Existence of beta(3)-adrenoceptors in rat heart: functional implications.

1. beta(3)-Adrenoceptors (AR) have been reported to be present in numerous species, where they mediate multiple responses. 2.

Ouabain triggers preconditioning through activation of the Na+,K+-ATPase signaling cascade in rat hearts.

Objective: Because ouabain activates several pathways that are critical to cardioprotective mechanisms such as ischemic preconditioning, we tested if this digitalis compound could protect the heart against ischemia-reperfusion injury through activation of the Na+,K+-ATPase/c-Src receptor complex.

Methods And Results: In Langendorff-perfused rat hearts, a short (4 min) administration of ouabain 10 muM followed by an 8-minute washout before 30 min of global ischemia and reperfusion improved cardiac function, decreased lactate dehydrogenase release and reduced infarct size by 40%. Western blot analysis revealed that ouabain activated the cardioprotective phospholipase Cgamma1/protein kinase Cepsilon (PLC-gamma1/PKCepsilon) pathway.

Na+/H+ exchange inhibition in hypertrophied myocardium subjected to cardioplegic arrest: an effective cardioprotective approach.

Objective: This study was designed to assess whether the protective effects of Na+/H+ exchange (NHE) inhibition, which have been largely demonstrated in normal hearts, are also manifest in a more surgically relevant model of hypertrophied myocardium subjected to cardioplegic arrest.

Methods: Left ventricular hypertrophy was created in 3-week-old rats by coarctation of the ascending thoracic aorta with a hemoclip. Eight weeks later, hearts were excised, isovolumetrically perfused and subjected to 1 h of potassium cardioplegic arrest followed by 2 h of reperfusion.

Backtable heat-enhanced preconditioning: a simple and effective means of improving function of heart transplants.

Background: Cardiac harvest teams are usually committed to immediately transfer the explanted donor heart into its cold storage solution. We tested the opposite hypothesis that a brief prestorage episode of heat-enhanced ischemic preconditioning could be protective.

Methods: Fifty-three isolated isovolumic rat hearts underwent 4 hours of cold (4 degrees C) storage in the Celsior preservation solution and 2 hours of reperfusion.

Ischemic preconditioning with opening of mitochondrial adenosine triphosphate-sensitive potassium channels or Na/H exchange inhibition: which is the best protective strategy for heart transplants?

Objective: This study was designed to compare ischemic preconditioning with opening of mitochondrial adenosine triphosphate-sensitive potassium channels and Na(+)/H(+) exchange inhibition in an isolated heart model of cold storage, simulating the situation of cardiac allografts.

Methods: Sixty-seven isolated isovolumic buffer-perfused rat hearts were arrested with and stored in Celsior solution (Imtix-Sangstat) at 4 degrees C for 4 hours before a 2-hour reperfusion. Group I hearts served as controls and were arrested with and stored in Celsior solution.

Opening of mitochondrial potassium channels: a new target for graft preservation strategies?

Background: This study was designed to assess the protective effects of the mitochondrial adenosine triphosphate-sensitive potassium channel (KATP) opener diazoxide as an additive to heart preservation solution.

Methods: Forty isolated isovolumic buffer-perfused rat hearts were divided into four groups. Groups I and III hearts were arrested with and cold-stored in Celsior solution for 4 hr and 10 hr, respectively.

Preconditioning by mitochondrial ATP-sensitive potassium channel openers: An effective approach for improving the preservation of heart transplants.

Background: Recent studies have implicated mitochondrial ATP-sensitive potassium (K(ATP)) channels in the cardioprotective effects of ischemic preconditioning. The present study used a model of prolonged cold heart storage to assess whether the mitochondrial K(ATP) opener diazoxide could reproduce the protection conferred by ischemic preconditioning.

Methods And Results: Fifty-four isolated rat hearts were arrested with and stored in Celsior at 4 degrees C for 10 hours before a 2-hour reperfusion.

Opening of potassium channels: the common cardioprotective link between preconditioning and natural hibernation?

Background: The tolerance of hibernating mammals to cold hypoxia is related to a factor similar to agonists of delta-opioid receptors. This study was designed to assess whether activation of these receptors could reproduce the protection conferred by ischemic preconditioning and whether such cardioprotection was similarly mediated by an opening of ATP-sensitive potassium (KATP) channels.

Methods And Results: Thirty-two isolated rat hearts were arrested with and stored in Celsior at 4 degrees C for 5 hours before being reperfused for 2 hours.

Protective effects of Celsior in lung transplantation.

Background: Celsior is a new preservation solution for heart transplants that recently has been shown also to improve protection of pulmonary grafts. As these data were obtained in isolated lung preparations, we sought to perform further tests with an in vivo model of allogeneic lung transplantation.

