Glomerular hypertension and injury in desoxycorticosterone–salt rats on antihypertensive therapy

Dworkin, Lance D.; Feiner, Helen; Randazzo, Joseph

doi:10.1038/ki.1987.57

Cited by 62 publications

(27 citation statements)

References 19 publications

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“…10,11 The DOCA model is also characterized by increased plasma volume, which is most marked during the initial 6 weeks of DOCA-salt treatment, 12 and severe renal lesions that consist of segmental sclerosis and mesangial expansion in the glomeruli, vascular wall thickening, typical onion skin pattern and ultimately fibrinoid necrosis with tubular atrophy and casts, and interstitial inflammation. 2,13 In the present study, we confirmed that elevated blood pressure is the major determinant of the decrease of coronary vascular reserve in the DOCA rats. 14 Indeed, amlodipine and mibefradil reduced systemic blood pressure to the same extent.…”

Section: Discussionsupporting

confidence: 74%

Contrasting Effects of Selective T- and L-Type Calcium Channel Blockade on Glomerular Damage in DOCA Hypertensive Rats

et al. 1999

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Abstract-Mibefradil and amlodipine are calcium antagonists with different channel selectivities. Mibefradil blocks both L-and T-type calcium channels; although in the usual pharmacological doses, it predominantly blocks the T-type channels. In contrast, amlodipine selectively blocks L-type channels. The goal of the present study was to assess whether this differential selectivity would result in different effects on end-organ damage in experimental hypertension. For this purpose, deoxycorticosterone acetate (DOCA)-salt hypertensive rats were treated either with equipotent doses of mibefradil or amlodipine (30 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 as food admix). Despite the fact that both drugs decreased systolic arterial pressure to the same extent (140Ϯ5 mm Hg in the mibefradil group and 144Ϯ3 mm Hg in the amlodipine group versus 225Ϯ5 mm Hg in the untreated-DOCA group), only mibefradil decreased proteinuria (35.5Ϯ6.5 versus 103.3Ϯ14.1 mg/24 h in untreated DOCA-salt animals) and prevented glomerular lesions. Both drugs, however, prevented the occurrence of vascular renal lesions. To elucidate the mechanism responsible for this difference, we evaluated in an additional series of experiments the effects of mibefradil and amlodipine on plasma and renal renin concentrations, as well as the effects of the addition of enalapril, an ACE inhibitor, given on top of both drugs on proteinuria. Amlodipine, in contrast to mibefradil, markedly stimulated the plasma (17.8Ϯ2.6 ng Ang I ⅐ mL Ϫ1 ⅐ h Ϫ1 in the amlodipine group versus 3.9Ϯ0.4 ng Ang I ⅐ mL Ϫ1 ⅐ h Ϫ1 in the mibefradil group and 3.2Ϯ0.3 ng Ang I ⅐ mL Ϫ1 ⅐ h Ϫ1 in the untreated-DOCA group) and renal (2.42Ϯ0.37 ng Ang I ⅐ mL Ϫ1 ⅐ h Ϫ1 in the amlodipine group versus 0.36Ϯ0.04 ng Ang I ⅐ mLin the mibefradil group and 0.26Ϯ0.08 ng Ang I ⅐ mL Ϫ1 ⅐ h Ϫ1 in the untreated-DOCA group) renin concentrations. Stimulation of the renin-angiotensin system could explain the absence of a renal protective effect of amlodipine. This was also suggested by the fact that enalapril given in addition to amlodipine could decrease proteinuria. In conclusion, T-type channel blockade by mibefradil decreases blood pressure without stimulation of the renin-angiotensin system and therefore prevents most of the glomerular damage in DOCA hypertensive rats. (Hypertension. 1999;34:673-678.)

