Effect of N<sup>G</sup>‐monomethyl‐L‐arginine on kinin‐induced vasodilation in the human forearm.

Cockcroft, JR; Chowienczyk, Phil; Brett, SE; Ritter, JM

doi:10.1111/j.1365-2125.1994.tb04358.x

Cited by 55 publications

(42 citation statements)

References 25 publications

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“…5-MTHF normalised NO-mediated vasodilation in patients with Type II diabetes (s) (#p<0.05) others [9,10]. However, whereas decreased responsiveness of the smooth muscle cells to NO and/or enhanced generation of endothelium-derived constricting factors [27,28] might have contributed to the impaired endothelium-dependent NO-mediated vasodilator response, this data suggests a vital defect in endothelium-derived NO bioavailability in patients with Type II diabetes.…”

Section: Discussionmentioning

confidence: 53%

Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

et al. 2002

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Aims/hypothesis. Patients with diabetes are characterised by endothelial dysfunction and cardiovascular mortality. In particular endothelium-derived nitric oxide has emerged as a first line mechanism against atherosclerosis. Hyperglycaemia causes oxygen radical stress but has also been associated with endothelial nitric oxide synthase uncoupling, both lead to decreased nitric oxide-availability. We recently showed that folate reverses eNOS uncoupling in vitro. Therefore we hypothesise that folate improves endothelial function in Type II (non-insulin-dependent) diabetes mellitus in vivo. Methods. Using forearm plethysmography, we evaluated the effect of local, intra-arterial administration of 5-methyltetrahydrofolate (5-MTHF, the active form of folic acid, 1 µg/100 ml FAV/min) on forearm blood flow in 23 patients with Type II diabetes and 21 control subjects, matched for age, sex, blood pressure, body mass index, weight and smoking habits. Serotonin as a stimulator of nitric oxide-dependent vasodilation and sodium nitroprusside as a stimulator of endothelium-independent vasodilation were infused. Results. Serotonin-induced vasodilation was blunted (53±30 vs 102±66 M/C%, p<0.005) and nitroprussideinduced vasodilation was mildly reduced (275±146 vs 391±203 M/C%, p<0.05) in patients with Type II diabetes compared to control subjects. 5-MTHF improved nitric oxide-mediated vasodilation (from 53±30 to 88±59 M/C%, p<0.05) in patients with Type II diabetes mellitus. As expected, 5-MTHF had no effect on forearm blood flow in control subjects. Conclusion/interpretation. These data imply that folate can be used to improve nitric oxide status and to restore endothelial dysfunction in patients with Type II diabetes. Our results provide a strong rationale for the initiation of studies that investigate whether supplementation with folic acid prevents future cardiovascular events in this patient group. [Diabetologia (2002[Diabetologia ( ) 45:1004[Diabetologia ( -1010

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Section: Discussionmentioning

confidence: 53%

Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

et al. 2002

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“…This is consistent with data from previous studies demonstrating that NOS inhibition decreases basal FBF and attenuates the FBF response to BK. 11,24 In contrast, coadministration of L-NMMA had no effect on the tPA response to BK when administered either alone or in combination with indomethacin. This finding conflicts with the observations of Newby et al, 25 who reported that coadministration of L-NMMA attenuated the tPA response to another agonist, substance P; however, Tranquille and Emeis 26 observed no effect of N G -nitro-Larginine on BK-stimulated tPA release from rat vasculature.…”

Section: Discussionmentioning

confidence: 84%

Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B ₂ Receptor–Dependent, NO Synthase–Independent, and Cyclooxygenase-Independent Pathway

et al. 2000

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Background-Bradykinin stimulates dose-dependent tissue plasminogen activator (tPA) release from human endothelium.Although bradykinin is known to cause vasodilation through B 2 receptor-dependent effects on NO, prostacyclin, and endothelium-derived hyperpolarizing factor production, the mechanism(s) underlying tPA release is unknown. Methods and Results-We measured the effects of intra-arterial bradykinin (100, 200, and 400 ng/min), acetylcholine (15, 30, and 60 g/min), and nitroprusside (0.8, 1.6, and 3.2 g/min) on forearm vasodilation and tPA release in healthy volunteers in the presence and absence of (1) the B 2 receptor antagonist HOE 140 (100 g/kg IV), (2) the NO synthase inhibitor L-N G -monomethyl-L-arginine (L-NMMA, 4 mol/min intra-arterially), and (3) the cyclooxygenase inhibitor indomethacin (50 mg PO TID). B 2 receptor antagonism attenuated vasodilator (Pϭ0.004) and tPA (Pϭ0.043) responses to bradykinin, without attenuating the vasodilator response to nitroprusside (Pϭ0.36). L-NMMA decreased basal forearm blood flow (from 2.35Ϯ0.31 to 1.73Ϯ0.22 mL/min per 100 mL, Pϭ0.01) and blunted the vasodilator response to acetylcholine (Pϭ0.013) and bradykinin (Pϭ0.07, Pϭ0.038 for forearm vascular resistance) but not that to nitroprusside (Pϭ0.47). However, there was no effect of L-NMMA on basal (Pϭ0.7) or bradykinin-stimulated tPA release (Pϭ0.45). Indomethacin decreased urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin F 1␣ (Pϭ0.04). The vasodilator response to endothelium-dependent (Pϭ0.019 for bradykinin) and endotheliumindependent (Pϭ0.019) vasodilators was enhanced during indomethacin administration. In contrast, there was no effect of indomethacin alone (Pϭ0.99) or indomethacin plus L-NMMA (Pϭ0.36) on bradykinin-stimulated tPA release. Conclusions-These data indicate that bradykinin stimulates tPA release from human endothelium through a B 2 receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway. Bradykinin-stimulated tPA release may represent a marker for the endothelial effects of endothelium-derived hyperpolarizing factor. (Circulation.

