Susana Cavallero

Effect of early versus late AT1 receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits

To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT(1)R) expression and ANG II levels from 3 h to 35 days. The effects of losartan (12.5 mg.kg(-1).day(-1)) on functional and histomorphometric parameters when treatment was initiated early (3 h) and late (day 15) post-MI and maintained for different periods of time [short term (4 days), midterm (20 days), and long term (35 days)] were also studied. AT(1)R expression increased in the MI zone at 15 and 35 days (P < 0.05). ANG II levels increased (P < 0.05) in the non-MI zone at 24 h and in the MI zone as well as in plasma at 4 days and then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long-term-treated animals. Diastolic pressure-volume curves in MI at 35 and 56 days shifted to the right (P < 0.05). This shift was even more pronounced in long-term-treated groups (P < 0.05). Contractility decreased (P < 0.05 vs. sham) in the untreated and long-term-treated groups and was attenuated in the midterm-treated group. The early administration of losartan reduced RAM 11-positive macrophages from 4.15 +/- 0.05 to 3.05 +/- 0.02 cells/high-power field (HPF; P < 0.05) and CD45 RO-positive lymphocytes from 2.23 +/- 0.05 to 1.48 +/- 0.01 cells/HPF (P < 0.05) in the MI zone at 4 days. Long-term treatment reduced the scar collagen (MI: 70.50 +/- 2.35% and MI + losartan: 57.50 +/- 2.48, P < 0.05), determined the persistency of RAM 11-positive macrophages (3.02 +/- 0.13 cells/HPF) and CD45 RO-positive lymphocytes (2.77 +/- 0.58 cells/HPF, P < 0.05 vs. MI), and reduced the scar thinning ratio at 35 days (P < 0.05). Consequently, the temporal expressions of cardiac AT(1)R and ANG II post-MI in rabbits are different from those described in other species. Long-term treatment unfavorably modified post-MI remodeling, whereas midterm treatment attenuated this harmful effect. The delay in wound healing (early reduction and late persistency of inflammatory infiltrate) and adverse remodeling observed in long-term-treated animals might explain the unfavorable effect observed in rabbits.

Controversy about COOPERATE ABPM Trial Data

mm Hg, 63% between 120 and 150 mm Hg, and the remaining 19% more than 150 mm Hg. A similar incidence was observed among treatment groups. Interestingly, the high variability of the systolic BP values was more characteristic among patients who were able to effectively restrict their salt intake. As compared with the systolic values, the nighttime values were constant throughout the measurements, partly because the drugs were taken at night or bedtime. Naoyuki Nakao, MD, PhD Division of Nephrology Rokko Island Hospital Koh-Yoh Cho Naka 2-11 Higashinada, Kobe, Japan

Renal Protective Role of Atrial Natriuretic Peptide in Acute Sodium Overload-Induced Inflammatory Response

Background: The present study was performed to explore the effect of exogenous infusions of atrial natriuretic peptide (ANP) on the early inflammatory response during acute sodium overload in normal rats. Methods: Sprague Dawley rats were exposed to acute sodium overload (Na 1.5 M). Nonhypotensive doses of ANP (1 and 5 µg ·kg–1 ·h–1) were infused simultaneously with sodium or after sodium infusion in order to evaluate prevention or reversion of the inflammatory response, respectively. We determined inflammation markers in renal tissue by immunohistochemistry. Results: Creatinine clearance was not reduced in any case. Sodium tubular reabsorption increased after sodium overload (334.3 ± 18.7 vs. control 209.6 ± 27.0 mEq·min–1, p < 0.05) without changes in mean arterial pressure. This increase was prevented (228.9 ± 26.4; p < 0.05) and reversed (231.5 ± 13.9; p < 0.05) by ANP-5 µg ·kg–1 ·h–1. Sodium overload increased the expression of: RANTES (38.4.3 ± 0.8 vs. 2.9 ± 0.6%, p < 0.001), transforming-growth-factor-β1 (35.3 ± 1.0 vs. 5.0 ± 0.7%, p < 0.001), α-smooth muscle actin (15.6 ± 0.7 vs. 3.1 ± 0.3%, p < 0.001), NF-ĸB (9.4 ± 1.3 to 2.2 ± 0.5 cells/mm2, p < 0.001), HIF-1α (38.2 ± 1.7 to 8.4 ± 0.8 cells/mm2, p < 0.001) and angiotensin II (35.9 ± 1.3 to 8.2 ± 0.5%, p < 0.001). ANP-5 µg ·kg–1 ·h–1 prevented and reversed inflammation: RANTES (9.2 ± 0.5 and 6.9 ± 0.7, p < 0.001); transforming growth factor-β1 (13.2 ± 0.7 and 10.2 ± 0.5, p < 0.001) and α-smooth muscle actin (4.1 ± 0.4 and 5.2 ± 0.4, p < 0.001). Both prevention and reversion by ANP were associated with downregulation of NF-ĸB (3.2 ± 0.4 and 2.8 ± 0.5, p < 0.001) and angiotensin II (8.2 ± 0.5 and 9.1 ± 0.7, p < 0.001) and diminished hypoxia evaluated through HIF-1α expression (8.4 ± 0.8 and 8.8 ± 0.7, p < 0.001). Conclusion: Our study provides evidence supporting a protective role of ANP in both prevention and reversion of renal inflammation in rats with acute sodium overload.

