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We have previously reported that hypertension in the young spontaneously hypertensive rat (SHR) is associated with an elevation in tissue angiotensinogen and a novel polysomal protein known to stabilize angiotensinogen mRNA. In our current study we determined the role of the mRNA-stabilizing protein in the regulation of tissue angiotensinogen expression and mean arterial pressure (MAP) in the SHR utilizing antisense oligodeoxynucleotide (AON) inhibition. Three AONs (RNASTAAS1, position 31-50; RNASTAAS2, position 21-40; RNASTAAS3, position 143-162 of the cDNA coding for the polysomal protein) were administered intravenously (dose 450, 900, and 1,800 [micro]g/kg; 1 dosage/day over 3 days) in conscious, chronically instrumented male SHRs at the age of 7 wk. Control SHRs received corresponding scrambled oligodeoxynucleotide sequences (SCR1, SCR2, SCR3). Each animal received the increasing dose schedule. RNASTAAS2 resulted in a reduced expression of the polysomal protein to 21% (liver), 12% (brain), 27% (heart), 18% (renal cortex), and 22% (renal medulla) of control. Angiotensinogen expression was inhibited to 54% (liver), 41% (brain), 68% (heart), 52% (renal cortex), and 74% (renal medulla) compared with control SHRs. Decreases in plasma concentrations of angiotensinogen and plasma renin activities were associated with a significant decrease in MAP from 147 [+ or -] 6 mmHg (after SCR2) to 106 [+ or -] 4 mmHg after RNASTAAS2. The effects of the two other AONs on MAP were less (RNASTAAS1, -31 mmHg; RNASTAAS3, -16 mmHg) with corresponding decreases in mRNAs coding for angiotensinogen and the polysomal protein. A significant decrease in intracellular concentrations of the polysomal protein accompanied AON inhibition. The magnitude of effects (-15 to -41 mmHg) was comparable to the effects of captopril (100 mg*[kg.sup.-1]*[day.sup.-1] for 3 days: -32 mmHg) and an A[T.sub.1] receptor antagonist (L-158809, 1.5 mg*[kg.sup.-1]*[day.sup.-1] for 3 days: -36 mmHg). These data suggest an important role of the mRNA-stabilizing protein for hepatic and extrahepatic angiotensinogen expression and MAP in the SHR. renin-angiotensin system; ribonucleic acid half-life; mean arterial pressure; plasma renin activity

Heat shock (HS) proteins (Hsps) function in tissue protection through their chaperone activity and by interacting with cell signaling pathways to suppress apoptosis. Here, we investigated the effect of HS treatment on the nuclear factor (NF)-[kappa]B signaling pathway in the angiotensin II (ANG II) model of inflammation. Male Sprague-Dawley rats were divided into sham and HS-, ANG II-, and HS + ANG II-treated groups. HS treatment was administered 24 h before the initiation of ANG II infusion. HS treatment (42[degrees]C for 15 min) decreased 7-day ANG II-induced hypertension from 191 [+ or -] 4 to 147 [+ or -] 3 mmHg (P < 0.01). Histological staining of hearts showed that HS treatment reduced ANG II-induced leukocyte infiltration, perivascular and interstitial inflammation, and fibrosis. Heart NF-[kappa]B nuclear translocation and activity, examined by Western blot analysis and electrophoretic mobility shift assay, was suppressed by HS treatment. HS treatment depleted I[kappa]B kinase-[alpha] (IKK-[alpha]) and phosphorylated IKK-[alpha] and suppressed the depletion of I[kappa]B-[alpha] and the accumulation of phosphorylated I[kappa]B-[alpha]. HS treatment blocked ANG II induced expression of IL-6 and ICAM-1 in the heart. ANG II and HS treatment induced high-level expression of Hsp27 and Hsp70 and their phosphorylation. Phosphorylated isoforms of Hsp27 and Hsp70 may play an important role in protecting the heart against ANG II-induced inflammation. heat shock proteins; I[kappa]B-[alpha]; I[kappa]B kinase-[alpha]; nuclear factor-[kappa]B; protein phosphorylation; hypertension

