Arginase inhibition prevents the development of hypertension and improves insulin resistance in obese rats.

This study investigated the temporal activation of arginase in obese Zucker rats (ZR) and determined if arginase inhibition prevents the development of hypertension and improves insulin resistance in these animals. Arginase activity, plasma arginine and nitric oxide (NO) concentration, blood pressure, and insulin resistance were measured in lean and obese animals. There was a chronological increase in vascular and plasma arginase activity in obese ZR beginning at 8 weeks of age.

Arginase promotes endothelial dysfunction and hypertension in obese rats.

Objective: This study investigated whether arginase contributes to endothelial dysfunction and hypertension in obese rats.

Methods: Endothelial function and arginase expression were examined in skeletal muscle arterioles from lean and obese Zucker rats (ZRs). Arginase activity, arginine bioavailability, and blood pressure were measured in lean and obese animals.

Arginase promotes skeletal muscle arteriolar endothelial dysfunction in diabetic rats.

Endothelial dysfunction is a characteristic feature in diabetes that contributes to the development of vascular disease. Recently, arginase has been implicated in triggering endothelial dysfunction in diabetic patients and animals by competing with endothelial nitric oxide synthase for substrate l-arginine. While most studies have focused on the coronary circulation and large conduit blood vessels, the role of arginase in mediating diabetic endothelial dysfunction in other vascular beds has not been fully investigated.

Transfusion-related acute lung injury in a rat model of trauma-hemorrhage.

Background: Major trauma often causes hemorrhage and predisposes to transfusion-related acute lung injury (TRALI). TRALI is a leading cause of transfusion-related deaths; however, its pathophysiology is uncertain. In the existing two-event models of TRALI, infection (lipopolysaccharide injection) is followed by the infusion of aged blood products.

Vascular arginase contributes to arteriolar endothelial dysfunction in a rat model of hemorrhagic shock.

Background: Hemorrhagic shock causes hypoperfusion of peripheral tissues and promotes endothelial dysfunction, which may lead to further tissue injury. Trauma increases extrahepatic activity of arginase, an enzyme which competes for l-arginine with nitric oxide synthase, and plays a key role in the development of endothelial dysfunction during aging, hypertension, and diabetes. However, the role of arginase in hemorrhage-induced endothelial dysfunction has not been studied.

Hypochlorous acid-induced heme oxygenase-1 gene expression promotes human endothelial cell survival.

Hypochlorous acid (HOCl) is a unique oxidant generated by the enzyme myeloperoxidase that contributes to endothelial cell dysfunction and death in atherosclerosis. Since myeloperoxidase localizes with heme oxygenase-1 (HO-1) in and around endothelial cells of atherosclerotic lesions, the present study investigated whether there was an interaction between these two enzymes in vascular endothelium. Treatment of human endothelial cells with the myeloperoxidase product HOCl stimulated a concentration- and time-dependent increase in HO-1 protein that resulted in a significant rise in carbon monoxide (CO) production.

Development of a sleeve gastrectomy weight loss model in obese Zucker rats.

Background: Obesity promotes the development of diabetes and cardiovascular disease. The most effective weight loss treatment is bariatric surgery, but results greatly vary depending on the procedure. Sleeve gastrectomy (SG) has recently emerged as a reduced risk weight loss procedure for super obese patients.

Heme oxygenase-derived endogenous carbon monoxide impairs flow-induced dilation in resistance vessels.

Vascular tissues normally express heat shock protein 32 (heme oxygenase [HO] 1), which degrades heme. A product of this reaction, carbon monoxide (CO), has been shown to promote relaxation of vascular smooth muscle, but it also inhibits NOS. Because flow-induced dilation is dependent upon the formation of endothelium-derived NO, we conducted the current study to determine if HO-mediated formation of CO impairs flow-induced dilation.

Arginase: a critical regulator of nitric oxide synthesis and vascular function.

1. Arginase is the focal enzyme of the urea cycle hydrolysing L-arginine to urea and L-ornithine. Emerging studies have identified arginase in the vasculature and have implicated this enzyme in the regulation of nitric oxide (NO) synthesis and the development of vascular disease.

Influence of the heme-oxygenase pathway on cerebrocortical blood flow.

Heme-oxygenase (HO)-derived carbon monoxide (CO) is generated in the cardiovascular and in the central nervous systems. Endogenous CO exerts direct vascular effects and has also been shown to inhibit nitric oxide synthase (NOS). In the current study, the heme-oxygenase blockade [zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG), 45 micromol/kg intraperitoneally] decreased cerebral CO production and increased cerebrocortical blood flow (CBF) in anesthetized rats.

Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells.

