The Development of Renal Pathology

Heptinstall, R. H.

doi:10.1016/s0272-6386(12)81042-0

Cited by 21 publications

(27 citation statements)

References 15 publications

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“…22 These changes were also observed in kidney specimens obtained from rats treated with L-NAME in the present study. We found that imidapril protected against the progressive deterioration of renal function in rats treated with L-NAME.…”

Section: Discussionsupporting

confidence: 82%

Antihypertensive Agents Prevent Nephrosclerosis and Left Ventricular Hypertrophy Induced in Rats by Prolonged Inhibition of Nitric Oxide Synthesis

Akuzawa

Nakamura

Kurashina

et al. 1998

American Journal of Hypertension

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We investigated the ability of the angiotensin converting enzyme (ACE) inhibitor imidapril hydrochloride, and of the calcium channel blocker amlodipine besilate, to prevent nephrosclerosis and left ventricular hypertrophy (LVH) in rats with hypertension induced by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), N G -nitro-L-arginine methyl ester (L-NAME) 500 mg/L, L-NAME plus imidapril 10 mg/L or 100 mg/L, or L-NAME plus amlodipine 50 mg/L or 100 mg/L in the drinking water (n ‫؍‬ ‫؍‬ 10 -12). We then collected 24-h urine samples at 2, 4, and 6 weeks, obtained blood samples at 6 weeks, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90 ؎ ؎ 0.65 v 0.05 ؎ ؎ 0.02 mg/day/100 g in control), and the area of the left ventricular wall (83.3 ؎ ؎ 3.0 v 69.8 ؎ ؎ 1.8 mm 2 in control). Nephrosclerosis and myocardial interstitial fibrosis were documented histologically. The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of imidapril (10 mg/L) with L-NAME completely normalized the tail-cuff pressure, the LVH (70.8 ؎ ؎ 1.8 mm 2 ), the albuminuria (0.05 ؎ ؎ 0.01 mg/day/100 g), and the histologic changes. Amlodipine (50 mg/L) also ameliorated the L-NAME-induced effects, but to a lesser extent. Thus, the chronic inhibition of NO synthesis in rats produced nephrosclerosis and LVH that were effectively prevented by giving imidapril at a dose lower than that of amlodipine. We conclude that ACE inhibitors can prevent nephrosclerosis and LVH even in the presence of a reduction in NO production, implying that in rats the inhibition of the renin-angiotensin system is more effective than the blockade of calcium channels in preventing hypertensive tissue injury. Am J Hypertens 1998;11:697-707

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Section: Discussionsupporting

confidence: 82%

Antihypertensive Agents Prevent Nephrosclerosis and Left Ventricular Hypertrophy Induced in Rats by Prolonged Inhibition of Nitric Oxide Synthesis

Akuzawa

Nakamura

Kurashina

et al. 1998

American Journal of Hypertension

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“…Some of these, such as arteriolar wall thickening, are characteristic of prolonged arterial hypertension. 26 Focal glomerular collapse, also described in association with long-standing hypertension, 26 may provide a morphological basis for the increased PRA frequently observed in the present study. 27 In addition, a substantial fraction of the animals exhibited microvascular lesions characteristic of malignant hypertension, such as extreme arteriolar hypertrophy with luminal obliteration.…”

Section: Discussionsupporting

confidence: 64%

Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension.

