Inhibition of Rho kinase protects from ischaemia-reperfusion injury via regulation of arginase activity and nitric oxide synthase in type 1 diabetes.

Aim: RhoA/Rho-associated kinase and arginase are implicated in vascular complications in diabetes. This study investigated whether RhoA/Rho-associated kinase and arginase inhibition protect from myocardial ischaemia-reperfusion injury in type 1 diabetes and the mechanisms behind these effects.

Methods: Rats with streptozotocin-induced type 1 diabetes and non-diabetic rats were subjected to 30 min myocardial ischaemia and 2 h reperfusion after being randomized to treatment with (1) saline, (2) RhoA/Rho-associated kinase inhibitor hydroxyfasudil, (3) nitric oxide synthase inhibitor N-monomethyl-l-arginine monoacetate followed by hydroxyfasudil, (4) arginase inhibitor N-omega-hydroxy-nor-l-arginine, (5) N-monomethyl-l-arginine monoacetate followed by N-omega-hydroxy-nor-l-arginine or (6) N-monomethyl-l-arginine monoacetate given intravenous before ischaemia.

The role of arginase and rho kinase in cardioprotection from remote ischemic perconditioning in non-diabetic and diabetic rat in vivo.

Background: Pharmacological inhibition of arginase and remote ischemic perconditioning (RIPerc) are known to protect the heart against ischemia/reperfusion (IR) injury.

Purpose: The objective of this study was to investigate whether (1) peroxynitrite-mediated RhoA/Rho associated kinase (ROCK) signaling pathway contributes to arginase upregulation following myocardial IR; (2) the inhibition of this pathway is involved as a cardioprotective mechanism of remote ischemic perconditioning and (3) the influence of diabetes on these mechanisms.

Methods: Anesthetized rats were subjected to 30 min left coronary artery ligation followed by 2 h reperfusion and included in two protocols.

Arginase as a target for treatment of myocardial ischemia-reperfusion injury.

Two distinct enzymes of arginase (1 and 2) are critically regulating nitric oxide (NO) bioavailability by competing with NO synthase for their common substrate l-arginine. Increased expression and activity of arginase is observed in atherosclerosis and myocardial ischemia-reperfusion (I/R). Several studies have demonstrated a key pathophysiological role of increased activity of arginase during I/R.

Myocardial protection by co-administration of L-arginine and tetrahydrobiopterin during ischemia and reperfusion.

Background: Reduced bioavailability of nitric oxide (NO) is a key factor contributing to myocardial ischemia and reperfusion injury. The mechanism behind the reduction of NO is related to deficiency of the NO synthase (NOS) substrate L-arginine and cofactor tetrahydrobiopterin (BH4) resulting in NOS uncoupling. The aim of the study was to investigate if the combination of L-arginine and BH4 given iv or intracoronary before reperfusion protects from reperfusion injury.

Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity.

The theory that red blood cells (RBCs) generate and release nitric oxide (NO)-like bioactivity has gained considerable interest. However, it remains unclear whether it can be produced by endothelial NO synthase (eNOS), which is present in RBCs, and whether NO can escape scavenging by hemoglobin. The aim of this study was to test the hypothesis that arginase reciprocally controls NO formation in RBCs by competition with eNOS for their common substrate arginine and that RBC-derived NO is functionally active following arginase blockade.

Arginase inhibition reduces infarct size via nitric oxide, protein kinase C epsilon and mitochondrial ATP-dependent K+ channels.

Reduced bioavailability of nitric oxide (NO) contributes to the development of myocardial ischemia-reperfusion (I/R) injury. Increased activity of arginase is a potential factor that reduces NO bioavailability by competing for the substrate L-arginine. The aim of the study was to test the hypothesis that inhibition of arginase after coronary artery occlusion protects from I/R injury and to explore possible mechanisms behind this effect.

Local arginase inhibition during early reperfusion mediates cardioprotection via increased nitric oxide production.

Consumption of L-arginine contributes to reduced bioavailability of nitric oxide (NO) that is critical for the development of ischemia-reperfusion injury. The aim of the study was to determine myocardial arginase expression and activity in ischemic-reperfusion myocardium and whether local inhibition of arginase within the ischemic myocardium results in increased NO production and protection against myocardial ischemia-reperfusion. Anesthetized pigs were subjected to coronary artery occlusion for 40 min followed by 4 h reperfusion.

