours. ALM treatment consisted of 1) a high dose bolus (A (0.82 mg/kg), L (1.76 mg/kg), M (0.92 mg/kg)), 2) one hour continuous infusion (A (300 μg∙kg^-1 ∙min^-1), L (600 μg∙kg^-1 ∙min^-1), M (336 μg∙kg^-1 ∙min^-1)) and three hours at a lower dose (A (240∙kg^-1∙min^-1), L (480 μg∙kg^-1∙min^-1), M (268 μg∙kg^-1 ∙min^-1)); controls received normal saline. Hemodynamic, cardiac, pulmonary, metabolic and renal functions were evaluated. Results ALM lowered mean arterial pressure (Mean value during infusion period: ALM: 47 (95% confidence interval (CI): 44 to 50) mmHg versus control: 79 (95% CI: 75 to 85) mmHg, P <0.0001). After cessation of ALM, mean arterial pressure immediately increased (end of study: ALM: 88 (95% CI: 81 to 96) mmHg versus control: 86 (95% CI: 79 to 94) mmHg, P = 0.72). Whole body oxygen consumption was significantly reduced during ALM infusion (ALM: 205 (95% CI: 192 to 217) ml oxygen/min versus control: 231 (95% CI: 219 to 243) ml oxygen/min, P = 0.016). ALM treatment reduced pulmonary injury evaluated by PaO(2)/FiO(2) ratio (ALM: 388 (95% CI: 349 to 427) versus control: 260 (95% CI: 221 to 299), P = 0.0005). ALM infusion led to an increase in heart rate while preserving preload recruitable stroke work. Creatinine clearance was significantly lower during ALM infusion but reversed after cessation of infusion. ALM reduced tumor necrosis factor-α peak levels (ALM 7121 (95% CI: 5069 to 10004) pg/ml versus control 11596 (95% CI: 9083 to 14805) pg/ml, P = 0.02). Conclusion ALM infusion induces a reversible hypotensive and hypometabolic state, attenuates tumor necrosis factor-α levels and improves cardiac and pulmonary function, and led to a transient drop in renal function that was reversed after the treatment was stopped

Pretreatment with phenoxybenzamine attenuates the radial artery's vasoconstrictor response to α-adrenergic stimuli

AbstractBackgroundAlthough the radial artery bypass conduit has excellent intermediate-term patency, it has a proclivity to vasospasm. We tested the hypothesis that brief pretreatment of a radial artery graft with the irreversible adrenergic antagonist phenoxybenzamine attenuates the vasoconstrictor response to the vasopressors phenylephrine and norepinephrine compared with the currently used papaverine/lidocaine.MethodsSegments of human radial artery grafts were obtained after a 30-minute intraoperative pretreatment with a solution containing 20 mL of heparinized blood, 0.4 mL of papaverine (30 mg/mL), and 1.6 mL of lidocaine (1%). The segments were transported to the laboratory and placed into a bath containing Krebs-Henseleit solution and 10, 100, or 1000 μmol/L phenoxybenzamine or vehicle. The segments were tested in organ chambers for contractile responses to increasing concentrations of phenylephrine and norepinephrine (0.5-15 μmol/L).ResultsContractile responses to 15 μmol/L phenylephrine in control radial artery segments averaged 44.2% ± 9.1% of the maximal contractile response to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated contraction to 15 μmol/L phenylephrine (32.1% ± 5.9%; P = .22), but 1000 μmol/L phenoxybenzamine completely abolished radial artery contraction (−7.2% ± 4.4%; P < .001). The effect of 10 and 100 μmol/L phenoxybenzamine on attenuating vasocontraction was intermediate between 1000 μmol/L phenoxybenzamine and papaverine/lidocaine. Responses to 15 μmol/L norepinephrine in control radial artery segments averaged 54.7% ± 7.5% of maximal contraction to 30 mmol/L KCl. Papaverine/lidocaine modestly attenuated the contraction response of radial artery segments (35.6% ± 5.1%; P = .04). In contrast, 1000 μmol/L phenoxybenzamine showed the greatest attenuation of norepinephrine-induced contraction (−10.5% ± 2.0%; P < .001).ConclusionsA brief pretreatment of the human radial artery bypass conduit with 1000 μmol/L phenoxybenzamine completely attenuates the vasoconstrictor responses to the widely used vasopressors norepinephrine and phenylephrine. Papaverine/lidocaine alone did not block vasoconstriction to these α-adrenergic agonists

Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery

To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research

Novel targets and future strategies for acute cardioprotection: Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart

Ischaemic heart disease and the heart failure that often results, remain the leading causes of death and disability in Europe and worldwide. As such, in order to prevent heart failure and improve clinical outcomes in patients presenting with an acute ST-segment elevation myocardial infarction and patients undergoing coronary artery bypass graft surgery, novel therapies are required to protect the heart against the detrimental effects of acute ischaemia/reperfusion injury. During the last three decades, a wide variety of ischaemic conditioning strategies and pharmacological treatments have been tested in the clinic - however, their translation from experimental to clinical studies for improving patient outcomes has been both challenging and disappointing. Therefore, in this Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart, we critically analyse the current state of ischaemic conditioning in both the experimental and clinical settings, provide recommendations for improving its translation into the clinical setting, and highlight novel therapeutic targets and new treatment strategies for reducing acute myocardial ischaemia/reperfusion injury

Myocardial Protection: An Overview

The goals of myocardial protection during cardiac surgery are not only to facilitate the operation by providing a quiet bloodless field, thereby facilitating the precision of the operation, but also to avoid iatrogenic injury induced by cardiopulmonary bypass itself or by surgically imposed ischemia. In addition, myocardial protective strategies are geared to preventing reperfusion injury upon resolution of the coronary occlusion and the ultimate release of the aortic cross clamp. Cardioplegia plays a very important role in myocardial protection strategies. Acting as a selective perfusion agent, cardioplegia solutions can alter or inhibit ischemic injury by virtue of hypothermia and asystole. In addition, cardioplegia can be used to avoid reperfusion injury by altering the conditions of its delivery and the composition of the solution using various adjunctive agents and pharmacologic therapies for which cardioplegia solutions serve as a vector. Future strategies, particularly for off-pump surgical procedures, may incorporate systemic delivery of therapeutic agents to the heart directly either in conjunction with or without cardioplegia