et al. 1992

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Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginlne orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angjotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164±6 mm Hg at 4-6 weeks, compared with 108±3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125±6 mm Hg, still elevated compared with rats receiving losartan alone (98±3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfuslon, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomerull. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension. Activation of the renin-angiotensin system may account, at least in part, for the vasoconstrictor activity after such inhibition. (Hypertension 1992^0:298-303) KEY WORDS • endothelium-derived relaxing factor • kidney • hypertension, malignant • blood pressure • nitric oxide • rat studies T he endothelium releases a labile, diffusable vasorelaxing substance that has been termed endothelium-derived relaxing factor (EDRF). 1Recent observations have suggested that a major portion of the vascular effects of EDRF can be attributed to nitric oxide (NO). inhibition of NO biosynthesis. 4-67 These observations indicate that local release of NO in the microcirculation may occur on a continuous basis, thus modulating the effects of local and circulating vasoconstrictors and helping to finely regulate blood pressure and organ blood flow. In addition, micropuncture studies have suggested that angiotensin II (Ang II) may account for some of the renal microcirculatory alterations associated with acute NO inhibition. 6If NO exerts a tonic vasorelaxing effect on the microcirculation, its persistent inhibition might lead to the predominance of vasoconstrictor agents, resulting in arterial hypertension similar to that observed after chronic infusion of Ang II, 8 norepinephrine, 9 or thromboxane. 10 Recently, Gardiner and coworkers" demonstrated a marked blood pressure elevation in Brattleboro rats receiving ...

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“…28,51,62 This abnormality has been shown previously in association with human essential hypertension. 100 It has also been described in the neighborhood of the scarred areas in the renal ablation model. 101 These glomeruli are likely responsible for the enhanced renin secretion observed in the late phases of the chronic NOS inhibition model, although direct evidence favoring this hypothesis is lacking.…”

Section: Chronic Nos Inhibition As a Model Of Organ Damagementioning

confidence: 99%

Chronic Nitric Oxide Inhibition Model Six Years On

1998

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Keywords models; cardiovascular diseases; nitric oxide synthase; nitric oxide; blood pressure; reninangiotensin system; vasodilationThe discovery in 1987 that endothelium-derived nitric oxide (NO) mediates the vasodilatory effect of certain endothelium-dependent agonists 1,2 inaugurated the current huge field of NO biology. It is now recognized that NO plays essential roles in many diverse physiological processes and in some pathophysiologic events. Development of these concepts has been based largely on evidence obtained by limiting NO biosynthesis. This review is centered on the cardiovascular and particularly the renal functional and structural consequences of chronic pharmacologic NO inhibition by L-arginine analogues. We devoted special attention to the mechanisms of hypertension and organ injury that occur under these circumstances, while appreciating the inherent limitations surrounding interpretation of this data. Ubiquity and Heterogeneity of NO BiosynthesisNO is made by the enzymatic action of several widely distributed NO synthases (NOS). In the presence of the substrates L-arginine and oxygen, as well as a number of essential cofactors, NO is produced in response to appropriate stimuli. The constitutively expressed NOS play a major role in the physiological control of vascular tone and kidney function. 3,4 Vascular endothelial NOS (eNOS) and brain-type NOS (bNOS) are widely distributed throughout the kidney 5 as well as the cardiovascular system and in strategic locations in the peripheral and central nervous system (CNS). 6,7 Both eNOS and particularly bNOS are abundant in the kidney, glomeruli, and vasculature as well as in most segments of the tubule, 3,5 and NOS activity in medulla is considerably greater than in cortex. 8 NO generated within the kidney controls the glomerular filtration rate (GFR), total renal and medullary blood flow, pressure natriuresis, epithelial sodium transport, and production of various vasoactive factors including renin. 3-5 eNOS is distributed throughout most parts of the arterial and venous circulation, although there is considerable heterogeneity in the extent to which NO controls tone in regional circulations. 9 Although there is some basal NO release from eNOS, shear stress is the physiologically important regulator of vascular NO production. 3 In the CNS, NO is made in the nucleus tractus solitarius, the paraventricular nucleus, and the ventral medulla and can control sympathetic outflow. 6,10 In addition to central regulation of efferent renal sympathetic nerve activity, there is direct nitrergic innervation to several locations including the renal vasculature. 7

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The Development of Renal Pathology

Cited by 21 publications

References 15 publications

Antihypertensive Agents Prevent Nephrosclerosis and Left Ventricular Hypertrophy Induced in Rats by Prolonged Inhibition of Nitric Oxide Synthesis

Antihypertensive Agents Prevent Nephrosclerosis and Left Ventricular Hypertrophy Induced in Rats by Prolonged Inhibition of Nitric Oxide Synthesis

Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension.

Chronic Nitric Oxide Inhibition Model Six Years On

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