Evolution of Chronic Nitric Oxide Inhibition Hypertension

Qiu, Chunhua; Muchant, Dianne G.; Beierwaltes, William H.; Racusen, Lorraine C.; Baylis, Chris

doi:10.1161/01.hyp.31.1.21

Cited by 67 publications

(48 citation statements)

References 24 publications

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“…When losartan was administered with L-NAME, the 24-h NOx remained at similar low levels. This dose of L-NAME elevated blood pressure, which is in agreement with other studies that showed that systemic NO blockade at different doses causes general vasoconstriction and hypertension (28,30). In addition, there was a decrease in RBF and GFR as well as an increase in proteinuria, which accompanied the hypertension that has been previously reported (11,25).…”

Section: Discussionsupporting

confidence: 92%

“…In the micro-CT images of the present study, it is unlikely that the microvessels were constricted so that the microvasculature was incompletely filled with Microfil for several reasons: before infusion with Microfil, the vasculature was flushed with calcium-free saline to provide vasorelaxation; the opacity values were above background levels; the micro-CT images showed that the venous circulation was filled with Microfil; and the high-resolution synchrotron micro-CT images showed Microfil in the microvessels down to ϳ10-m diameter. In other studies, Qiu et al (28) showed that administration of L-arginine in acute phases of NO inhibition reversed the hypertensive effect, but following chronic NO inhibition the administration of L-arginine did not reverse the hypertension. This observation implies mechanisms other than vasoconstriction were responsible for the chronic hypertension.…”

Section: Discussionmentioning

confidence: 93%

“…It is possible that by 40 days, the nonatrophic, remnant glomeruli and nephrons had undergone further hypertrophy and expansion of the mesangial matrix than at the 19 days of treatment of the present study. In fact, Qiu et al (28) observed that at 21 days of L-NAME treatment, the glomerular lesions were mild but were more pronounced after 28 days. In addition to glomerular atrophy, we also observed tubular atrophy in both the group treated with L-NAME and the group treated with L-NAME and losartan.…”

Section: Discussionmentioning

confidence: 99%

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Effect of losartan on renal microvasculature during chronic inhibition of nitric oxide visualized by micro-CT

Fortepiani

Ruiz

Passardi

et al. 2003

American Journal of Physiology-Renal Physiology

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G -nitro-Larginine methyl ester (L-NAME) leads to an elevated systemic blood pressure and reduction in renal blood flow without significant changes in urinary sodium and water excretion. Simultaneous administration of ANG II AT 1 receptor antagonist losartan and L-NAME prevents the alterations in blood pressure and renal hemodynamics. Microcomputed tomography (micro-CT) was used to investigate the role of ANG II in the changes of renal microvasculature during chronic NO inhibition. Sprague-Dawley rats were given L-NAME with or without AT 1 receptor antagonist losartan (40 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 each) in their drinking water for 19 days. Kidneys from each group (control, L-NAME-, and L-NAME ϩ losartan-treated rats) were perfusion-fixed in situ, infused with a silicon-based polymer containing lead chromate, and scanned by micro-CT. The microvasculature in the reconstructed three-dimensional renal images was studied using computerized analytic techniques. Kidneys of L-NAMEtreated rats had significantly fewer normal glomeruli (28,824 Ϯ 838) than those of control rats (36,266 Ϯ 3,572). Losartan normalized the number to control values (34,094 Ϯ 1,536). The amount of vasculature in the cortex, outer medulla, and inner medulla of L-NAME-treated rats was about two-thirds that of control rats; losartan normalized the values to control levels. These data indicate that chronic treatment with the NO synthase inhibitor L-NAME produces a generalized rarefaction of renal capillaries. Because simultaneous AT1 receptor blockade abolished those changes, the data suggest that the reduction in vasculature is mediated by ANG II through AT 1 receptors. NG -nitro-L-arginine methyl ester; angiotensin II NITRIC OXIDE (NO) is a physiologically important vasodilator, which plays a major role in the regulation of systemic and renal hemodynamics (16). Chronic inhibition of NO synthesis produces a general vasoconstriction that leads to an increased blood pressure and impairment of renal function including decreased renal blood flow (RBF) and glomerular filtration rate (GFR) without significant changes in urinary sodium and water excretion (3,11,30). Besides the functional changes, the inhibition of NO synthesis produces renal vascular damage including glomerulosclerosis, ischemia, necrosis, and increased interstitium (12, 24). The mechanism underlying the effect of NO synthesis inhibition is not completely understood, but it is likely that the renin-angiotensin system is responsible for the renal and systemic alterations induced by the chronically reduced NO bioavailability. For instance, the simultaneous blockade of NO synthesis and ANG II AT 1 receptor prevents the hypertension, renal functional and morphological consequences of the inhibition of NO synthesis alone (35). Ohishi et al. (20) found that the blockade of ANG II AT 1 receptors attenuated the vasoconstriction elicited by the inhibition of NO synthesis in juxtamedullary afferent and efferent arterioles perfused in vitro. In vivo experiments (23) showed that NO modulated the ANG II re...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of losartan on renal microvasculature during chronic inhibition of nitric oxide visualized by micro-CT