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Section: Discussionsupporting

confidence: 74%

Contrasting Effects of Selective T- and L-Type Calcium Channel Blockade on Glomerular Damage in DOCA Hypertensive Rats

et al. 1999

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“…Elevations in glomerular capillary pressure are thought to contribute to the development of proteinuria in these conditions (5,6,11,21,24,31), but the mechanisms involved are not well understood. A rise in glomerular capillary pressure may contribute to the development of renal injury by increasing the production of transforming growth factor-␤ (TGF-␤) (1,18).…”

mentioning

confidence: 99%

“…glomeruli; HET0016; N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; glomerular permeability to albumin; 20-hydroxyeicosatetraenoic acid; epoxyeicosatetraenoic acids HYPERTENSION-AND DIABETES-INDUCED NEPHROPATHIES are the leading causes of end-stage renal disease (3,16,22). Elevations in glomerular capillary pressure are thought to contribute to the development of proteinuria in these conditions (5,6,11,21,24,31), but the mechanisms involved are not well understood. A rise in glomerular capillary pressure may contribute to the development of renal injury by increasing the production of transforming growth factor-␤ (TGF-␤) (1, 18).…”

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confidence: 99%

Role of endogenous CYP450 metabolites of arachidonic acid in maintaining the glomerular protein permeability barrier

Sharma

Anjaiahh

Falck³

et al. 2007

American Journal of Physiology-Renal Physiology

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Role of endogenous CYP450 metabolites of arachidonic acid in maintaining the glomerular protein permeability barrier. Am J Physiol Renal Physiol 293: F501-F505, 2007. First published May 16, 2007; doi:10.1152/ajprenal.00131.2007.-This study examined the metabolism of arachidonic acid (AA) by cytochrome P-450 enzymes in isolated glomeruli and the effects of selective inhibitors of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatetraenoic acids (EETs) on glomerular permeability to albumin (Palb). Glomeruli avidly produced 20-HETE, EETs, dihydroxyeicosatetraenoic acids (diHETEs), and HETEs when incubated with exogenous AA. N-hydroxy-NЈ-(4-butyl-2-methylphenyl)formamidine (HET0016; 10 M) selectively inhibited the formation of 20-HETE by 95% and increased Palb from 0.00 Ϯ 0.08 to 0.73 Ϯ 0.10 (n ϭ 43 glomeruli, 4 rats). Addition of a 20-HETE mimetic, 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (20-5,14-HEDE; 1 M) opposed the effects of HET0016 (10 M) to increase Palb (0.21 Ϯ 0.10, n ϭ 36 glomeruli, 4 rats). Preincubation of glomeruli with exogenous AA to increase basal production of 20-HETE had a similar effect. We also examined the effect of an epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MSPPOH; 5 M), on Palb. MSPPOH (5 M) significantly increased Palb but had no effect on the synthesis of EETs in glomeruli incubated with AA. However, MSPPOH (5 M) selectively reduced epoxygenase activity by 50% in glomeruli incubated without added AA. Pretreatment with 8,9-EET (100 nM) attenuated the effects of MSPPOH (5 M) on Palb. These results indicate that glomeruli produce 20-HETE, EETs, diHETEs, and HETEs and that endogenously formed 20-HETE and EETs play an essential role in the maintenance of the glomerular permeability barrier to albumin. glomeruli; HET0016; N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; glomerular permeability to albumin; 20-hydroxyeicosatetraenoic acid; epoxyeicosatetraenoic acids HYPERTENSION-AND DIABETES-INDUCED NEPHROPATHIES are the leading causes of end-stage renal disease (3,16,22). Elevations in glomerular capillary pressure are thought to contribute to the development of proteinuria in these conditions (5,6,11,21,24,31), but the mechanisms involved are not well understood. A rise in glomerular capillary pressure may contribute to the development of renal injury by increasing the production of transforming growth factor-␤ (TGF-␤) (1, 18). TGF-␤ is now known to increase glomerular permeability to albumin (P alb ), and this is associated with a fall in the endogenous formation of 20-HETE (4). Exogenous administration of a stable 20-HETE mimetic opposes the effects of TGF-␤ to increase P alb (4). Similarly, 20-HETE has been reported to oppose the increase in P alb following administration of puromycin (12). However, it remains to be determined to what extent cytochrome P-450 (CYP) metabolites of arachidonic acid (AA) are produced by glomeruli and whether they contribute to the maintenance of the glomerular permeability barrier to albumin. Th...