The purpose of this study was to evaluate the reversibility of right ventricular (RV) remodelling after pulmonary artery hypertension (PAHT) secondary to 3 wk of hypobaric hypoxia. A group of 10 adult male Wistar rats were studied and were the following: control normoxic (C), after 3 wk of chronic hypoxia (CH), and after 3 wk of exposure to hypoxia followed by 3 wk of normoxia recovery (N-RE). Mean pulmonary artery pressure was 11 [+ or -] 2 mmHg in the C group, 35 [+ or -] 2 mmHg in the CH group, and 14 [+ or -] 3 mmHg in the N-RE group. RV function was assessed by echocardiography. In the CH group, the pulmonary flow measured in Doppler mode depicted a midsystolic notch and a decrease of the pulmonary acceleration time compared with control [17 [+ or -] 1 vs. 34 [+ or -] 1 ms (n = 10), respectively; P < 0.05]. RV thickening measured in M-mode was apparent in the CH group compared with the control group [2.84 [+ or -] 0.40 vs. 1.73 [+ or -] 0.26 mm (n = 10), P < 0.05]. In the N-RE group, the RV wall was significantly thinner compared with the CH group [1.56 [+ or -] 0.08 vs. 1.73 [+ or -] 0.26 mm (n = 10), P < 0.05]. The calculated RV diameter shortness fraction was not different between the CH group and C group (34 [+ or -] 4.2% vs. 36 [+ or -] 2.8%) but decreased in the N-RE group [20 [+ or -] 2.4% (n = 10), P < 0.01]. The E-to-A wave ratio on the tricuspid Doppler inflow was significantly lower in the CH group and N-RE group compared with the C group [0.70 [+ or -] 0.8 and 0.72 [+ or -] 0.1 vs. 0.88 [+ or -] 0.2 (n = 10), respectively; P < 0.05]. In the isolated perfused heart using the Langendorff method, RV compliance was increased in the CH group and decreased in the N-RE group. In the N-RE group, fibrous bands with metaplasia were observed on histological sections of the RV free wall. We conclude that PAHT induces nonreversible RV dysfunction with dysplasia. pulmonary hypertension; echocardiography; remodelling

The study investigated whether the amelioration of endothelial dysfunction by candesartan (2 mg*[kg.sup.-1]*[day.sup.-1]; 10 wk) in spontaneously hypertensive rats (SHR) was associated with modification of hepatic redox system. Systolic arterial pressure (SAP) was higher (P < 0.05) in SHR than in Wistar-Kyoto rats (WKY) and was reduced (P < 0.05) by candesartan in both strains. Acetylcholine (ACh) relaxations were smaller (P < 0.05) and contractions induced by ACh + [N.sup.G]-nitro-L-arginine methyl ester (L-NAME) were greater (P < 0.05) in SHR than in WKY. Treatment with candesartan enhanced (P < 0.05) ACh relaxations in SHR and reduced (P < 0.05) ACh + L-NAME contractions in both strains. Expression of aortic endothelial nitric oxide synthase (eNOS) mRNA was similar in WKY and SHR, and candesartan increased (P < 0.05) it in both strains. Aortic mRNA expression of the subunit p22phox of NAD(P)H oxidase was higher (P < 0.05) in SHR than in WKY. Treatment with candesartan reduced (P < 0.05) p22phox expression only in SHR. Malonyl dialdehyde (MDA) levels were higher (P < 0.05), and the ratio reduced/oxidized glutathione (GSH/GSSG) as well as glutathione peroxidase activity (GPx) were lower (P < 0.05) in liver homogenates from SHR than from WKY. Candesartan reduced (P < 0.05) MDA and increased (P < 0.05) GSH/GSSG ratio without affecting GPx. Vessel, lumen, and media areas were bigger (P < 0.05) in SHR than in WKY. Candesartan treatment reduced (P < 0.05) media area in SHR without affecting vessel or lumen area. The results suggest that hypertension is not only associated with elevation of vascular superoxide anions but with alterations of the hepatic redox system, where ANG II is clearly involved. The results further support the key role of ANG II via A[T.sub.1] receptors for the functional and structural vascular alterations produced by hypertension. oxidative stress; antioxidant defense; nitric oxide; hypertension; angiotensin II; angiotensin II receptor antagonists

