Altered Vascular Reactivity in Mice Made Hypertensive by Nitric Oxide Synthase Inhibition

Linder, A. Elizabeth; Weber, David S.; Whitesall, Steven E.; DʼAlecy, Louis G.; Webb, R.

doi:10.1097/01.fjc.0000175879.14994.63

Cited by 25 publications

(32 citation statements)

References 39 publications

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“…The peak increases in MAP were observed 3 days after the NOS inhibition protocol was started (105 Ϯ 3.8 for TRPV4 KO vs. 99.3 Ϯ 3.8 mmHg for WT, n ϭ 8 for each group) and returned toward baseline levels by day 5. Although the effect of L-NNA on MAP was transient in both groups, as has been observed in other studies employing mice (20), the present findings clearly indicate that TRPV4 channels can have a moderating effect on MAP during NOS inhibition-induced hypertension.…”

Section: Trpv4 Gene Deletion Exacerbates Nos Inhibition-induced Hypersupporting

confidence: 85%

TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

Earley

Pauyo²,

Drapp³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

196

273

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Earley S, Pauyo T, Drapp R, Tavares MJ, Liedtke W, Brayden JE. TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure. Am J Physiol Heart Circ Physiol 297: H1096 -H1102, 2009. First published July 17, 2009 doi:10.1152/ajpheart.00241.2009.-Transient receptor potential vanilloid 4 (TRPV4) channels have been implicated as mediators of calcium influx in both endothelial and vascular smooth muscle cells and are potentially important modulators of vascular tone. However, very little is known about the functional roles of TRPV4 in the resistance vasculature or how these channels influence hemodynamic properties. In the present study, we examined arterial vasomotor activity in vitro and recorded blood pressure dynamics in vivo using TRPV4 knockout (KO) mice. Acetylcholine-induced hyperpolarization and vasodilation were reduced by ϳ75% in mesenteric resistance arteries from TRPV4 KO versus wild-type (WT) mice. Furthermore, 11,12-epoxyeicosatrienoic acid (EET), a putative endothelium-derived hyperpolarizing factor, activated a TRPV4-like cation current and hyperpolarized the membrane of vascular smooth muscle cells, resulting in the dilation of mesenteric arteries from WT mice. In contrast, 11,12-EET had no effect on membrane potential, diameter, or ionic currents in the mesenteric arteries from TRPV4 KO mice. A disruption of the endothelium reduced 11,12-EET-induced hyperpolarization and vasodilatation by ϳ50%. A similar inhibition of these responses was observed following the block of endothelial (small and intermediate conductance) or smooth muscle (large conductance) K ϩ channels, suggesting a link between 11,12-EET activity, TRPV4, and K ϩ channels in endothelial and smooth muscle cells. Finally, we found that hypertension induced by the inhibition of nitric oxide synthase was greater in TRPV4 KO compared with WT mice. These results support the conclusion that both endothelial and smooth muscle TRPV4 channels are critically involved in the vasodilation of mesenteric arteries in response to endothelial-derived factors and suggest that in vivo this mechanism opposes the effects of hypertensive stimuli.calcium-activated potassium channels; endothelium; vascular smooth muscle; blood pressure; epoxyeicosatrienoic acid; transient receptor potential vanilloid 4 THE VASCULAR ENDOTHELIUM produces a variety of potent vasoactive factors that are critically important for blood flow and blood pressure regulation. Epoxyeicosatrienoic acids (EETs) are produced by cytochrome P-450 epoxygenase enzymes from arachidonic acid and act as an endothelium-derived hyperpolarizing factor (EDHF) in some vascular beds (3, 24). Vasodilation and smooth muscle cell hyperpolarization in response to EETs are associated with the increased activity of large-conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels. The vanilloid transient receptor potential channel TRPV4 can be activated by EETs, suggesting that the channel can also serve as a cell-surface receptor for these compounds. We recently demonstrated that in cerebr...