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“…20,21 A possible explanation could be that both studies did not use the NO clamp technique; that is, L-NMMA was infused, resulting in vasoconstriction, and subsequently BK was infused while basal flow was not restored. Therefore, the attenuated vasodilation by BK in both studies could have been a result of the changed basal contractile state of the vascular smooth muscles, because it is demonstrated that the greater the precontraction of a vessel, the lesser the relaxant response to the vasodilator.…”

Section: Discussionmentioning

confidence: 99%

Bradykinin-Induced Vasodilation of Human Forearm Resistance Vessels Is Primarily Mediated by Endothelium-Dependent Hyperpolarization

Honing¹,

Smits²,

Morrison³

et al. 2000

Hypertension

102

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Abstract-Bradykinin (BK) stimulates endothelial cells to release a number of relaxing factors, such as NO, prostanoids (PGs), and an endothelium-derived hyperpolarizing factor (EDHF). However, the contributions of NO, PG, and EDHF in the vascular relaxation to BK vary with species and anatomic origin of blood vessels used. Therefore, the present study was designed to investigate the contributions of NO, PG, and EDHF in vasodilation caused by BK in human forearm resistance vessels. Forearm blood flow (FBF) was recorded with venous occlusion plethysmography in healthy nonsmoking subjects. At first, studies were performed to validate the NO clamp technique for its ability to inhibit endogenous NO generation. Brachial artery infusion of serotonin (0.6, 1.8, and 6 ng ⅐ 100 mL forearm volume [FAV] Ϫ1 ⅐ min Ϫ1) caused significant forearm vasodilation (2.6 to 4.6 mL ⅐ 100 mL FAV Ϫ1 ⅐ min Ϫ1), which is known to be NO mediated. Indeed, during the NO clamp, cumulative doses of serotonin caused no vasodilation (2.4 to 2.6 mL ⅐ 100 mL FAV Ϫ1 ⅐ min Ϫ1 ), indicating that the generation of endogenous NO was completely blocked. Thereafter, the vasodilative actions of BK were investigated. Brachial artery infusion of BK (50, 100, and 200 ng ⅐ 100 mL FAV Ϫ1 ⅐ min Ϫ1 ) caused significant forearm vasodilation in all studies (from 3.1 to 20.4 mL ⅐ 100 mL FAV Ϫ1 ⅐ min Ϫ1). After the inhibition of cyclooxygenase and NO synthase activity through the use of aspirin and the NO-clamp technique, BK increased FBF in a similar manner (3.9 to 18.9 mL ⅐ 100 mL FAV Ϫ1 ⅐ min Ϫ1 ), indicating that the vasodilative actions of BK are independent of NO and PG generation. However, vasodilation caused by the 2 lower doses of BK were significantly attenuated after K Ca channel activity was blocked with tetraethylammonium chloride (0.1 mg ⅐ 100 mL FAV Ϫ1 ⅐ min Ϫ1), suggesting that in the lower dose range, BK mediates vasodilation through the opening of vascular potassium channels. In conclusion, BK is a potent vasodilator peptide in human forearm resistance vessels, causing vasodilation through hyperpolarization of the vascular wall independent of NO and PG production. In addition, the NO-clamp technique is a valid instrument to investigate the contribution of NO in the vasodilative response to different agents. , and an endothelium-derived hyperpolarizing factor (EDHF). 1-3 However, the contributions of NO, PG, and EDHF to the vascular relaxation to BK vary with species and anatomic origin of the blood vessels used. 4,5 In vitro studies performed on isolated blood vessels demonstrate that the stimulation of NO release by acetylcholine is more prominent in larger arteries. In contrast, the contribution of EDHF to endothelium-dependent relaxation by BK is significant larger in microvessels. 6 These findings become relevant when interpreting the results of in vivo studies that measure hemodynamic parameters such as blood pressure and vascular resistance. For example, Mügge et al 7 investigated in vivo the response to acetylcholine in the perfused rabbit...

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Effect of N^G‐monomethyl‐L‐arginine on kinin‐induced vasodilation in the human forearm.

Cited by 55 publications

References 25 publications

Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B ₂ Receptor–Dependent, NO Synthase–Independent, and Cyclooxygenase-Independent Pathway

Bradykinin-Induced Vasodilation of Human Forearm Resistance Vessels Is Primarily Mediated by Endothelium-Dependent Hyperpolarization

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Effect of NG‐monomethyl‐L‐arginine on kinin‐induced vasodilation in the human forearm.

Cited by 55 publications

References 25 publications

Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B 2 Receptor–Dependent, NO Synthase–Independent, and Cyclooxygenase-Independent Pathway

Bradykinin-Induced Vasodilation of Human Forearm Resistance Vessels Is Primarily Mediated by Endothelium-Dependent Hyperpolarization

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Effect of N^G‐monomethyl‐L‐arginine on kinin‐induced vasodilation in the human forearm.

Bradykinin Stimulates Tissue Plasminogen Activator Release From Human Forearm Vasculature Through B ₂ Receptor–Dependent, NO Synthase–Independent, and Cyclooxygenase-Independent Pathway