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The novel peptide, angiotensin (ANG)-(1-12), elicits a systemic pressor response and vasoconstriction. These effects are blocked by ANG converting enzyme (ACE) inhibitors or AT1 receptor antagonists, suggesting a role as an ANG II precursor. However, ANG-(1-12) can serve as a substrate for either ANG II or ANG-(1-7) formation, depending on the local tissue enzymes. Although levels of ANG-(1-12) are higher than ANG I or ANG II in brain, the role and processing of this peptide for autonomic control of heart rate (HR) has yet to be considered. Thus we examined the effects of nucleus tractus solitarii (NTS) microinjection of ANG-(1-12) on baroreflex sensitivity for control of HR, resting arterial pressure (AP) and HR, and indexes of sympathovagal balance in urethane/chloralose anesthetized Sprague-Dawley rats. NTS injection of ANG-(1-12) (144 fmol/120 nl) significantly impaired the evoked baroreflex sensitivity to increases in AP [n = 7; 1.06 [+ or -] 0.06 baseline vs. 0.44 [+ or -] 0.07 ms/mmHg after ANG-(1-12)], reduced the vagal component of spontaneous baroreflex sensitivity and HR variability, and elicited a transient depressor response (P < 0.05). NTS pretrcatment with an AT1 receptor antagonist or ACE inhibitor prevented ANG-(1-12)-mediated autonomic and depressor responses. ANG-(1-12) immunostaining was observed in cells within the NTS of SpragueDawley rats, providing a potential intracellular source for the peptide. However, acute NTS injection of an ANG-(1-12) antibody did not alter resting baroreflex sensitivity, AP, or HR in these animals. Collectively, these findings suggest that exogenous ANG-(1-12) is processed to ANG II for cardiovascular actions at AT1 receptors within the NTS. The lack of acute endogenous ANG-(1-12) tone for cardiovascular regulation in Sprague-Dawley rats contrasts with chronic immunoneutralization in hypertensive rats, suggesting that ANG-(1-12) may be activated only under hypertensive conditions. baroreflex; autonomic doi: 10.1152/ajpheart.00345.2010.

To accelerate lung development and protect neonates from other early developmental problems, synthetic steroids are administered maternally in the third trimester, exposing fetuses that are candidates for premature delivery to them. However, steroid exposure at this point of gestation may lead to elevated blood pressure [mean arterial pressure (MAP)] during adolescence. We hypothesize that fetal exposure to steroids activates the renin-angiotensin system, inducing an elevation in blood pressure and attenuation of baroreflex sensitivity (BRS) that is angiotensin II dependent in early adulthood. To test this hypothesis, fetal sheep were exposed to betamethasone (Beta) or vehicle (control) administered to ewes at day 80 of gestation and delivered at full term. At 1.8 yr of age, male offspring were instrumented for conscious recording of MAP, heart rate, and measurement of BRS [as low-frequency-[alpha], high-frequency-co, sequence (seq) UP, seq DOWN, and seq TOTAL]. Beta-exposed sheep (n = 6) had higher MAP than control sheep (n = 5) (93 [+ or -] 2 vs. 84 [+ or -] 2 mmHg, P < 0.01). Acute blockade of angiotensin type 1 receptors with candesartan (0.3 mg/kg iv) normalized MAP in Beta-exposed sheep (85 [+ or -] 4 mmHg), with no effect in control sheep (82 [+ or -] 3 mmHg). Before angiotensin type 1 blockade, BRS maximum gain was significantly lower in Beta-exposed vs. control sheep (11 [+ or -] 3 vs. 26 [+ or -] 3 ms/mmHg, P < 0.0.01). However, 45 min after candesartan injection, BRS was increased in Beta-exposed (21 [+ or -] 5 ms/mmHg) and control (35 [+ or -] 4 ms/mmHg) sheep. Heart rate variability (HRV) and blood pressure variability (BPV) revealed lower HRV (SD of beat-to-beat interval and root mean square of successive beat-to-beat differences in R-R interval duration) and higher BPV (SD of MAP, systolic arterial pressure in low-frequency range) in Beta-exposed sheep. Candesartan partially restored HRV in Beta-exposed sheep and fully corrected BPV. Thus, in utero exposure to synthetic glucocorticoids causes long-lasting programming of the cardiovascular system via renin-angiotensin system-dependent mechanisms. spectral analysis; fetal programming; heart rate variability; blood pressure variability; renin-angiotensin system; hypertension doi: 10.1152/ajpheart.00100.2010.

The mRen(2).Lewis (mRen2) strain is an ANG If-dependent model of hypertension expressing marked sex differences in blood pressure and tissue injury that also exhibits estrogen and salt sensitivity. Because estrogen and salt influence angiotensinogen (AGT), circulating and renal expression of the protein were assessed in the mRen2 using a sensitive and specific ELISA. Hemizygous female and male mRen2 were placed on normal (1% NaCl, NS)- or high (8% NaCl, HS)-salt diets from 5 to 15 wk of age while a separate NS cohort was ovariectomized (OVX). The OVX mRen2 exhibited higher blood pressure (184 [+ or -] 6 vs. 149 [+ or -] 5 mmHg, n = 6), a 16-fold increase in urinary AGT (uAGT) (0.2 [+ or -] 0.02 vs. 0.01 [+ or -] 0.01 [micro]gx[kg.sup.-1]x[day.sup.-1], P < 0.01), but no change in proteinuria (PROT). Excretion of AGT was correlated with blood pressure and PROT in the female groups. The HS diet led to higher blood pressure (224 [+ or -] 8 mmHg), a 180-fold increase in uAGT (1.8 [+ or -] 0.2 [micro]gx[kg.sup.-1]x[day.sup.-1]), and increased PROT (98 [+ or -] 9 vs. 7 [+ or -] 1 mgx[kg.sup.-1]x[day.sup.-1]). Compared with females, NS males expressed higher excretion of uAGT (3.0 [+ or -] 0.4 [micro]gx[kg.sup-1]x[day.sup.-1]) and PROT (32 [+ or -] 5 mgx[kg.sup.-1]x[day.sup.-1]); both were increased eightfold with HS (uAGT: 23 [+ or -] 3 [micro]gx[kg.sup.-1]x[day.sup.-1]; PROT: 285 [+ or -] 28 mgx[kg.sup.-1]x[day.sup.-1]) without a change in blood pressure. Although uAGT was markedly higher in the OVX and HS groups, neither renal cortical AGT mRNA or protein expression was increased. Moreover, AGT release in cortical slices was similar for the NS and HS females. We conclude that the increase in uAGT with estrogen depletion or HS likely may be a biomarker for glomemlar damage reflecting filtration of the circulating protein in the mRen2. angiotensin II; normal salt diet; high-salt diet doi: 10.1152/ajprenal.00138.2010.

