Mechanisms underlying renoprotection during renin-angiotensin system blockade.

Potential determinants of chronic renal disease (CRD) progression were studied in male Munich-Wistar rats subjected to 5/6 nephrectomy and treated with candesartan (Csn; n = 30) or enalapril (Ena; n = 27) from 5 wk postsurgery. Despite control of systolic blood pressure (SBP; 24 wk: Csn = 143 +/- 9; Ena = 148 +/- 8 mmHg), urinary protein excretion rates (U(pr)V) increased over 24 wk (Csn = 92 +/- 10; Ena = 99 +/- 8mg/day). Glomerulosclerosis scores (GS) at 24 wk were similar for Csn (42 +/- 7%) vs. Ena (42 +/- 4%), values close to those of untreated controls at 12 wk (43 +/- 4%). At 24 wk, SBP and UprV correlated strongly with GS, together accounting for 72% of the variance in GS. Renal cortex mRNA levels (determined by competitive RT-PCR) for transforming growth factor (TGF)-beta1 and monocyte chemoattractant protein (MCP)-1 were elevated in Csn and Ena at 12 wk and remained higher at 24 wk vs. sham. Strong correlations were evident among TGF-beta1, MCP-1, and interleukin-1beta and renal injury at 24 wk. Cns and Ena are thus equally effective renoprotective agents in this model. During renin-angiotensin system inhibition, renoprotection is dependent on control of both SBP and UprV. Incomplete suppression of renal cytokine gene expression may also contribute to CRD progression.

Renal allograft protection with losartan in Fisher-->Lewis rats: hemodynamics, macrophages, and cytokines.

BACKGROUND: We sought to assess the effects of angiotensin receptor blockade on glomerular hypertension, macrophage recruitment, and cytokine expression, all of which contribute to the development of chronic graft injury in this model. METHODS: The effects of treatment with the specific angiotensin II type 1 (AT1) receptor antagonist, losartan, were assessed over 24 weeks in F344-->LEW rats (LOS, N = 9) versus vehicle-treated F344-->LEW controls (CON, N = 9). RESULTS: UprotV rose progressively in CON (from 7.0 +/- 2.9 to 41 +/- 17 mg/day at 24 wk) but remained at baseline in LOS (4.2 +/- 0.6 to 9.4 +/- 1.3 mg/day, P < 0.05 vs. CON). Glomerular capillary pressure (PGC) was increased in CON (71 +/- 1 mm Hg at week 20), but remained within the normal range in LOS rats (54 +/- 2 mm Hg, P < 0.05). Glomerulosclerosis averaged 0.3 +/- 0.2% in LOS versus 4 +/- 2% in CON rats (P < 0.05). Tubulointerstitial injury was minimal in both LOS and CON rats (+). The overexpression of renal cortical cytokine mRNA levels for the monocyte chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and RANTES, as well as interleukin-1, inducible nitric oxide synthase, and transforming growth factor-beta, assessed by competitive reverse transcription-polymerase chain reaction, was suppressed in LOS versus CON rats at 20 weeks. Macrophage and T-cell numbers were decreased, and MCP-1, RANTES, and intercellular adhesion molecule-1 staining in the graft, identified by immunohistochemistry, were attenuated in LOS versus CON rats. CONCLUSIONS: The renoprotective effects of losartan in F344-->LEW rats were associated with lowered PGC, inhibition of macrophage chemoattractants and recruitment, and suppression of macrophage-associated cytokines at 20 weeks. These findings suggest that chronic allograft injury in F344-->LEW rats is, to a large extent, mediated by angiotensin II-dependent mechanisms and that these involve glomerular hemodynamics, macrophages, and macrophage-associated cytokines.

Periocular deep cutaneous basal cell carcinoma.

