The arginine‐nitric oxide pathway: A target for new drugs

Kerwin, James F.; Heller, Michael

doi:10.1002/med.2610140103

Cited by 206 publications

(123 citation statements)

References 466 publications

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“…However, as mentioned above, the present data are the first to show that a documented suppression of islet cNOS activity is accompanied by an increase in glucose-stimulated insulin release. In the present study we also found that a marked and significant inhibition of islet cNOS required a rather high concentration of L-NAME (5 mM) when compared with some other tissues previously investigated (Kerwin & Heller 1994, Knowles & Moncada 1994) although high concentrations were required for e.g. human platelets and granulocytes (Chen & Mehta 1996).…”

Section: Insulin Secretionsupporting

confidence: 73%

“…It is now well documented that nitric oxide (NO) is a novel type of messenger molecule, which is involved in the signal transduction of many different physiological functions (Kerwin & Heller 1994, Knowles & Moncada 1994. NO is formed from the metabolism of -arginine through the action of NO synthase (NOS).…”

Section: Introductionmentioning

confidence: 99%

“…The purpose of the present investigation was to measure directly, both in vitro and in vivo, the islet cNOS activity in the absence and presence of a selective inhibitor of NOS, the arginine analogue N G -nitro--arginine methyl ester (L-NAME) (Moncada et al 1991, Kerwin & Heller 1994, Southan & Szabó 1996 in relation to the effects of cNOS-derived NO on glucose regulation of insulin and glucagon release. It will be shown here, for the first time, that the potentiating effect of L-NAME on glucoseinduced insulin release is correlated to its ability to inhibit islet cNOS activity both in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice

Åkesson¹,

Henningsson²,

Salehi³

et al. 1999

Journal of Endocrinology

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We have studied, by a combined in vitro and in vivo approach, the relation between the inhibitory action of N G -nitro--arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide synthase (NOS), on the activity of islet constitutive NOS (cNOS) and glucose regulation of islet hormone release in mice. The cNOS activity in islets incubated in vitro at 20 mM glucose was not appreciably affected by 0·05 or 0·5 mM L-NAME, but was greatly suppressed (-60%) by 5 mM L-NAME. Similarly, glucosestimulated insulin release was unaffected by the lower concentrations of L-NAME but greatly enhanced in the presence of 5 mM of the NOS inhibitor. In incubated islets inhibition of cNOS activity resulted in a modestly enhanced insulin release in the absence of glucose, did not display any effect at physiological or subphysiological glucose concentrations, but resulted in a markedly potentiated insulin release at hyperglycaemic glucose concentrations. In the absence of glucose, glucagon secretion was suppressed by L-NAME. The dynamics of glucoseinduced insulin release and 45 Ca 2+ efflux from perifused islets revealed that L-NAME caused an immediate potentiation of insulin release, and a slight increase in 45 Ca 2+ efflux. In islets depolarized with 30 mM K + in the presence of the K + ATP channel opener, diazoxide, L-NAME still greatly potentiated glucose-induced insulin release. Finally, an i.v. injection of glucose to mice pretreated with L-NAME was followed by a markedly potentiated insulin response, and an improved glucose tolerance. In accordance, islets isolated directly ex vivo after L-NAME injection displayed a markedly reduced cNOS activity. In conclusion, we have shown here, for the first time, that biochemically verified suppression of islet cNOS activity, induced by the NOS inhibitor L-NAME, is accompanied by a marked potentiation of glucosestimulated insulin release both in vitro and in vivo. The major action of NO to inhibit glucose-induced insulin release is probably not primarily linked to changes in Ca 2+ fluxes and is exerted mainly independently of membrane depolarization events.

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Section: Insulin Secretionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice

Åkesson¹,

Henningsson²,

Salehi³

et al. 1999

Journal of Endocrinology

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show abstract

“…NO is involved in a variety of physiological and pathological processes; it is also one of the final effectors in the immune system, where it is generated in large amounts (mM range) after induction of iNOS, in particular by macrophages. It diffuses into parasitic cells or into cancer cells, and kills them by producing reactive species and by inhibiting enzymes or other functional proteins [7,8]. In tumours, NO regulates a number of signalling pathways, and its effects are complex and closely dependent on concentration.…”

Section: Introductionmentioning

confidence: 99%

Thymopentin down-regulates both activity and expression of iNOS in blood cells of Sézary syndrome patients

et al. 2012

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While thymopentin has been used for many years in the experimental treatment of Sézary syndrome (SS), a rare and very aggressive lymphoma, its mechanism of action is still not known.Herein we show that this peptide acts as an inhibitor of isolated iNOS and nNOS isoforms, and reduces iNOS protein/mRNA levels and iNOS activity in blood cells obtained from both healthy donors and SS patients. Similar results were obtained with TPN-2, the N  -nitro analogue of the Arg-Lys motif present in thymopentin. Additional investigations are necessary to confirm the role and the relative importance of the two mechanisms of iNOS down-regulation in the therapeutic action of these peptides against SS.

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“…Indeed, NO is a physiological messenger that triggers a variety of actions in different systems. [15] In particular, it plays very important roles in the cardiovascular system in maintaining a number of homeostatic responses: preservation of endothelial integrity, arterial blood vessel dilation including pulmonary arterial vasculature, inhibition of platelet adherence and aggregation, attenuation of leukocyte adherence, and activation and inhibition of vascular smooth muscle cell proliferation. [16] NO also triggers relevant action in airways, inducing relaxation of airway smooth muscle, pro-inflammatory or anti-inflammatory effects, and regulation of mucociliary clearance.…”

mentioning

confidence: 99%

Multitarget Drugs: Synthesis and Preliminary Pharmacological Characterization of Zileuton Analogues Endowed with Dual 5‐LO Inhibitor and NO‐Dependent Activities

et al. 2010

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The arginine‐nitric oxide pathway: A target for new drugs

Cited by 206 publications

References 466 publications

Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice

Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice

Thymopentin down-regulates both activity and expression of iNOS in blood cells of Sézary syndrome patients

Multitarget Drugs: Synthesis and Preliminary Pharmacological Characterization of Zileuton Analogues Endowed with Dual 5‐LO Inhibitor and NO‐Dependent Activities

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