Fortepiani

Ruiz

Passardi

et al. 2003

American Journal of Physiology-Renal Physiology

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“…9,24 It has also been suggested that hypertension induced by L-NAME treatment is sustained by an interaction of several mechanisms, including activation of the SNS and the renin-angiotensin system. 10,26,27 Because it is well known that the brain angiotensin system has excitatory effects in several areas, including the RVLM, this system may be involved in this model of hypertension. 28 -30 Another possibility is that NO could be acting as a neurotransmitter or neuromodulator in the RVLM to produce cardiovascular effects.…”

Section: Discussionmentioning

confidence: 99%

Rostral Ventrolateral Medulla

1999

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Abstract-The major aim of the present study was to evaluate the role of the rostral ventrolateral medulla (RVLM) in the maintenance of hypertension in rats subjected to long-term treatment with N G -nitro-L-arginine methyl ester (L-NAME) (70 mg/kg orally for 1 week). We inhibited or stimulated RVLM neurons with the use of drugs such as glycine, L-glutamate, or kynurenic acid in urethane-anesthetized rats (1.2 to 1.4 g/kg IV). Bilateral microinjection of glycine (50 nmol, 100 nL) into the RVLM of hypertensive rats produced a decrease in mean arterial blood pressure (MAP) from 158Ϯ4 to 71Ϯ4 mm Hg (PϽ0.05), which was similar to the decrease produced by intravenous administration of hexamethonium. In normotensive rats, glycine microinjection reduced MAP from 106Ϯ4 to 60Ϯ3 mm Hg (PϽ0.05). Glutamate microinjection into the RVLM produced a significant increase in MAP in both hypertensive rats (from 157Ϯ3 to 201Ϯ6 mm Hg) and normotensive rats (from 105Ϯ5 to 148Ϯ9 mm Hg). No change in MAP was observed in response to kynurenic acid microinjection into the RVLM in either group. These results suggest that hypertension in response to long-term L-NAME treatment is dependent on an increase in central sympathetic drive, mediated by RVLM neurons. However, glutamatergic synapses within RVLM are probably not involved in this response. Key Words: vasomotor system Ⅲ rostral ventrolateral medulla Ⅲ hypertension, experimental Ⅲ L-NAME Ⅲ glutamate I t is well known that pharmacological inhibition of nitric oxide synthase (NOS) produces acute and chronic hypertension, but the mechanisms mediating the hypertension are not completely understood. [1][2][3][4][5] Although this hypertension was first attributed solely to inhibition of endothelial nitric oxide (NO), more recently a large body of evidence suggests the involvement of the central nervous system. In particular, inhibition of neuronal NO may contribute to the hypertension induced by long-term treatment with N G -nitro-L-arginine methyl ester (L-NAME). 6 -8 Contradictory results have been reported about the role of the sympathetic nervous system (SNS) in the maintenance of hypertension induced by NOS blockade. In some studies, blockade of the SNS had no effect on this hypertension, 9,10 whereas other studies using similar methods showed a significant reduction in hypertension. 6,8,11 Because the rostral ventrolateral medulla (RVLM) contains sympathetic premotor neurons and is considered to be the final common pathway for several cardiovascular responses and for the control of sympathetic vasomotor tone, it is reasonable to suggest that these premotor neurons may be involved in the maintenance of hypertension due to NOS inhibition. 12 To test this hypothesis, we performed a study in which we compared the effects of pharmacological inhibition of the RVLM with the effects of ganglionic blockade on mean arterial pressure (MAP) and heart rate (HR) in hypertensive and control groups. We also tested the role of glutamatergic synapses within the RVLM in this model. MethodsExperiments wer...