PURPOSE: The distinction between benign and malignant cutaneous periocular lesions can be difficult, as the clinical history and appearance are often quite similar. When present, typical cutaneous changes are often helpful in distinguishing between benign and malignant neoplasms. However, when tumors lack characteristic epidermal change, histopathologic examination may be necessary to confirm the diagnosis. The authors present their experience in the evaluation and management of two patients with periocular basal cell carcinoma who were initially diagnosed as having benign cysts. METHODS: The case records for two patients with periocular basal cell carcinoma were reviewed. Preoperative and postoperative photographs were available for comparison in one case. For each patient, the medical history, clinical presentation, histology, and surgical outcome were reviewed. RESULTS: In each case, the periocular mass was initially diagnosed as a benign process. Histopathologic examination following excisional biopsy established the diagnosis of basal cell carcinoma in both patients. Following biopsy, residual tumor was removed by the Mohs micrographic technique. There were no surgical complications and no tumor recurrences during follow-up of one year and eight years. CONCLUSIONS: Periocular basal cell carcinoma may mimic benign cystic lesions of the central face. Incorrect diagnosis may result in delayed or inappropriate therapy, or failure to submit seemingly benign lesions for histopathologic examination. Definitive treatment requires complete excision with histologic margin control.

Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats.

BACKGROUND: Glomerular macrophage accumulation in diabetes implicates monocyte recruitment mechanisms in the pathogenesis of diabetic nephropathy. To test the hypothesis that overexpression of monocyte chemoattractant protein-1 (MCP-1), a monocyte chemoattractant, is attenuated by renin-angiotensin system (RAS) inhibition, we assessed expression of genes regulating monocyte transmigration in the glomeruli of diabetic rats. METHODS: Competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to semiquantitate mRNA expression in glomeruli harvested by sieving at serial intervals after the induction of diabetes by streptozotocin in Munich-Wistar rats. Although subject to limitations, competitive RT-PCR provides an objective measure suited to the minute quantities of RNA extractable from glomerular isolates. RESULTS: Time-dependent elevation of MCP-1 expression was dramatically suppressed by treatment with the angiotensin-converting enzyme inhibitor enalapril or the AT1 receptor antagonist candesartan, and was closely associated with effects on proteinuria and glomerular macrophage number. By contrast, no sustained suppression of the cell adhesion molecules intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 or the classic MCP-1 stimulators tumor necrosis factor-alpha or interleukin-1beta followed RAS inhibition, and suppression of transforming growth factor-beta1 expression was transient. CONCLUSION: These data suggest that glomerular macrophage recruitment in experimental diabetes is largely determined by angiotensin-stimulated MCP-1 expression. We conclude that the RAS is an important regulator of local MCP-1 expression, either directly or through glomerular hemodynamic effects, and that our data strongly implicate macrophage recruitment and activation in the pathogenesis of early diabetic glomerular injury.

Upregulation of atrial natriuretic peptide gene expression in remnant kidney of rats with reduced renal mass.

Atrial natriuretic peptide (ANP) is synthesized in the kidney but its physiologic significance there is unclear. To determine whether renal expression of the ANP gene is regulated, renal ANP mRNA expression was assessed in remnant kidneys after 5/6 nephrectomy in Munich-Wistar rats. In normal sodium intake groups, ANP mRNA expression in the remnant kidney was significantly increased by 5.0 +/- 0.8-fold (n = 7, mean +/- SEM) at 4 d when compared with sham-operated controls (n = 6, all sham-operated groups) (*P < 0.001 by Scheffe's test) and by 28.3 +/- 5.1-fold at 14 d. This latter response was markedly diminished to 7.6 +/- 2.1-fold (n = 7, versus sham) in rats maintained on a low sodium diet. At 4 d, on the other hand, no significant downregulation was observed with dietary sodium restriction. Because natriuretic peptides have previously been shown by us to play a major role in the adaptive responses of remnant nephrons to renal mass ablation, these data suggest that ANP of renal origin may contribute to the overall mechanism for enhancing sodium excretion in the face of declining nephron number.

Effects of combination therapy with enalapril and losartan on the rate of progression of renal injury in rats with 5/6 renal mass ablation.

Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (AT1RA) slow the rate of progression of experimental renal disease. Although the end result of both classes of drugs is to block the renin-angiotensin system (RAS), ACEI and AT1RA act at different sites in the RAS cascade. The aim of this study was to compare the effects of an ACEI (enalapril) and AT1RA (losartan), alone or in combination, in slowing the progression of experimental renal disease in a model of reduced renal mass. Two weeks after 5/6 renal ablation, rats were divided into five groups matched for body weight, systolic BP (SBP), and urinary protein excretion rate (UprotV). The effects on SBP and UprotV of treatment with 25 and 40 mg/L enalapril (groups I and II; both n = 7), 180 mg/L losartan (group III, n = 8), or a combination of enalapril (25 mg/L) + losartan (180 mg/L) (group IV, n = 9) versus vehicle (group V, n = 9) were studied for 12 wk. Remnant kidneys were then assessed histologically for evidence of focal and segmental glomerulosclerosis and hyalinosis (FSGS), and interstitial fibrosis. There were no significant differences (NSD) in body weight among the groups at any time. Combination therapy reduced SBP (122 +/- 8 mmHg) significantly at 12 wk to levels similar to losartan (127 +/- 3 mmHg) or enalapril (40 mg/L) alone (124 +/- 5 mmHg) (P < 0.05 versus vehicle controls). With equivalent antihypertensive effects, no differences in frequency of FSGS were discerned among the treatment groups (groups II through IV; F = 1.7, NSD). Tubulointerstitial injury scores followed a similar pattern. BP was highly correlated with the extent of FSGS, both among individual rats (r = 0.68, P = 0.05) and the group means (r = 0.99, P = 0.001). We conclude that the renoprotective effects of enalapril, losartan, or combination therapy are similar in this model over the 12 wk of the study, and are closely related to the magnitude of their antihypertensive effects.

A major role for neutrophils in experimental bullous pemphigoid.

Bullous pemphigoid (BP) is an inflammatory subepidermal blistering disease associated with an IgG autoimmune response to the hemidesmosomal protein, BP180. Using a passive transfer mouse model, our group has shown previously that antibodies to the murine BP180 (mBP180) ectodomain are capable of triggering a blistering skin disease that closely mimics human BP. In this study, we investigated the role of neutrophils in the immunopathogenesis of this disease model. BALB/c mice depleted of circulating neutrophils by treatment with neutrophil-specific antibodies were no longer susceptible to the pathogenic effects of anti-mBP180 IgG. IgG and complement were deposited at the dermal-epidermal junction of these animals, but there was no evidence of inflammatory infiltration or blistering. C5-deficient mice, which are resistant to the pathogenic activity of anti-mBP180 IgG, could be made susceptible to this IgG-mediated blistering disease by intradermal administration of a neutrophil chemoattractant, IL-8 or C5a. Intraperitoneal injection of IL-8, which sequesters neutrophils in the peritoneal cavity, interferes with anti-mBP180-induced neutrophilic infiltration of the skin and prevented the development of BP disease in BALB/c mice. These findings provide the first direct evidence that neutrophils recruited to the skin via a C5-dependent pathway play an essential role in subepidermal blister formation in experimental BP, and suggest new directions for disease intervention.

Candesartan cilexetil reduces chronic renal allograft injury in Fisher-->Lewis rats.

OBJECTIVES: To determine the effects of the angiotensin II receptor antagonist, candesartan cilexetil, on glomerular and systemic blood pressures and the development of renal injury in Lewis rat recipients of a single Fisher kidney (F334--> LEW transplantation), an established rat model of chronic renal allograft failure. DESIGN: Recent studies have shown that chronic injury of renal allografts in F334-->LEW rats may be virtually abrogated by supplying the Lewis recipients with two Fisher kidneys or, alternatively, by retaining a native kidney. These findings imply a major contribution from processes associated with nephron loss to the pathogenesis of chronic renal allograft failure, a notion supported by the observation that transplanting two kidneys also normalizes glomerular capillary pressure (PGC) in F344-->LEW rats. Thus, a pharmacological reduction in PGC, by blocking the effects of angiotensin II, should also lessen renal injury in F344-->LEW rats. MATERIALS AND METHODS: Bilaterally nephrectomized F344--> LEW rats were treated with the angiotensin II receptor blocker candesartan cilexetil (TCV-116) at 40 mg/l or with vehicle, administered in drinking water. Proteinuria and systolic blood pressure were assessed monthly, and histological studies were carried out after 24 weeks. The glomerular filtration rate and glomerular pressures were determined after 10 weeks in additional rats by clearance and micropuncture studies. RESULTS: Treatment with candesartan cilexetil lowered systemic blood pressure, normalized PGC at 10 weeks and greatly reduced proteinuria and allograft glomerulosclerosis at 24 weeks. CONCLUSIONS: These data indicate that the development of renal injury in F344-->LEW renal allografts can be prevented by the pharmacological blockade of angiotensin II receptors using candesartan cilexetil. This suggests that angiotensin-dependent processes contribute significantly to chronic injury in this model of late renal allograft failure.