Methods: The left lungs of 41 rats were either transplanted immediately after harvest (controls) or flushed with and cold stored in Celsior or the blood-based Wallwork solution for 5 or 12 hours.

Inhibition of the pacemaker current: a bradycardic therapy for off-pump coronary operations.

Background: The accurate performance of coronary anastomoses on the beating heart requires some form of myocardial immobilization that can be achieved pharmacologically. Different classes of drugs can be used to induce bradycardia, but the most effective in this setting of off-pump operation has not yet been determined.

Methods: Fifty-six isolated buffer-perfused rabbit hearts were divided into seven equal groups.

Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation.

Increasing evidence suggests that mineralo- and glucocorticoids modulate cardiovascular homeostasis via the effects of circulating components generated within the adrenals but also through local synthesis. The aim of this study was to assess the existence of such a steroidogenic system in heart. Using the quantitative reverse transcriptase-polymerase chain reaction, the terminal enzymes of corticosterone and aldosterone synthesis (11beta-hydroxylase and aldosterone synthase, respectively) were detected in the rat heart.

Failure of preconditioning to improve postcardioplegia stunning of minimally infarcted hearts.

Background: Ischemic preconditioning is an effective means of reducing myocardial infarct size, but its ability to attenuate stunning after an episode of surgically relevant global ischemia remains elusive. Likewise, the role played by adenosine in this setting has not been established conclusively. This study was designed to address these two issues.

Evidence for an involvement of the neutrophil integrin lymphocyte function-associated antigen-1 in early failure of heart transplants.

Background: The adhesion of neutrophils to the coronary vascular wall contributes to reperfusion injury of cardiac allografts. This phenomenon involves interactions between neutrophil beta 2-integrins (CD11a/CD18 [lymphocyte function-associated antigen-1, or LFA-1], CD11b/CD18 [membrane attack complex-1, or MAC-1], and CD11c/CD18 [p150,95]) and their endothelial ligands. Whereas the roles of the common beta-chain (CD18) and of the alpha-subunit of MAC-1 (CD11b) have been studied extensively, the role of the alpha-subunit of LFA-1 (CD11a) remains less well defined.

Is potassium channel opening an effective form of preconditioning before cardioplegia?

Background: Opening of adenosine triphosphate-sensitive potassium channels might be one of the mechanisms by which preconditioning preserves the myocardium against ischemic damage. The present study was therefore designed to compare the protective efficacy of ischemic preconditioning with that of pharmacologic preconditioning involving the use of a potassium channel opener in a surgically relevant model of cold cardioplegic arrest.

Methods: Thirty isolated isovolumic rat hearts were subjected to 2 hours of potassium arrest at an average myocardial temperature of 23 degrees C, followed by 1 hour of reperfusion.

Poststorage diastolic abnormalities of heart transplants: is vascular dysfunction or myocardial contracture the culprit?

Background: Vascular dysfunction and myocardial contracture can both contribute to posttransplantation diastolic abnormalities commonly exhibited by heart transplants, but their respective importance remains incompletely elucidated. To address this issue, we assessed the effects of supplementing a new heart preservation solution, Celsior, with a nitric oxide precursor (L-arginine) and a compound known to uncouple excitation from contraction (2, 3-butanedione monoxime).

Methods: Fifty isolated buffer-perfused rat hearts were divided into four groups.

Preconditioning with potassium channel openers. A new concept for enhancing cardioplegic protection?

Ischemic preconditioning defines an adaptive endogenous mechanism in which a brief episode of reversible ischemia renders the heart more resistant to a subsequent period of sustained ischemia. Because the cardioprotective effects of ischemic preconditioning might be mediated by an activation of adenosine triphosphate-sensitive potassium channels, this study was designed to assess whether these effects could be duplicated by the preischemic administration of a potassium channel opener. Fifty isolated isovolumic buffer-perfused rat hearts underwent 45 minutes of normothermic potassium arrest followed by 1 hour of reperfusion.

Increased cardiac types I and III collagen mRNAs in aldosterone-salt hypertension.

Cardiac fibrosis is one of the deleterious events accompanying hypertension that may be implicated in the progression toward heart failure. To determine the mechanisms involved in fibrosis and the role of hemodynamic versus humoral factors, we studied the expression of genes involved in hypertrophy and fibrosis in the heart of rats treated with aldosterone for 2 months with addition of 1% NaCl and 0.3% KCl in water.

Experimental evaluation of Celsior, a new heart preservation solution.