Atrial natriuretic peptide behaviour and myocyte hypertrophic profile in combined pressure and volume-induced cardiac hypertrophy.

Objective To investigate cardiomyocyte hypertrophy and hormonal profile in cardiac hypertrophy resulting from sequentially applied overloads. Methods We studied Sprague–Dawley rats with renovascular hypertension (RV), where pressure overload predominates, or deoxycorticosterone acetate (DOCA)-salt (DS), where volume overload predominates, at 2 and 4 weeks of treatment, and the combination of both models in inverse sequence: RV 2 weeks/DS 2 weeks (RV2/DS2) and DS 2 weeks/RV 2 weeks (DS2/RV2), and their sham controls (Sh). Results Blood pressure and cardiomyocyte diameter increased to a similar extent in RV and DS at 2 and 4 weeks and in combined models. Cardiomyocyte length increased remarkably in the DS4 group. Circulating atrial natriuretic peptide (ANP) was elevated in all hypertensive groups after 2 and 4 weeks. The RV2/DS2 group showed similar plasma ANP levels to RV4, but DS2/RV2 exhibited a three-fold increase in ANP levels (P < 0.001 versus Sh4, DS2 and DS4). Atrial ANP mRNA remained unchanged in all groups. DS treatment alone or in combination with RV increased left ventricular ANP mRNA, meanwhile only RV treatment increased left ventricular B-type natriuretic peptide (BNP) mRNA. Ventricular ANP expression levels, but not circulating ANP, correlated with both cardiomyocyte diameter (r = 0.859, P < 0.01) and length (r = 0.848, P < 0.01). Renal expression of natriuretic peptide receptor C (NPR-C) was unchanged in RV4 but decreased to a similar extent in the DS4 group and both combined treatments. Conclusion Morphometric patterns seem to be more related to the paracrine function of the heart than to the secretion of ANP and the endocrine function. Plasma ANP in the DS2/RV2 group could indicate a different evolution of the remodelling process. ANP expression seems to be a more sensitive marker for volume than for pressure overload.

Ventricular function and natriuretic peptides in sequentially combined models of hypertension

Hemodynamic parameters and natriuretic peptide levels were evaluated in cardiac hypertrophy produced by sequentially applied renovascular (RV) and deoxycorticosterone acetate-salt (DS) models of hypertension. We studied hypertensive rats by RV or DS treatment at 2 and 4 wk, as well as by the combination of 2 wk of each treatment in an inverse sequence: RV 2 wk/DS 2 wk (RV2/DS2) and DS 2 wk/RV 2 wk (DS2/RV2). The in vivo cardiac function, interstitial fibrosis, and synthesis and secretion of types A (ANP) and B (BNP) natriuretic peptides were monitored in hypertensive models compared with their corresponding sham (Sh2, Sh4). There were no differences in relaxation parameters among RV or DS groups and combined treatments. Left ventricular +dP/dt(max) increased only in RV4 (P < 0.01 vs. Sh4), and this increase was abolished in RV2/DS2. Interstitial collagen concentration increased after 4 wk in both RV4 and RV2/DS2 groups. Although there were no changes in collagen concentration in either DS2 or DS4 groups, clipping after 2 wk of DS (DS2/RV2) remarkably stimulated interstitial fibrosis (P < 0.01 vs. DS2). Plasma BNP increased in RV treatment at 4 wk (P < 0.001 vs. Sh4), but not in DS. Interestingly, RV applied after the 2 wk of DS treatment induced a marked increase in BNP levels (P < 0.001 vs. Sh4). In this regard, plasma BNP appears to be a reliable indicator of pressure overload. Our results suggest that the second stimulus of mechanical overload in combined models of hypertension determines the evolution of hypertrophy and synthesis and secretion of ANP and BNP.

Consultants for the American Journal of Nephrology 2006

Kevin Abbott Christina Abrass Rajiv Agarwal Farah Ali Efthyvoulos Anastassiades Gema Ariceta Akhtar Ashfaq John Asplin Phyllis August Susan Bagby Asad Bakir George Bakris Vinod Bansal Amelia Bartholomew Amy Barton Pai David Basile Enrico Benedetti Angelito Bernardo Rajendra Bhimma Peter Blake Amy Bobrowski Michael Braun Carolyn Brecklin Ursula Brewster Ellen Brooks Nigel Brunskill Vito Campese Huseyin Celiker Michael Choi Giorgio Coen Richard Cohn Jay Cohn Terezila Coimbra James Cook Scott Cotler Mario Cozzolino Stanislaw Czekalski Mohamed Daha Farhard Danesh Robert Danziger Jie Ding