The angiotensin receptor antagonist, irbesartan, reduces renal injury in experimental chronic renal failure.

The effects of chronic treatment with the specific AT1 angiotensin receptor antagonist, irbesartan, or the angiotensin converting enzyme inhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hypertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/liter) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates (UprotV) were determined monthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normalized at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6); all comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lower in irbesartan (44 +/- 12 mg/day) and enalapril (19 +/- 2) groups versus vehicle (123 +/- 10 mg/day). Treatment with both drugs was associated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In identically prepared rats, glomerular capillary hydraulic pressure (PGC, estimated from stop-flow pressure, Psf) was lower in FHH receiving irbesartan (58 +/- 1 mm Hg, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom PGC was greatly elevated (68 +/- 2 mm Hg; N = 7). Despite this, GFR and single nephron GFR were well maintained. These data support a critical role for AT1 receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension in FHH, and further implicate elevated PGC as a major determinant of glomerular injury in this model.

Cutaneous keratocyst in naevoid basal cell carcinoma syndrome.

We report a patient with naevoid basal cell carcinoma syndrome (NBCCS) who developed cutaneous cysts on her digits. Histological examination of one of the cysts showed a festooned lining epithelium maturing without a granular cell layer, similar to that of the jaw keratocyst characteristic of this syndrome. This type of cutaneous keratocyst has been reported only once previously. in two patients with NBCCS.

Augmenting kidney mass at transplantation abrogates chronic renal allograft injury in rats.

Conventional renal transplantation, which substitutes a single allograft for two native kidneys, imposes an imbalance between nephron supply and the metabolic and excretory demands of the recipient. This discrepancy, which stimulates hyperfunction and hypertrophy of viable allograft nephrons, may be intensified by nephron loss through ischemia-reperfusion injury or acute rejection episodes occurring soon after transplantation. In other settings where less than 50% of the total renal mass remains, progressive glomerular injury develops through mechanisms associated with compensatory nephron hyperfiltration and hypertrophy. To determine whether responses to nephron loss contribute to chronic injury in renal allografts, nephron supply was restored to near-normal levels by transplanting Lewis recipients with two Fisher 344 kidneys (group 2A) compared with the standard single allograft F344 --> LEW rat model of late renal allograft failure (group 1A). At 20 weeks, indices of injury were observed in 1A but not 2A rats. These indices included proteinuria (1A: 45 +/- 13; 2A: 4.0 +/- 0.29 mg/day) and glomerulosclerosis (1A: 23 +/- 4.9%, 2A: 0.7 +/- 0.3%) (p < .05). Double-allograft recipients maintained near normal renal structure and function, whereas 1A rats showed evidence of compensatory hyperfiltration (single-nephron glomerular filtration rate of 63 +/- 10 versus 44 +/- 2.0 nl/min in 2A rats) and hypertrophy (mean glomerular volume of 2.64 +/- 0.15 versus 1.52 +/- 0.05 microns3 x 10(6) in 2A rats) (p < .05). Thus, we conclude that a major component of late allograft injury is attributable to processes associated with inadequate transplanted renal mass, a finding that has major implications for kidney transplantation biology and policy.

Molecular mapping of a pathogenically relevant BP180 epitope associated with experimentally induced murine bullous pemphigoid.