An original heart preservation solution (Celsior) has been developed, the formulation of which has been designed to fulfil two major objectives: (1) to combine the general principles of hypothermic organ preservation with those specific for the myocardium, and (2) to offer the possibility of being used not only as a storage medium but also as a perfusion fluid during initial donor heart arrest, poststorage graft reimplantation and early reperfusion. The major principles addressed by the Celsior formulation include (1) prevention of cell swelling (by mannitol and lactobionate), (2) prevention of by the Celsior formulation include (1) prevention of cell swelling (by mannitol and lactobionate), (2) prevention of oxygen-derived free radical injury (by reduced glutathione, histidine and mannitol), and (3) prevention of contracture by enhancement of energy production (glutamate) and limitation of calcium overload (high magnesium content, slight degree of acidosis). Two experimental preparations were used: The isolated isovolumic buffer-perfused rat heart model and the heterotopic rabbit heart transplantation model.

Efficacy of lactobionate-enriched cardioplegic solution in preserving compliance of cold-stored heart transplants.

Cardioplegic solutions of the extracellular type are commonly used as storage media for heart transplants. Because this type of formulation was not originally designed for preventing hypothermically induced edema, we assessed the effects of supplementing a standard, extracellular-like cardioplegic solution with the high molecular weight impermeant lactobionate on water content and postischemic compliance of isolated rat hearts. In one series of experiments, hearts were immersed in either a standard cardioplegic solution of the extracellular type or in the same solution supplemented with lactobionate (80 mmol/L).

Improved recovery of heart transplants with a specific kit of preservation solutions.

In the course of cardiac transplantation, donor hearts undergo a four-step sequence of events (arrest, cold storage, global ischemia during implantation, and reperfusion) during which myocardial damage can occur. We tested the hypothesis that the functional recovery of these hearts could be improved by exposure to two interdependently formulated preservation solutions throughout this four-step sequence. Solution I was used as a perfusion and storage medium during the first three steps, and solution II served as a modified reperfusate.

[Towards an integrated protection of heart grafts].

In an attempt to provide a consistent protection of cardiac allografts during the sequence of events inherent in transplantation procedures, we developed two preservation solutions of which one is used for initial arrest, storage and cardioplegia during graft implantation, whereas the other serves as initial reperfusate. The formulations of these solutions are closely interrelated and their design has integrated the basic principles of organ preservation with those of myocardium-specific metabolism. Based upon experimental studies in the isolated rat heart model, this integrated approach has yielded better functional recoveries than conventional preservation protocols.

Aortic perfusion pressure as early determinant of beta-isomyosin expression in perfused hearts.

Pressure overload in vivo induces an increase in cardiac protooncogene and stress protein expression that may initiate the long-term genetic changes observed in hypertrophy. To known whether mechanical stimulus is linked to specific gene transcription, expression of immediate early genes and synthesis of total proteins and myosin heavy chains (MHCs) were studied in beating and KCl-arrested isolated rat hearts perfused for 2 h under various coronary pressures. The main result of this study is that in the beating heart an augmentation of aortic pressure from 60 to 120 mmHg results in a pronounced enhancement of the synthesis of MHC (+59%) and of the expression of the beta-MHC isomyosin mRNA (iso-mRNA; +104%).

Maintenance of the myocardial thiol pool by N-acetylcysteine. An effective means of improving cardioplegic protection.

The reduced thiol pool of myocardial tissue represents an important defense mechanism against oxygen toxicity. Since the ischemia-induced depletion of this pool might favor the cytotoxicity of oxygen-derived free radicals produced during reperfusion, we assessed the effects of the thiol group donor N-acetylcysteine in an isolated buffer-perfused rat heart model of ischemia/reperfusion. Fifty hearts were studied.

Hormonal induction of c-fos and HSP68 mRNAs on an isolated coronary perfused adult rat heart.

Transient growth signals which can be related to protein synthesis and cellular growth are of particular interest in the heart because of the incidence of cardiac hypertrophy in man. The isolated coronary perfused adult rat heart or the so-called Langendorff preparation, is an useful model in exploring not only protein synthesis but also c-fos/c-myc protooncogene and Heat Shock Protein (HSP) gene expression. Phenylephrine infusion in this preparation induces c-fos expression whether the heart is beating or reversibly or irreversibly arrested by solutions enriched in KCl.

Pretreatment with captopril improves myocardial recovery after cardioplegic arrest.

Among the interventions designed to limit postischemic oxidative injury, those that enhance the myocardial content of thiol groups are attractive because thiols are powerful antioxidant. Indeed, part of the protection afforded by the angiotensin-converting enzyme (ACE) inhibitor captopril in regional myocardial ischemia is attributed to its thiol group. This study assesses the effects of captopril in a surgically relevant model of global ischemic arrest.