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“…The finding of protection against progressive chronic renal failure without an antiproteinuric effect by Eliahou et al [15] as well as by Harris et al [14] is unique. In all other studies of protection afforded by antihypertensive drugs [1,2,5,11,12], by dietary measures such as low-protein diet [23,24], low-phosphorus diet [25], or polyunsaturated fatty acid supplemented diet [26], or by other drugs such as lipid-lowering agents [27] or heparin [28], the beneficial effect was always associated with decreased proteinuria.…”

Section: Discussionmentioning

confidence: 99%

“…Antihypertensive therapy has been shown to retard progressive chronic renal failure in various rat models of experimental renal disease [1][2][3][4][5][6] and also in humans with diabetic nephropathy [7,8] as well as other primary renal diseases [9][10][11]. However, in the most extensively studied model of chronic renal failure, the remnantkidney rat, the response to different antihypertensive regimens is not uniform.…”

Section: Introductionmentioning

confidence: 99%

Control of Hypertension by Yerapamil Enhances Renal Damage in a Rat Remnant Kidney Model

Brunner

Bock

Hermle

et al. 1991

Nephrology Dialysis Transplantation

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Abstract. The effect of calcium channel blockers on the progression of renal failure is controversial. In contrast with earlier studies, we recently reported that moderately large doses of verapamil significantly accelerated chronic renal failure in the rat remnant kidney model [1]. Studies reporting beneficial effects of verapamil were characterised by a much lower dose of verapamil and by the start of treatment immediately after renal ablation, which potentially interfered with the initial phase of remnant kidney hypertrophy. We therefore studied the effects of a high, fully antihypertensive oral dose of verapamil (100-150 mg/kg/per day; group Vera high) and a low, haemodynamically almost ineffective dose (10-15 mg/kg per day; group Vera low), on the progression of chronic renal failure in female Wistar rats with 5/6 nephrectomy. The treatment was started no earlier than 5 weeks after renal ablation, and matched groups of 20 animals were followed for 16 weeks thereafter. High-dose verapamil reduced systolic blood pressure to median values of 130-140 mmHg throughout the experimental period, whereas blood pressure in Vera low animals remained elevated at median values of 165-172 mmHg similar to non-treated rats with 172-185 mmHg median systolic blood pressure.Despite control of hypertension, proteinuria increased more rapidly and to more elevated values in the Vera high animals (5.98 ± 0.91 mg/jumol creatinine before death/sacrifice) than in the Vera low and control groups (3.08 ± 0.91 and 3.60 ± 0.71 mg//imol creatinine, respectively, P < 0.05 vs Vera high), and signifiCorrespondence and offprint requests to: Professor F. P. Brunner, Kantonsspital Basel, 4031 Basel, Switzerland. cantly more animals died during the observation period in the Vera high compared to the control group (6 of 20 vs lof 20, P < 0.05). Kidney remnants were larger in the Vera high group, mainly due to tubulointerstitial changes with filling of dilated tubular lumina with proteinaceous casts. Mean glomerular diameter did not differ between groups, and the percentage of glomeruli with segmental or global glomerulosclerosis was not significantly increased in the Vera high group.It is concluded that chronic high-dose verapamil therapy in the 5/6 nephrectomy model, albeit effective in controlling hypertension, is deleterious to renal function when remnant hypertrophy has previously been allowed to occur. A low, haemodynamically barely effective, dose of verapamil fails to alter the course of renal failure in this setting.

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Glomerular hypertension and injury in desoxycorticosterone–salt rats on antihypertensive therapy

Cited by 62 publications

References 19 publications

Contrasting Effects of Selective T- and L-Type Calcium Channel Blockade on Glomerular Damage in DOCA Hypertensive Rats

Contrasting Effects of Selective T- and L-Type Calcium Channel Blockade on Glomerular Damage in DOCA Hypertensive Rats

Role of endogenous CYP450 metabolites of arachidonic acid in maintaining the glomerular protein permeability barrier

Control of Hypertension by Yerapamil Enhances Renal Damage in a Rat Remnant Kidney Model

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