Bullous pemphigoid (BP) and herpes gestationis (HG) are subepidermal blistering diseases associated with an autoimmune response directed against BP180, an epidermal hemidesmosomal glycoprotein. The pathogenic relevance of this Ag/Ab system was established by the recent demonstration that IgG Abs reactive with the murine form of BP180 (mBP180) are capable of triggering a subepidermal blistering disease after passive transfer into neonatal BALB/c mice. The aim of the present study was to determine the fine specificity of the pathogenically relevant Abs in this experimental model of BP. Four high titer rabbit-anti-mBP180 antisera were included in this analysis--only two of which exhibited pathogenic activity in the passive transfer model. Immunoblot analysis using a panel of mBP180 deletion mutants revealed that each of the four rabbit sera reacted with at least three distinct sites on the mBP180 ectodomain; however, this technique failed to distinguish between the reactivity patterns of the pathogenic and nonpathogenic sera. An alternative technique, liquid phase immunoadsorption analysis, was used to identify one mBP180 antigenic site, comprising 9 to 12 amino acids and designated mBP1, that was specifically recognized by the two pathogenic sera. Pre-adsorption of pathogenically active IgG preparations with fusion proteins containing the mBP1 antigenic site resulted in complete blocking of immunofluorescence reactivity with the murine basement membrane zone (BMZ) and in complete neutralization of pathogenic activity. Anti-BMZ reactivity displayed by nonpathogenic Abs was not altered or diminished by pre-adsorption with this same mBP180 recombinant protein. These findings should help to elucidate the immunopathologic mechanisms responsible for human BP and HG and may have significant implications in the diagnosis and treatment of these autoimmune diseases.

Renal effects of high-dose natriuretic peptide receptor blockade in rats with congestive heart failure.

Previous studies suggest that elevated plasma atrial natriuretic peptide (ANP) levels participate in regulating renal excretory function in rats with congestive heart failure (CHF). To define the role of natriuretic peptides (NPs) in the regulation of renal function in CHF, the renal responses to HS-142-1 (HS), a potent NP receptor antagonist, were studied in anesthetized rats subjected to coronary ligation that developed left ventricular infarction and CHF or in sham-operated (SO) control rats. Plasma ANP levels averaged > 14-fold higher in rats with CHF than in SO rats. In response to HS (20 mg/kg IV bolus), both mean arterial pressure and renal vascular resistance increased in rats with CHF but not in SO rats; glomerular filtration rate (GFR, 1.26 +/- 0.04 versus 0.76 +/- 0.11 mL/min) and renal plasma flow rate (RPF, 3.52 +/- 0.27 versus 2.70 +/- 0.32 mL/min) were significantly reduced in rats with CHF; and in SO rats, GFR (1.26 +/- 0.06 versus 1.20 +/- 0.07 mL/min) and RPF (3.98 +/- 0.21 versus 3.99 +/- 0.18 mL/min) were not significantly affected by HS. The sodium excretion rate (0.18 +/- 0.04 to 0.06 +/- 0.01 muEq/min) and fractional sodium excretion (0.01 +/- 0.02% to 0.04 +/- 0.01%) also fell markedly after HS administration in rats with CHF, but these parameters were unchanged in SO rats. These data indicate that NPs play a critical role in maintaining renal hemodynamic function and inhibiting tubule sodium reabsorption in rats with CHF, thus opposing sodium retention and preserving sodium balance in this model.

The role of complement in experimental bullous pemphigoid.

Bullous pemphigoid (BP) is a blistering skin disease associated with an IgG autoimmune response directed against the ectodomain of the hemidesmosomal protein, BP180. An animal model of BP has recently been developed by our laboratory based on the passive transfer of rabbit antimurine BP180 antibodies into neonatal BALB/c mice. The experimental animals develop a blistering disease that reproduces all of the key immunopathological features of BP. In the present study we have investigated the role of complement in the pathogenesis of subepidermal blistering in the mouse model of BP. We demonstrate the following. (a) Rabbit anti-murine-BP180 IgG was effective in inducing cutaneous blisters in a C5-sufficient mouse strain, but failed to induce disease in the syngeneic C5-deficient strain; (b) neonatal BALB/c mice, pretreated with cobra venom factor to deplete complement, became resistant to the pathogenic effects of the anti-BP180 IgG; (c) F(ab')2 fragments generated from the anti-BP180 IgG exhibited no pathogenic activity in the mouse model; and (d) histologic evaluation of the skin of mice described in points b and c above showed minimal or no neutrophilic cell infiltration in the upper dermis. Thus, anti-BP180 antibodies trigger subepidermal blistering in this BP model via complement activation. This experimental model of BP should greatly facilitate future studies on the pathophysiology of autoantibody-mediated diseases of the dermal-epidermal junction.