The incidence of hypertension increases during the late stages of aging; however, the vascular mechanisms involved are unclear. We investigated whether the late stages of aging are associated with impaired nitric oxide (NO)-mediated vascular relaxation and enhanced vascular contraction and whether oxidative stress plays a role in the age-related vascular changes. Aging (16 mo) male spontaneously hypertensive rats (SHR) nontreated or treated for 8 mo with the antioxidant tempol (1 mM in drinking water) or vitamin E (E; 5,000 IU/kg chow) and vitamin C (C; 100 mg*[kg.sup.-1]*[day.sup.-1] in drinking water) and adult (12 wk) male SHR were used. After the arterial pressure was measured, aortic strips were isolated from the rats for measurement of isometric contraction. The arterial pressure and phenylephrine (Phe)-induced vascular contraction were enhanced, and the ACh-induced vascular relaxation and nitrite/nitrate production were reduced in aging compared with adult rats. In aging rats, the arterial pressure was nontreated (188 [+ or -] 4), tempol-treated (161 [+ or -] 6), and E + C-treated (187 [+ or -] 1 mmHg). Phe ([10.sup.-5] M) caused an increase in active stress in nontreated aging rats (14.3 [+ or -] 1.0) that was significantly (P < 0.05) reduced in tempol-treated (9.0 [+ or -] 0.7) and E + C-treated rats (9.8 [+ or -] 0.6 x [10.sup.4] N/[m.sup.2]). ACh produced a small relaxation of Phe contraction in non-treated aging rats that was enhanced (P < 0.05) in tempoland E + C-treated rats. L-NAME ([10.sup.-4] M), inhibitor of NO synthase, or ODQ ([10.sup.-5] M), inhibitor of cGMP production in smooth muscle, inhibited ACh relaxation and enhanced Phe contraction in tempol- and E + C-treated but not the nontreated aging rats. ACh-induced vascular nitrite/nitrate production was not different in nontreated, tempol-and E + C-treated aging rats. Relaxation of Phe contraction with sodium nitroprusside, an exogenous NO donor, was smaller in aging than adult rats but was not different between nontreated, tempol- and E + C-treated aging rats. Thus, during the late stages of aging in SHR rats, an age-related inhibition of a vascular relaxation pathway involving not only NO production by endothelial cells but also the bioavailability of NO and the smooth muscle response to NO is partially reversed during chronic treatment with the antioxidants tempol and vitamins E and C. The data suggest a role for oxidative stress in the reduction of vascular relaxation and thereby the promotion of vascular contraction and hypertension during the late stages of aging. arterial pressure; endothelium; nitric oxide; vascular smooth muscle; contraction; spontaneously hypertensive rats

The brain renin-angiotensin system (RAS) has long been considered pivotal in cardiovascular regulation and important in the pathogenesis of hypertension and heart failure. However, despite more than 30 years of study, the brain RAS continues to defy explanation. Our lack of understanding of how the brain RAS is organized at the cellular and regional levels has made it difficult to resolve long-sought questions of how ANG II is produced in the brain and the precise mechanisms by which it exerts its actions. A major reason for this is the difficulty in experimentally dissecting the brain RAS at the regional, cellular, and whole organism levels. Recently, we and others developed a series of molecular tools for selective manipulation of the murine brain RAS, in parallel with technologies for integrative analysis of cardiovascular and volume homeostasis in the conscious mouse. This review, based in part on a lecture given in conjunction with the American Physiological Society Young Investigator Award in Regulatory and Integrative Physiology (Water and Electrolyte Homeostasis Section), outlines the physiological genomics strategy that we have taken in an effort to unravel some of the complexities of this system. It also summarizes the principles, progress, and prospects for a better understanding of the brain RAS in health and disease. transgenic mice; gene transfer; blood pressure; heart rate; dipsogenesis; reactive oxygen species; Cre-lox system; hypertension; heart failure

The cardiovascular consequences of eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-specific intake were evaluated in vivo in a hyperinsulinemia (HI) model induced by dietary fructose intake. Wistar rats were fed a diet containing (or not for control) either EPA or DHA. The rise in blood pressure (BP), heart rate, and ECG were continuously monitored using an intra-abdominal telemetry system. The myocardial phospholipid fatty acid profile was significantly affected by DHA intake but less by EPA intake. The data indicated a reduced rise in BP in both DHA and EPA HI groups compared with controls. This result was confirmed by tail-cuff measurement after 5 wk [133.3 [+ or -] 1.67 and 142.5 [+ or -] 1.12 mmHg in n-3 polyunsaturated fatty acid (PUFA) and control groups, respectively], whereas n-3 PUFA did not affect BP in non-HI rats (116.3 [+ or -] 3.33 mmHg). The heart rate was lower in the HI DHA group than in the other two dietary HI groups. Moreover, DHA induced a significantly shorter QT interval. It is concluded that the cardioactive component offish oils is DHA through a mechanism that may involve the cardiac adrenergic system. hypertension; nutrition; prevention; telemetry; heart