Contag SA, Bi J, Chappell MC, Rose JC. Developmental effect of antenatal exposure to betamethasone on renal angiotensin H activity in the young adult sheep. Am J Physiol Renal Physiol 298: F847-F856, 2010. First published January 13, 2010; doi:10.1152/ajprenal.00497.2009.--Antenatal corticosteroids may have long-term effects on renal development which have not been clearly defined. Our objective was to compare the responses to intrarenal infusions of ANG II in two groups of year-old, male sheep: one group exposed to a clinically relevant dose of betamethasone before birth and one not exposed. We wished to test the hypothesis that antenatal steroid exposure would enhance renal responses to ANG II in adult life. Six pairs of male sheep underwent unilateral nephrectomy and renal artery catheter placement. The sheep were infused for 24 h with ANG II or with ANG II accompanied by blockade of the angiotensin type 1 (A[T.sub.1]) or type 2 (AT2) receptor. Baseline mean arterial blood pressure among betamethasone-exposed sheep was higher than in control animals (85.8 [+ or -] 2.2 and 78.3 [+ or -] 1.0 mmHg, respectively, P = 0.003). Intrarenal infusion of ANG II did not increase systemic blood pressure (P [greater than or equal to] 0.05) but significantly decreased effective renal plasma flow and increased renal artery resistance (P < 0.05). The decrease in flow and increase in resistance were significantly greater in betamethasone- compared with vehicleexposed sheep (betamethasone P < 0.05, vehicle P [greater than or equal to] 0.05). This effect appeared to be mediated by a heightened sensitivity to the A[T.sub.1] receptor among betamethasone-exposed sheep. Sodium excretion initially decreased in both groups during ANG II infusion; however, a rebound was observed after 24 h. A[T.sub.1] blockade was followed by a significant rebound after 24 h in both groups. A[T.sub.2] blockade blunted the 24-h rebound effect among the vehicle-exposed sheep compared with the betamethasone-exposed sheep. In conclusion, antenatal corticosteroid exposure appears to modify renal responsiveness to ANG II by increasing A[T.sub.1]- and decreasing A[T.sub.2] receptor-mediated actions particularly as related to renal blood flow and sodium excretion. angiotensin receptor; renal plasma flow; glomerular filtration rate; corticosteroids doi: 10.1152/ajprenal.00497.2009.

Am J Physiol Renal Physiol 298: F37-F48, 2010. First published October 21, 2009; doi: 10.1152/ajprenal.00519.2009.--Combination therapy of angiotensin-converting enzyme (ACE) inhibition and [AT.sub.1] receptor blockade has been shown to provide greater renoprotection than ACE inhibitor alone in human diabetic nephropathy, suggesting that ACE-independent pathways for ANG II formation are of major significance in disease progression. Studies were performed to determine the magnitude of intrarenal ACE-independent formation of ANG II in type II diabetes. Although renal cortical ACE protein activity [2.1 [+ or -] 0.8 vs. 9.2 [+ or -] 2.1 arbitrary fluorescence units (AFU) x [mg.sup.-1] x [min.sup.-1]] and intensity of immunohistochemical staining were significantly reduced and ACE2 protein activity (16.7 [+ or -] 3.2 vs. 7.2 [+ or -] 2.4 AFU x [mg.sup.-1] x [min.sup.-1]) and intensity elevated, kidney ANG I (113 [+ or -] 241 vs. 110 [+ or -] 45 fmol/g) and ANG II (1,017 [+ or -] 165 vs. 788 [+ or -] 99 fmol/g) levels were not different between diabetic and control mice. Afferent arteriole vasoconstriction due to conversion of ANG I to ANG II was similar in magnitude in kidneys of diabetic (-28 [+ or -] 3% at 1 [micro]M) and control (-23 [+ or -] 3% at 1 [micro]M) mice; a response completely inhibited by AT1 receptor blockade. In control kidneys, afferent arteriole vasoconstriction produced by ANG I was significantly attenuated by ACE inhibition, but not by serine protease inhibition. In contrast, afferent arteriole vasoconstriction produced by intrarenal conversion of ANG I to ANG II was significantly attenuated by serine protease inhibition, but not by ACE inhibition in diabetic kidneys. In conclusion, there is a switch from ACE-dependent to serine protease-dependent ANG II formation in the type II diabetic kidney. Pharmacological targeting of these serine protease-dependent pathways may provide further protection from diabetic renal vascular disease. afferent arteriole; juxtamedullary nephron; db/db mouse; angiotensin-converting enzyme; serine protease; angiotensinogen; angiotensin-converting enzyme 2