Opioid receptor agonist Eribis peptide 94 reduces infarct size in different porcine models for myocardial ischaemia and reperfusion.

Eribis peptide 94 (EP 94) is a novel enkephalin analog, thought to interact with the μ- and δ-opioid receptors. The purpose of the present study was to examine the cardioprotective potential of EP 94 in two clinically relevant porcine models of myocardial ischaemia and reperfusion, and to investigate if such an effect is associated with an increased expression of endothelial nitric oxide synthase (eNOS). Forty-one anesthetized pigs underwent 40min of coronary occlusion followed by 4h of reperfusion.

Arginase inhibition mediates cardioprotection during ischaemia-reperfusion.

Aims: Nitric oxide (NO) is vital for the integrity of the cardiovascular system and protection against ischaemic heart disease. Arginase is up-regulated during ischaemia-reperfusion (IR) and this enzyme might compete with NO synthase (NOS) for arginine. The present study investigated whether arginase blockade protects from myocardial IR injury and whether such an effect is coupled to increased NO bioavailability.

Adiponectin protects against myocardial ischaemia-reperfusion injury via AMP-activated protein kinase, Akt, and nitric oxide.

Aims: Cardiovascular disease and type 2 diabetes mellitus are associated with low plasma concentration of adiponectin. The aim of this study was to investigate whether adiponectin exerts cardioprotective effects during myocardial ischaemia-reperfusion and whether this effect is related to the production of nitric oxide (NO).

Methods And Results: Isolated rat hearts were subjected to 30 min of either global or local ischaemia followed by 60 min of reperfusion.

Cardioprotection mediated by rosiglitazone, a peroxisome proliferator-activated receptor gamma ligand, in relation to nitric oxide.

Unlabelled: Activation of peroxisome proliferator-activated receptor (PPAR) gamma protects from myocardial ischemia/reperfusion injury. The aim of the study was to investigate whether the cardioprotective effect of PPARgamma is related to nitric oxide (NO).

Methods: Wild type (WT) and endothelial NO synthase (eNOS) knockout (KO) mice received 3 mg/kg of the PPARgamma agonist rosiglitazone or vehicle (n = 6-9 in each group) i.

Cardioprotective effect of an endothelin receptor antagonist during ischaemia/reperfusion in the severely atherosclerotic mouse heart.

1. Endothelin (ET) receptor antagonists are cardioprotective during myocardial ischaemia and reperfusion through a nitric oxide (NO)-dependent mechanism. The aim of the present study was to investigate whether the ET receptor antagonist, bosentan, is cardioprotective in atherosclerotic mice.

The endothelin-1 receptor antagonist bosentan protects against ischaemia/reperfusion-induced endothelial dysfunction in humans.

Endothelial dysfunction may contribute to the extent of ischaemia/reperfusion injury. ET (endothelin)-1 receptor antagonism protects against myocardial ischaemia/reperfusion injury in animal models. The present study investigated whether oral administration of an ET(A)/ET(B) receptor antagonist protects against ischaemia/reperfusion-induced endothelial dysfunction in humans.

Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism.

A lot of interest has engendered in glucagon-like peptide-1 (GLP-1) as an emerging new drug in the treatment of type 2 diabetes. GLP-1 exerts several effects that reduce glycemia in type 2 diabetes patients. We recently also demonstrated that GLP-1 ameliorates endothelial dysfunction in type 2 diabetes mellitus patients with established coronary heart disease, suggesting a new important cardioprotective role for GLP-1.

Nitric oxide mediates protective effect of endothelin receptor antagonism during myocardial ischemia and reperfusion.

Endothelin (ET) receptor antagonism protects from ischemia-reperfusion injury. We hypothesized that the cardioprotective effect is related to nitric oxide (NO) bioavailability. Buffer-perfused rat and mouse hearts were subjected to ischemia and reperfusion.

Cardioprotective effect induced by brief exposure to nitric oxide before myocardial ischemia-reperfusion in vivo.

Administration of nitric oxide (NO) donors during ischemia and reperfusion protects from myocardial injury. However, whether administration of an NO donor during a brief period prior to ischemia protects the myocardium and the endothelium against ischemia-reperfusion injury in vivo is unknown. To study this possibility anesthetized pigs were subjected to 45-min ligation of the left anterior descending coronary artery (LAD) followed by 4h of reperfusion.