Effects of the New Arginase Inhibitor Nω-Hydroxy-nor-l-Arginine on NO Synthase Activity in Murine Macrophages

Tenu, Jean‐Pierre; Lepoivre, Michel; Moali, Catherine; Brollo, Maurice; Mansuy, Daniel; Boucher, Jean‐Luc

doi:10.1006/niox.1999.0255

Cited by 128 publications

(98 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Third, the contribution of arginase in these vasodilations was examined by treating vessels with the arginase inhibitor ␣-difluoromethylornithine (DFMO; 0.4 mmol/L, 60-minute intraluminal incubation; a gift from Ilex Oncology) 19 or N -hydroxy-nor-L-arginine (NOHA; 0.1 mmol/L, 60-minute intraluminal incubation; Alexis). 20,21 Drugs were obtained from Sigma, except when specifically stated otherwise.…”

Section: Functional Assessment Of Isolated Coronary Arteriolesmentioning

confidence: 99%

Upregulation of Vascular Arginase in Hypertension Decreases Nitric Oxide–Mediated Dilation of Coronary Arterioles

et al. 2004

View full text Add to dashboard Cite

Abstract-One characteristic of hypertension is a decreased endothelium-dependent nitric oxide (NO)-mediated vasodilation; however, the underlying mechanism is complex. In endothelial cells (ECs), L-arginine is the substrate for both NO synthase (NOS) and arginase. Because arginase has recently been shown to modulate NO-mediated dilation of coronary arterioles by reducing L-arginine availability, we hypothesized that upregulation of vascular arginase in hypertension contributes to decreased NO-mediated vasodilation. To test this hypothesis, hypertension (mean arterial blood pressure Ͼ150 mm Hg) was maintained for 8 weeks in pigs by aortic coarctation. Coronary arterioles from normotensive (NT) and hypertensive (HT) pigs were isolated and pressurized for in vitro study. NT vessels dilated dose-dependently to adenosine (partially mediated by endothelial release of NO) and sodium nitroprusside (endothelium-independent vasodilator). Conversely, HT vessels exhibited reduced dilation to adenosine but dilated normally to sodium nitroprusside. Adenosine-stimulated NO release was increased Ϸ3-fold in NT vessels but was reduced in HT vessels. Moreover, arginase activity was 2-fold higher in HT vessels. Inhibition of arginase activity by N -hydroxynor-L-arginine or incubation with L-arginine partially restored NO release and dilation to adenosine in HT vessels. Immunohistochemistry showed that arginase expression was increased but NOS expression was decreased in arteriolar ECs of HT vessels. These results suggest that NO-mediated dilation of coronary arterioles is inhibited in hypertension by an increase in arginase activity in EC, which limits L-arginine availability to NOS for NO production. The inability of arginase blockade or L-arginine supplementation to completely restore vasodilation may be related to downregulation of endothelial NOS expression. Key Words: arginine Ⅲ hypertension Ⅲ microcirculation Ⅲ nitric oxide synthase Ⅲ vasodilation H ypertension is a major risk factor for coronary artery disease. One characteristic of hypertension that appears to be critical in the development of vascular disease is the impairment of endothelial function. For example, there is a markedly reduced endothelium-dependent vasodilation in both large and small coronary arteries from hypertensive humans and animal models of hypertension. 1 Mounting evidence suggests that this vascular impairment may be related to a diminished production and bioavailability of the potent vasodilator nitric oxide (NO), which may result from an increased vascular production of superoxide anion 2 or decreased endothelial levels of tetrahydrobiopterin 3,4 or L-arginine. 5 Interestingly, administration of NO precursor L-arginine restores endothelium-mediated vasodilatory function in patients with essential hypertension, 5 improves coronary hemodynamics in spontaneously hypertensive rats, 6 and increases NO production and reduces blood pressure in hypertensive rats with 7 or without 8 renal failure. These results suggest the possible reduction of L-arginine ...

show abstract

Section: Functional Assessment Of Isolated Coronary Arteriolesmentioning

confidence: 99%

Upregulation of Vascular Arginase in Hypertension Decreases Nitric Oxide–Mediated Dilation of Coronary Arterioles

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Hence, such a mechanism could be responsible for the NO-independent CTL suppression by adherent progressor cells. To test this hypothesis, norNOHA, a potent and specific inhibitor for arginase (57), was added to the CTL cultures, either alone or in combination with the iNOS inhibitor L-NMMA. As shown in Fig.…”

Section: The Adherent Cells Of Progressors Exhibit High Arginase Actimentioning

confidence: 99%

Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells

Liu

Ginderachter

Brys

et al. 2003

The Journal of Immunology

View full text Add to dashboard Cite

Most of the mice bearing a s.c. BW-Sp3 lymphoma tumor mount a CD8+ T cell-mediated response resulting in tumor regression. Nonetheless, tumor progression occurs in some of the recipients and is associated with CTL inactivity. We demonstrated that T cell-activating APC were induced in regressors whereas T cell suppressive myeloid cells predominated in the spleen of progressors. Indeed, in vitro depletion of either the adherent or the CD11b+ populations restored T cell cytotoxicity and proliferation in these mice. This CTL inhibition was cell-to-cell contact-dependent but not mediated by NO. However, the same progressor suppressive cells prevented the activity of in vitro-restimulated CTLs derived from regressors in a cell-to-cell contact and NO-dependent fashion. Thus, either the NO-dependent or -independent suppressive pathway prevailed, depending on the target CTL population. In addition, the suppressive population expressed a high arginase activity, suggesting an association of the suppressive phenotype with alternatively activated (M2) myeloid cells. However, the high arginase activity is not directly involved in the suppressive process. Our results provide new insights for myeloid cell-mediated CTL inhibition during cancer progression.

show abstract

“…It is produced as an intermediary step when L-arginine is metabolized by the NOS enzymes and is also a direct substrate for NOS [14;15]. Recently, a more potent synthetic analogue of NOHA was identified, N-omega-hydroxy-nor-L-arginine (nor-NOHA) [15][16][17]. This compound increases L-arginine availability by inhibiting arginase activity, but does not directly increase NO or citrulline production as it is not a substrate for NOS [15].…”

Section: Introductionmentioning

confidence: 99%

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

et al. 2008

View full text Add to dashboard Cite

Background-Liver ischemia reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. Nitric oxide (NO), shown to have protective effects in I/R, is produced by nitric oxide synthase (NOS) from the substrate arginine. The purpose of this study was to determine if nor-NOHA, a novel arginase inhibitor, would be able to increase circulating arginine levels and decrease hepatic damage following warm I/R.

show abstract

Effects of the New Arginase Inhibitor Nω-Hydroxy-nor-l-Arginine on NO Synthase Activity in Murine Macrophages

Cited by 128 publications

References 40 publications

Upregulation of Vascular Arginase in Hypertension Decreases Nitric Oxide–Mediated Dilation of Coronary Arterioles

Upregulation of Vascular Arginase in Hypertension Decreases Nitric Oxide–Mediated Dilation of Coronary Arterioles

Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells

Arginase blockade protects against hepatic damage in warm ischemia-reperfusion

Contact Info

Product

Resources

About