Ischemia-induced angiogenic response is reduced in spontaneously hypertensive rats (SHR). To study whether exogenous basic fibroblast growth factor (bFGF) infusion is effective in expanding collateral circulation in frankly hypertensive SHR, femoral arteries of male SHR (weighing ~250 g) were kept intact (nonoccluded control; n = 9) or occluded for 4 h (n = 12) or for 16 days with vehicle (n = 14) or bFGF [0.5 (n = 17), 5.0 (n = 13), and 50.0 (n = 14) [micro]g*[kg.sup.-1]*[day.sup.-1] for 14 days] intra-arterially. Maximal collateral-dependent blood flows (BF) to the hindlimbs were determined with [sup.85]Sr- and [sup.141]Ce-labeled microspheres during running at 20 and 25 m/min (15% grade). Preexercise heart rates (~530 beats/min) and blood pressures (BP; ~200 mmHg) were similar across groups except in the high-dose bFGF group, where BP was reduced by ~12% (P < 0.05). Femoral artery occlusion for 4 h resulted in ~95% reduction of BF in calf muscles [199 [+ or -] 18.7 (nonoccluded group) to 10 [+ or -] 1.0 ml*[min.sup.-1]*100 [g.sup.-1]; p < 0.001]. BF to calf muscles of the vehicle and low-dose bFGF (0.5 [micro]g*[kg.sup.-1]*[day.sup.-1]) groups increased to 36 [+ or -] 3.2 and 45 [+ or -] 2.0 ml*[min.sup.-1]*100 [g.sup.-1], respectively (P < 0.001). bFGF infusion at 5.0 and 50.0 [micro]g*[kg.sup.-1]*[day.sup.-1] further increased (P < 0.001) BF to calf muscles (62 [+ or -] 4.6 and 62 [+ or -] 2.2 ml*[min.sup.-1]*100 [g.sup.-1], respectively). Our results show that bFGF can effectively increase BF in hypertensive rats. The reduced hypertension with high-dose bFGF suggests that a critical signal in arteriogenesis (nitric oxide bioavailability) may be restored. These findings suggest that the dulled endothelial nitric oxide synthase of SHR does not preempt collateral vessel remodeling. angiogenesis; vascular remodeling; peripheral arterial insufficiency; nitric oxide; arterial occlusion

We examined effects of a soy diet on blood pressure in 207 subjects (aged 45-93 y, mean age 71 y) with and without arterial hypertension. Subjects without arterial hypertension and patients with arterial hypertension were given soy protein (27 g/d for 35 d). We compared the effect of soy protein (textured soy protein and soymilk) with usual diet. Dietary supplementation with soy reduced the frequency of dizziness, headache, and noises in the ears. Systolic and diastolic arterial blood pressures are presented in Table 1. Our findings indicate that diet containing soy protein has beneficial effect on blood pressure in hypertensive subjects during 35-d diet period. TABLE 1 Systolic and diastolic arterial blood pressures (mean [+ or -] SE) Systolic blood Diastolic blood pressures pressures Nonhypertensive subjects with soy diet (n -- 108) Before soy diet 128 [+ or -] 3 82 [+ or -] 1 After soy diet 138 [+ or -] 2 * 84 [+ or -] 1 Patients with arterial hypertension with soy diet (n = 69) Before soy diet 173 [+ or -] 4 96 [+ or -] 2 After soy diet 146 [+ or -] 5 * 83 [+ or - 2] * Patients with arterial hypertension without soy diet (n = 30) Before soy diet 158 [+ or -] 4 93 [+ or -] 2 After soy diet 158 [+ or -] 4 92 [+ or -] 4 * P < 0.05 statistically significant between initial and final values; SE, standard error.

In recent studies the life span of stroke-prone spontaneously hypertensive (SHRSP) rats, one of the most suitable animal models for stroke in humans, was altered by the percentage of dietary protein. Death from stroke occurred significantly earlier in animals fed 10% protein casein diet compared with those fed 20% and 40% protein casein diets. This study was conducted to examine whether the source of dietary protein (casein vs. soybean protein isolate, alcohol washed to remove most isoflavones), type of supplemental sulfur amino acid (methionine vs. cystine), dietary isoflavones, and dietary anthocyanins modulate the life span of SHRSP rats. Groups of 47-d-old SHRSP rats matched for body weight and systolic blood-pressure received semipurified diets containing 200 g/kg protein (casein or soybean) supplemented with methionine or cystine (3 g/kg), 0 or 500 mg/kg isoflavones (from Novasoy), and 0 or 500 mg/kg anthocyanins (extracted from elderberries). All the experimental diets also contained 10% soybean oil and required levels of other nutrients. A 0.5% sodium chloride solution was used as drinking water to induce hypertension. After consuming the diets for 37 d, 10 animals from each dietary group were killed for the collection of blood and tissues for biochemical analyses, which are currently underway. The death rates of rats fed the casein and soybean protein diets were not different. Death from stroke was significantly earlier (P < 0.0001) in the animals fed cystine-supplemented diets compared with those fed methionine-supplemented diets. Addition of isoflavones or anthocyanins resulted in significantly shortened (P < 0.023 and P < 0.016, respectively) life span of SHRSP rats.