Proteinuria and impaired glomerular permselectivity in uninephrectomized fawn-hooded rats.

Previous studies of glomerular permselectivity have indicated that both size selectivity and charge selectivity changes play a role in the pathogenesis of proteinuria. In this study, we measured Ficoll sieving coefficients, hemodynamic parameters, and urinary protein excretion rates in the FHH strain of fawn-hooded rats. These animals spontaneously develop systemic and glomerular hypertension, proteinuria, and focal and segmental glomerulosclerosis at a relatively young age. Three groups of FHH rats were studied: two-kidney controls (2K), untreated uninephrectomized rats (CON-NX), and uninephrectomized rats treated with the angiotensin I converting enzyme inhibitor enalapril (ENA-NX). CON-NX rats had higher glomerular transcapillary pressures (delta P) and higher urinary excretion rates of both total protein (UpV) and albumin (UaV) than did 2K rats, whereas treatment with enalapril prevented both glomerular hypertension and the increased proteinuria. Ficoll sieving coefficients were significantly higher in both groups of NX rats compared with 2K rats only for Stokes-Einstein radii (rs) > or = 46 A. Fits of sieving data to pore models showed a small increase in the number of large, nonselective pores in NX, which was not prevented by enalapril treatment. Total clearances of Ficoll with rs = 36 A (the size of albumin) in CON-NX and ENA-NX groups were unchanged compared with 2K animals. In contrast, UaV in CON-NX rats was more than six times that of 2K and ENA-NX rats. Across groups, UpV, UaV, and the ratio (UaV)/(UpV) all correlated strongly with delta P.(ABSTRACT TRUNCATED AT 250 WORDS)

TCV 116 prevents progressive renal injury in rats with extensive renal mass ablation.

OBJECTIVE: The objective of this study was to determine the renal protective effects of TCV 116, a novel, non-competitive, angiotensin II type 1 (AT1) receptor antagonist, in rats with 5/6 renal mass ablation. DESIGN: Adult male Wistar rats were subjected to 5/6 nephrectomy and treated continuously with either TCV 116 (group I, n = 8; group III, n = 9) or vehicle (group II, n = 8; group IV, n = 8). The development of elevated systolic blood pressure, 24-h urinary protein excretion, glomerular hemodynamics and glomerular morphology were compared among groups. RESULTS: Systolic blood pressure rapidly reached hypertensive levels in group II, increasing from 175 +/- 8 mmHg after 3 weeks to 221 +/- 15 mmHg after 12 weeks, whereas group I rats remained normotensive (101 +/- 8 to 112 +/- 6 mmHg). Similarly, urinary protein excretion increased from 45 +/- 11 to 104 +/- 18 mg/day in group II, but remained low (6.9 +/- 1 to 19 +/- 4 mg/day) in group I. After 12 weeks, there was an average of 42 +/- 6% glomerulosclerosis in group II, but only 1.6 +/- 0.5% in group I. After 4-6 weeks, a markedly elevated glomerular capillary pressure (62 +/- 1.2 mmHg) was observed in group IV, but the pressure was normal in group III (50 +/- 1.1 mmHg). CONCLUSIONS: These data show that TCV 116 prevents the development of systemic hypertension, glomerular capillary hypertension, proteinuria and glomerulosclerosis in rats with reduced renal mass. We therefore conclude that the renal protection associated with angiotensin I converting enzyme inhibitors and other pharmacologic blockers of the renin-angiotensin system arises chiefly from blockade of AT1 receptor-mediated hemodynamic effects.

HS-142-1, a potent antagonist of natriuretic peptides in vitro and in vivo.