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“…NO is a key regulator of vascular tone (23), and the physiological importance of NO in the regulation of blood pressure is highlighted by the fact that pharmacological inhibition of NO synthases leads to severe hypertension (24).…”

Section: Hif-alpha | Arginase | Vascular Tonementioning

confidence: 99%

HIF isoforms in the skin differentially regulate systemic arterial pressure

Cowburn

Takeda²,

Boutin³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Vascular flow through tissues is regulated via a number of homeostatic mechanisms. Localized control of tissue blood flow, or autoregulation, is a key factor in regulating tissue perfusion and oxygenation. We show here that the net balance between two hypoxia-inducible factor (HIF) transcription factor isoforms, HIF-1α and HIF-2α, is an essential mechanism regulating both local and systemic blood flow in the skin of mice. We also show that balance of HIF isoforms in keratinocyte-specific mutant mice affects thermal adaptation, exercise capacity, and systemic arterial pressure. The two primary HIF isoforms achieve these effects in opposing ways that are associated with HIF isoform regulation of nitric oxide production. We also show that a correlation exists between altered levels of HIF isoforms in the skin and the degree of idiopathic hypertension in human subjects. Thus, the balance between HIF-1α and HIF-2α expression in keratinocytes is a control element of both tissue perfusion and systemic arterial pressure, with potential implications in human hypertension.HIF-alpha | arginase | vascular tone A utoregulation of vascular flow in peripheral tissues is essential both for controlling local tissue perfusion and for the regulation of systemic blood pressure. This dual role for peripheral blood flow is dependent in turn on a range of factors that act to adjust local vascular tone. A key element of this control is the balance between O 2 demand and O 2 supply (1). This balance causes increased need for oxygen to induce increased blood flow. This regulatory pathway in peripheral tissues has a direct impact on systemic arterial pressure, because peripheral vascular resistance in large part determines total vascular resistance in the arterial bed.The skin contains a very extensive series of vascular plexi. This vascular bed has a range of essential functions, which include regulating body temperature. Skin circulation also is altered in a number of disease states, including renal disease (2), hypercholesterolemia (3), peripheral vascular disease (4), heart failure, and hypertension (5). Identification of structural alterations to the subcutaneous microvasculature provides a powerful prognostic tool to predict cardiovascular events in hypertensive patients (6), and impaired microvascular vasodilation and capillary rarefaction is associated with familial predisposition to hypertension (7).The heterodimeric transcription factors hypoxia-inducible factoralpha (HIF-1α) and HIF-2α are essential for the maintenance of cellular oxygen homeostasis (8). In response to hypoxia, stabilized HIF-1α and HIF-2α proteins initiate the expression of genes that alleviate hypoxic stress, including genes promoting cell growth, adhesion, and migration, new vessel formation, and the development of vascular networks (9,10).Recent data from a number of groups have indicated that HIF-1α and HIF-2α can act in a dualistic manner to regulate a range of responses in vivo; these interactions include functionally opposing interactions with the Myc t...

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Evolution of Chronic Nitric Oxide Inhibition Hypertension

Cited by 67 publications

References 24 publications

Effect of losartan on renal microvasculature during chronic inhibition of nitric oxide visualized by micro-CT

Effect of losartan on renal microvasculature during chronic inhibition of nitric oxide visualized by micro-CT

Rostral Ventrolateral Medulla

HIF isoforms in the skin differentially regulate systemic arterial pressure

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