Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

Abstract

Fitzgerald SM, Kemp-Harper BK, Parkington HC, Head GA, Evans RG. Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endotheliumderived hyperpolarizing factor. Am J Physiol Regul Integr Comp Physiol 293: R707-R713, 2007. First published May 23, 2007; doi:10.1152/ajpregu.00807.2006.-We determined whether nitric oxide (NO) counters the development of hypertension at the onset of diabetes in mice, whether this is dependent on endothelial NO synthase (eNOS), and whether non-NO endothelium-dependent vasodilator mechanisms are altered in diabetes in mice. Male mice were instrumented for chronic measurement of mean arterial pressure (MAP). In wild-type mice, MAP was greater after 5 wk of N -nitro-L-arginine methyl ester (L-NAME; 100 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in drinking water; 97 Ϯ 3 mmHg) than after vehicle treatment (88 Ϯ 3 mmHg). MAP was also elevated in eNOS null mice (113 Ϯ 4 mmHg). Seven days after streptozotocin treatment (200 mg/kg iv) MAP was further increased in L-NAME-treated mice (108 Ϯ 5 mmHg) but not in vehicle-treated mice (88 Ϯ 3 mmHg) nor eNOS null mice (104 Ϯ 3 mmHg). In wild-type mice, maximal vasorelaxation of mesenteric arteries to acetylcholine was not altered by chronic L-NAME or induction of diabetes but was reduced by 42 Ϯ 6% in L-NAMEtreated diabetic mice. Furthermore, the relative roles of NO and endothelium-derived hyperpolarizing factor (EDHF) in acetylcholineinduced vasorelaxation were altered; the EDHF component was enhanced by L-NAME and blunted by diabetes. These data suggest that NO protects against the development of hypertension during earlystage diabetes in mice, even in the absence of eNOS. Furthermore, in mesenteric arteries, diabetes is associated with reduced EDHF function, with an apparent compensatory increase in NO function. Thus, prior inhibition of NOS results in endothelial dysfunction in early diabetes, since the diabetes-induced reduction in EDHF function cannot be compensated by increases in NO production. diabetes; endothelial function; endothelial nitric oxide synthase; mice IT IS CLEAR THAT DYSFUNCTION of endothelium-dependent vasodilation contributes to the pathogenesis of vascular diabetic complications (36). Endothelium-dependent vasodilation is mediated by multiple factors, including nitric oxide (NO), vasodilator prostanoids such as prostacyclin, and the so called endothelium-derived hyperpolarizing factor (EDHF) (36). To complicate matters further, EDHF appears to be not a unique substance but a range of factors whose contribution to endothelium-dependent vasodilation differs between various organs and species (5,12,13,16,21). Importantly, the relative contributions of dysfunction of these various endotheliumdependent relaxing factors to vascular diabetic complications remain a matter of intense debate (8,16,37).While in established diabetes reduced NO synthesis and enhanced NO breakdown likely make an important contribution to endothelium-dependent vasodilator dysfunction (36), there is also evidence t...

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“…The contribution of EDHF is most pronounced in smaller vessels, which limits a possible role for EDHF in diabetic endothelial dysfunction to the smaller resistance arteries and arterioles. Within the limited number of studies available, various effects of diabetes on EDHF production (reduction, compensatory increase, no contribution) have been reported depending on the type of vessel studied and experimental setting (De Vriese et al 2000;Fitzgerald et al 2007). …”

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“…The • NO diffuses into vascular smooth muscle cells and activates the guanylate cyclase, promoting cyclic GMP mediated vasodilation [29][30][31][32][33] . In normal conditions, the • NO performs key role in maintenance of vascular wall in quiescent status by inhibition of inflammation, cell proliferation and thrombus, reducing vascular tone, activation of platelet and leukocytes, proliferation of smooth muscle cells, extracellular matrix deposition and death of endothelial cells [34][35][36] .…”

“…However, the role of NADPH oxidase in such processes remain unknown, which is mainly attributable to occurrence of multiple isoforms of Nox (subunits which form the NADPH oxidase) and their vehicles, as well as to the lack of specific inhibitors 25,26 . The enzyme complex act as electron donor for reduction of O 2 into [29][30][31][32][33] . In normal conditions, the • NO performs key role in maintenance of vascular wall in quiescent status by inhibition of inflammation, cell proliferation and thrombus, reducing vascular tone, activation of platelet and leukocytes, proliferation of smooth muscle cells, extracellular matrix deposition and death of endothelial cells…”

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“…For example, using L-NAME mediated chronic NOS inhibition over four weeks in diabetic mice enhanced the contribution of EDHF, providing an alternative for endothelium-dependent relaxation in isolated mesenteric arteries (Fitzgerald et al, 2007). Since inflammation is present in the vasculature of subjects with both diabetes and hypertension (Brooks et al, 2008;Erdei et al, 2006), finding other ways to reverse the effects of inflammation will increase the health of the cardiovascular system.…”

“…This could include chronic inhibition of NO with minimal levels of a non-selective inhibitor (Fitzgerald et al, 2007) or targeting specific isozymes with inhibitors during their time of maximal activity (Lidington et al, 2007).…”