To determine whether HS-142-1 (HS), a potent atrial natriuretic peptide (ANP) receptor antagonist, also inhibits the effects of brain natriuretic peptide (BNP), urodilatin (URO), and C-type natriuretic peptide, in vitro studies were carried out, demonstrating that HS inhibited production of cGMP by rat fetal lung fibroblast cells induced by ANP, BNP, URO, and C-type natriuretic peptide. Acute clearance studies were conducted in euvolemic Munich-Wistar rats under inactin anesthesia to characterize the effects of HS in vivo. In response to ANP, BNP, or URO (4 micrograms/kg priming dose plus 0.5 micrograms/kg per minute for 20 min), urine flow, absolute sodium excretion rates, and fractional sodium excretion exhibited similar increases (four- to fivefold) in vehicle-treated rats; these responses were, however, completely abolished by prior HS treatment. The tendency for GFR to rise during the infusion of natriuretic peptides (NP) was also blocked after HS. By contrast, HS did not block the renal effects of L-arginine, a precursor of nitric oxide, or of furosemide. Furthermore, the inhibition of endogenous NP by HS was associated with small but significant reductions in GFR and absolute and fractional sodium excretion in normal rats under euvolemic but not hydropenic conditions. These studies provide evidence that the observed effects of HS in vivo and in vitro are mediated exclusively by receptors of NP. Together, these data support the view that HS is a highly specific ligand for NP receptors, capable of antagonizing the renal effects not only of exogenous ANP, but also those of BNP and URO.

Modulation of glomerular hypertension defines susceptibility to progressive glomerular injury.

The fawn-hooded rat constitutes a spontaneous model for chronic renal failure with early systemic and glomerular hypertension, proteinuria (UpV) and high susceptibility to development of focal and segmental glomerular sclerosis (FGS). It has been argued that uninephrectomy (UNX) accelerates the development of glomerular injury by aggravation of glomerular hypertension and by an independent effect to promote glomerular enlargement. The present study was performed to further delineate the importance of these parameters for the development of FGS. At the age of eight weeks male rats were UNX and randomly assigned to either control (CON), enalapril (ENA) or Nw-nitro L-arginine methyl ester (NAME) treatment. In all groups glomerular hemodynamic studies were performed four weeks post-UNX. Systemic blood pressure and UpV were monitored for 4 to 12 weeks post-UNX. Kidneys were then prepared for morphologic study. ENA treatment achieved control of both systemic and glomerular hypertension, maintenance of glomerular hyperfiltration and hyperperfusion, increased ultrafiltration coefficient(Kf), and long-term protection against UpV and FGS. NAME rats showed aggravation of both systemic and glomerular hypertension, decreased renal perfusion and filtration with reduced Kf, and high filtration fraction. The incidence of FGS in NAME and CON groups was similar at 8 and 12 weeks post-UNX, respectively. Glomerular enlargement was present in CON and ENA rats, but did not correlate with injury, while glomerular tuft size was lowest in NAME rats, which displayed prominent glomerular injury. Systemic blood pressure correlated strongly with glomerular capillary pressure. We conclude that systemic and glomerular hypertension govern the development of UpV and FGS.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of natriuretic peptide receptor inhibition on remnant kidney function in rats.

To identify the contribution of natriuretic peptide (NP) activity to the adaptative increases in glomerular filtration rate (GFR), effective renal plasma flow rate (ERPF) and fractional sodium excretion (FENa) observed in the remnant kidney, we investigated the acute effects of administering HS-142-1 (HS), a potent NP receptor antagonist, in 5/6th nephrectomized (NPX) rats. In addition to normal sodium intake, high or low sodium intakes were used to stimulate or suppress, respectively, endogenous NP activity in NPX rats. In rats three days after NPX on high sodium, HS (20 mg/kg bolus i.v.) reduced GFR from 0.55 +/- 0.05 to 0.35 +/- 0.04 ml/min; ERPF from 1.83 +/- 0.19 to 1.53 +/- 0.16 ml/min; and FENa from 7.1 +/- 1.1 to 1.6 +/- 0.4%, without affecting MAP. Similar changes of lesser magnitude were observed in NPX rats on normal sodium intake. By contrast, GFR, ERPF, FENa and MAP were unchanged following HS in NPX rats on low sodium intake, suggesting that the magnitude of responses to HS is dependent upon the expected levels of activity of NP. We conclude that in anesthetized rats, natriuretic peptides contribute to the compensatory increases in GFR, ERPF and FENa observed in the remnant kidney under normal and salt-replete conditions.