Arginine contains the guanidinium group and thus has structural similarity to ligands of imidazoline and alpha-2 adrenoceptors (alpha-2 AR). Therefore, we investigated the possibility that exogenous arginine may act as a ligand for these receptors in human umbilical vein endothelial cells and activate intracellular nitric oxide (NO) synthesis. Idazoxan, a mixed antagonist of imidazoline and alpha-2 adrenoceptors, partly inhibited L-arginine-initiated NO formation as measured by a Griess reaction.

Role of carbon monoxide in cardiovascular function.

Carbon monoxide (CO) is an endogenously derived gas formed from the breakdown of heme by the enzyme heme oxygenase. Although long considered an insignificant and potentially toxic waste product of heme catabolism, CO is now recognized as a key signaling molecule that regulates numerous cardiovascular functions. Interestingly, alterations in CO synthesis are associated with many cardiovascular disorders, including atherosclerosis, septic shock, hypertension, metabolic syndrome, and ischemia-reperfusion injury.

Metabolic syndrome increases endogenous carbon monoxide production to promote hypertension and endothelial dysfunction in obese Zucker rats.

Vascular heme oxygenase (HO) metabolizes heme to form carbon monoxide (CO). Increased heme-derived CO inhibits nitric oxide synthase and can contribute to hypertension via endothelial dysfunction in Dahl salt-sensitive rats. Obese Zucker rats (ZR) are models of metabolic syndrome.

Arginase inhibition restores arteriolar endothelial function in Dahl rats with salt-induced hypertension.

Vascular tissues express arginase that metabolizes L-arginine to L-ornithine and urea and thus reduces substrate availability for nitric oxide formation. Dahl salt-sensitive (Dahl-S) rats with salt-induced hypertension show endothelial dysfunction, including decreased vascular nitric oxide formation. This study tests the hypothesis that increased vascular arginase activity contributes to endothelial dysfunction in hypertensive Dahl-S rats.

Heme oxygenase-derived carbon monoxide promotes arteriolar endothelial dysfunction and contributes to salt-induced hypertension in Dahl salt-sensitive rats.

Vascular tissues express heme oxygenase (HO), which metabolizes heme to form carbon monoxide (CO). Heme-derived CO inhibits nitric oxide synthase and promotes endothelium-dependent vasoconstriction. After 4 wk of high-salt diet, Dahl salt-sensitive (Dahl-S) rats display hypertension, increased vascular HO-1 expression, and attenuated vasodilator responses to ACh that can be completely restored by acute treatment with an inhibitor of HO.

Cyclic strain stimulates L-proline transport in vascular smooth muscle cells.

Background: The increase in vessel wall strain in hypertension contributes to arterial remodeling by stimulating vascular smooth muscle cell (SMC) proliferation and collagen synthesis. Because L-proline is essential for the synthesis of collagen and cell growth, we examined whether cyclic strain regulates the transcellular transport of L-proline by vascular SMC.

Methods: Cultured rat aortic SMCs were subjected to mechanical strain using the Flexercell 3000 Strain Unit.

Enhanced heme oxygenase-mediated coronary vasodilation in Dahl salt-sensitive hypertension.

Background: Cardiovascular tissues express heme oxygenase (HO), which metabolizes heme to form carbon monoxide (CO). Carbon monoxide promotes relaxation of coronary vascular smooth muscle. Increased HO-1 expression provides cardioprotection during certain pathologic conditions.

Heme oxygenase-mediated endothelial dysfunction in DOCA-salt, but not in spontaneously hypertensive, rat arterioles.

Vascular heme oxygenase (HO) metabolizes heme to form carbon monoxide. Carbon monoxide inhibits nitric oxide synthase and promotes endothelium-dependent vasoconstriction. We reported HO-1-mediated endothelial dysfunction in Dahl salt-sensitive hypertension.

Carbon monoxide promotes endothelium-dependent constriction of isolated gracilis muscle arterioles.

Vascular tissues express heme oxygenase, which metabolizes heme to form carbon monoxide (CO). CO promotes relaxation of vascular smooth muscle but also inhibits nitric oxide (NO) formation. This study examines the hypothesis that CO promotes endothelium- and NO synthase-dependent vasoconstriction of isolated arterioles.

Heme oxygenase inhibitor restores arteriolar nitric oxide function in dahl rats.

Vascular tissues express heme oxygenase (HO), which metabolizes heme to form carbon monoxide (CO). CO relaxes vascular smooth muscle but inhibits nitric oxide (NO) formation. Decreased NO synthesis may contribute to salt-induced hypertension in Dahl salt-sensitive (DS) rats.

Vascular effects of a heme oxygenase inhibitor are enhanced in the absence of nitric oxide.

Background: Vascular endothelium and smooth muscle express heme oxygenase (HO) that metabolizes heme to biliverdin, iron and carbon monoxide (CO). Carbon monoxide promotes endothelium-independent vasodilation, but also inhibits nitric oxide formation. This study examines the hypothesis that an inhibitor of HO promotes endothelium-independent vasoconstriction, which is attenuated in the presence of unabated nitric oxide formation.