Efficacy of the Non-Adenosine Analogue A1 Adenosine Receptor Agonist (BR-4935) on Cardiovascular Function after Cardiopulmonary Bypass

Veres, Gábor; Radovits, Tamás; Otila, G.; Hirschberg, Kristóf; Haider, Humaira; Krieger, Nelli; Knoll, Alois; Weigang, Ernst; Szabo, Gábor; Kretzler, Matthias; Szabó, Gábor

doi:10.1055/s-0029-1186271

Cited by 7 publications

(4 citation statements)

References 28 publications

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“…In 4 animals without cardiopulmonary bypass the hearts were explanted and the coronary arteries were prepared for in vitro isolated vessel experiments (controls without cardiopulmonary bypass). 16 animals were used for the cardiopulmonary bypass studies, which were conducted according to our previously described experimental protocols [40; 41; 42]. All animals received humane care in compliance with the ”Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the ”Guide for the Care and Use of Laboratory Animals” prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No.…”

Section: Methodsmentioning

confidence: 99%

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Cardioprotective effects of hydrogen sulfide

et al. 2011

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The gaseous mediator hydrogen sulfide (H 2 S) is synthesized mainly by cystathionine gammalyase in the heart and plays a role in the regulation of cardiovascular homeostasis. Here we first overview the state of the art in the literature on the cardioprotective effects of H 2 S in various models of cardiac injury. Subsequently, we present original data showing the beneficial effects of parenteral administration of a donor of H 2 S on myocardial and endothelial function during reperfusion in a canine experimental model of cardiopulmonary bypass. Overview of the literature demonstrates that various formulations of H 2 S exert cardioprotective effects in cultured cells, isolated hearts and various rodent and large animal models of regional or global myocardial ischemia and heart failure. In addition, the production of H 2 S plays a role in myocardial pre-and post-conditioning responses. The pathways implicated in the cardioprotective action of H 2 S are multiple and involve K ATP channels, regulation of mitochondrial respiration, and regulation of cytoprotective genes such as Nrf-2. In the experimental part of the current article, we demonstrate the cardioprotective effects of H 2 S in a canine model of cardiopulmonary bypass surgery. Anesthetized dogs were subjected hypothermic cardiopulmonary bypass with 60 minutes of hypothermic cardiac arrest in the presence of either saline (control, n=8), or H 2 S infusion (1 mg/ kg/h for 2 h). Left ventricular hemodynamic variables (via combined pressure-volumeconductance catheter) as well as coronary blood flow, endothelium-dependent vasodilatation to acetylcholine and endothelium-independent vasodilatation to sodium nitroprusside were measured at baseline and after 60 minutes of reperfusion. Ex vivo vascular function and high-energy phosphate contents were also measured. H 2 S led to a significantly better recovery of preload recruitable stroke work (p<0.05) after 60 minutes of reperfusion. Coronary blood flow was also significantly higher in the H 2 S group (p<0.05). While the vasodilatory response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly higher increase in coronary blood flow in the H 2 S-treated group (p<0.05) both in vivo and ex vivo. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript high-energy phosphate contents were better preserved in the H 2 S group. Additionally, the cytoprotective effects of H 2 S were confirmed also using in vitro cell culture experiments in H9c2 cardiac m...

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Section: Methodsmentioning

confidence: 99%

“…Adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) contents were assessed with standard photometry using an enzyme-kinetic assay [40; 41; 42]. …”

Section: Methodsmentioning

confidence: 99%

Cardioprotective effects of hydrogen sulfide

et al. 2011

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“…4) (Albrecht-K€ upper et al 2012). Furthermore, it has been shown that pharmacological preconditioning with a non-adenosine analogue A1R agonist improves cardiac function recovery as well as endothelial function after cardiopulmonary bypass surgery in dogs (Veres et al 2010). In a study by Yao et al, stimulation of myocardial A1Rs was cardioprotective during repetitive and brief periods of coronary artery occlusion in anesthetized dogs (Yao and Gross 1993).…”

Section: Preconditioning and Cardioprotectionmentioning

confidence: 99%

Partial Adenosine A1 Agonist in Heart Failure

et al. 2016

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Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.

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“…Adenosine and its primary metabolite inosine are ubiquitous nucleosides that can be released from ischemic or reperfused tissue [2]. Adenosine and adenosine analogues have been shown to act as an endogenous cardio-protective agent against ischemia-reperfusion injury [3,4]. Until recently, inosine was generally considered an inactive metabolite.…”

Section: Introductionmentioning

confidence: 99%

Effects of inosine on reperfusion injury after cardiopulmonary bypass

Veres

Radovits

Serés

et al. 2010

J Cardiothorac Surg

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ObjectiveInosine, a break-down product of adenosine has been recently shown to exert inodilatory and anti-inflammatory properties. Furthermore inosine might be a key substrate of pharmacological post-conditioning. In the present pre-clinical study, we investigated the effects of inosine on cardiac function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation.MethodsTwelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or inosine (100 mg/kg, n = 6). Left ventricular end-systolic pressure volume relationship (ESPVR) was measured by a combined pressure-volume-conductance catheter at baseline and after 60 minutes of reperfusion. Left anterior descendent coronary blood flow (CBF), endothelium-dependent vasodilatation to acetylcholine (ACh) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were also determined.ResultsThe administration of inosine led to a significantly better recovery (given as percent of baseline) of ESPVR 90 ± 9% vs. 46 ± 6%, p < 0.05. CBF and was also significantly higher in the inosine group (56 ± 8 vs. 23 ± 4, ml/min, p < 0.05). While the vasodilatatory response to SNP was similar in both groups, ACh resulted in a significantly higher increase in CBF (58 ± 6% vs. 25 ± 5%, p < 0.05) in the inosine group.ConclusionsApplication of inosine improves myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest.

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Efficacy of the Non-Adenosine Analogue A1 Adenosine Receptor Agonist (BR-4935) on Cardiovascular Function after Cardiopulmonary Bypass

Abstract: Pharmacological preconditioning with a new, potent non-adenosine analogue A1AdoR agonist improves biventricular function recovery and endothelial function after hypothermic cardiac arrest.

Cited by 7 publications

References 28 publications

Cardioprotective effects of hydrogen sulfide

Cardioprotective effects of hydrogen sulfide

Partial Adenosine A1 Agonist in Heart Failure

Effects of inosine on reperfusion injury after cardiopulmonary bypass

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