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Section: Trpv4 Gene Deletion Exacerbates Nos Inhibition-induced Hypersupporting

confidence: 85%

TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

Earley

Pauyo²,

Drapp³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

196

273

View full text Add to dashboard Cite

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“…Surprisingly, acetylcholine-induced vasorelaxation of vessels from mice treated chronically with L-NAME was attenuated following acute treatment with L-NAME, the soluble guanylate cyclase inhibitor ODQ, and indomethacin, but not indomethacin alone. This suggests that chronic L-NAME treatment may not completely abolish NO synthesis, as has been previously observed with chronic administration of N -nitro-L-arginine (19). If NOS inhibition was incomplete under the conditions of our experiment, the residual source of NO appears to be lost upon induction of diabetes, since we found that acetylcholineinduced vasorelaxation was unaffected by L-NAME ϩ ODQ in mesenteric arteries from diabetic mice chronically treated with L-NAME.…”

Section: Discussionsupporting

confidence: 71%

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

Fitzgerald

Kemp-Harper²,

Parkington³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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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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“…24 The aorta was used in this protocol because many previous studies have suggested that levels of basal NO are higher in the aorta than in smaller vessels. In brief, aortic rings were connected to a force transducer at a final tension of 0.5 g. Dose-response curves to phenylephrine were obtained.…”

Section: Vasomotor Studies In Vitromentioning

confidence: 99%

Overexpression of Dimethylarginine Dimethylaminohydrolase Inhibits Asymmetric Dimethylarginine–Induced Endothelial Dysfunction in the Cerebral Circulation

Dayoub

Rodionov

Lynch

et al. 2008

Stroke

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Background and Purpose-Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). An elevation of plasma ADMA levels is associated with cardiovascular disease. ADMA is hydrolyzed by dimethylarginine dimethylaminohydrolases (DDAHs). The goal of this study was to determine whether overexpression of human DDAH-1 in transgenic (DDAH-1-Tg) mice inhibits the vascular effects of ADMA. Methods-Using nontransgenic (non-Tg) and DDAH-1-Tg mice, we compared responses of the carotid artery and aorta (in vitro) and of the cerebral arterioles (in vivo) in the absence or presence of ADMA. DDAH-1 expression and plasma levels of ADMA were also measured. Results-Western blotting indicated that vascular expression of DDAH-1 was increased markedly in DDAH-1-Tg mice.Plasma levels of ADMA were reduced by Ϸ50% in DDAH-1-Tg mice compared with non-Tg mice (0.19Ϯ0.02 vs 0.37Ϯ0.04 mol/L, PϽ0.05). Contraction of the aorta to nitro-L-arginine methyl ester (an inhibitor of NOS), an index of basal production of NO, was increased in DDAH-1-Tg mice compared with controls (50Ϯ4% vs 34Ϯ4%, PϽ0.05).Relaxation of the carotid artery to acetylcholine (an endothelium-dependent agonist) was enhanced in DDAH-1-Tg animals compared with control mice (relaxation of 74Ϯ6% vs 59Ϯ5%, respectively, in response to 10 mol/L acetylcholine, PϽ0.05). ADMA (100 mol/L) impaired the vascular response to acetylcholine in both non-Tg and DDAH-1-Tg mice, but the relative difference between the 2 strains remained. Responses to the endotheliumindependent NO donor nitroprusside were similar in all groups. In vivo, ADMA (10 mol/L) reduced responses of the cerebral arterioles to acetylcholine by Ϸ70% in non-Tg mice (PϽ0.05), and this inhibitory effect was largely absent in DDAH-1-Tg mice. Conclusions-These findings provide the first evidence that overexpression of DDAH-1 increases basal levels of vascular NO and protects against ADMA-induced endothelial dysfunction in the cerebral circulation. Key Words: carotid arteries Ⅲ cerebral arterioles Ⅲ endothelium Ⅲ genetically altered mice Ⅲ nitric oxide N itric oxide (NO) production by NO synthases (NOSs) regulates cerebrovascular tone and brain perfusion as well as inhibits abnormal vascular growth. 1,2 Methylated arginine analogues such as N G -monomethyl-L-arginine (L-NMMA) and asymmetric dimethylarginine (ADMA) are produced endogenously during cellular turnover of methylated proteins and competitively inhibit NOS. [3][4][5] The major pathway for metabolism of ADMA is through hydrolysis by dimethylarginine dimethylaminohydrolases (DDAH). 4,6,7 Two DDAH genes, DDAH-1 and DDAH-2, have been described. 8,9 Exogenous ADMA produces vasoconstriction and inhibition of endothelial function in cerebral arteries from several species, including humans. 10,11 In healthy human subjects, ADMA decreases brain perfusion and increases arterial stiffness. 12 Increased plasma levels of ADMA are present in patients with atherosclerosis, 13 cerebral small-vessel disease, 14 transient ischemic attacks and stroke, 15,1...

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Altered Vascular Reactivity in Mice Made Hypertensive by Nitric Oxide Synthase Inhibition

Cited by 25 publications

References 39 publications

TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure

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

Overexpression of Dimethylarginine Dimethylaminohydrolase Inhibits Asymmetric Dimethylarginine–Induced Endothelial Dysfunction in the Cerebral Circulation

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