The predominant role of brain angiotensinogen and angiotensin in environmentally induced hypertension

Rats exposed chronically to a cold environment (5 degrees C/4 degrees F) develop hypertension. This cold-induced hypertension (CIH) is a non-genetic, non-pharmacological, non-surgical model of environmentally induced hypertension in rats. The renin-angiotensin system (RAS) appears to play a role in both initiating and/or maintaining the high blood pressure in CIH. The goal of the present study was to evaluate the role of central and peripheral circulating RAS components, angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin (Ang) II, in CIH. Seventy-two Sprague-Dawley adult male rats were used. Thirty-six rats were kept in cold room at 5 degrees C while the other 36 were at 24 degrees C as controls for 5 weeks. Systolic blood pressure (SBP) was recorded by tail cuff. The SBP was increased in rats exposed to cold within 1 week, and this increase was significant for the next 2-5 weeks of the cold exposure (p<0.01). Three subgroups of the cold-treated and control rats (n=12) were sacrificed at 1, 3 and 5 weeks. The brain and liver were removed and plasma was saved. The AGT mRNA significantly increased in the hypothalamus and liver in cold-treated rats from the first week of exposure to cold, and was maintained throughout the time of exposure to cold (n=4, p<0.01). The AGT protein levels in the brain, liver and plasma did not differ significantly between cold-treated and control rats (p>0.05, n=4). The hypothalamic Ang II levels were significantly increased, whereas plasma Ang II levels significantly decreased, in the rats of 5 weeks of cold exposure (n=8, p<0.05). Plasma ACE significantly increased in the rats of 1 week of cold exposure (p<0.05, n=12). The results show differential regulation of RAS components, AGT, ACE and Ang II, between brain and periphery in cold-exposed rats. We conclude that the exposure to low temperature initially increases plasma RAS but with continuous exposure to cold, the brain RAS maintains the hypertension, probably by sustained sympathetic activation, which would provide increased metabolism but also vasoconstriction leading to hypertension.     

Reversibility of cold-induced hypertension after removal of rats from cold

Chronic exposure of rats to cold air induces hypertension, including elevation of blood pressure and cardiac hypertrophy. The present study was designed to assess reversibility of these changes after removal from cold. Five groups of six male rats each were exposed to cold (5 +/- 2 degrees C) for 39 days, while six control rats were maintained at 26 +/- 2 degrees C. Systolic blood pressures of the rats in one of the cold-treated groups, as well as the controls, were measured twice weekly throughout the experiment. Blood pressure of the cold-exposed rats (150 +/- 3 mmHg; 1 mmHg = 133.3 Pa) became elevated significantly above that of controls (129 +/- 3 mmHg) within 4 weeks. On day 39 of cold exposure, one group (six rats) of the cold-treated rats was sacrificed while still in the cold. The remaining four groups of cold-treated rats were than removed from cold and kept at 26 +/- 2 degrees C. One group of cold-treated rats was sacrificed weekly thereafter. During the last week, the six control rats were also sacrificed. At death, the heart, kidneys, and adrenal glands were removed and weighed. Mean heart weight of the cold-treated group (346 +/- 7 mg/100 g body weight), sacrificed prior to removal from cold, was significantly (p less than 0.01) greater than that of controls (268 +/- 5 mg/100 g body weight). The increased heart weight of the cold-treated group appeared to result mainly from an increase in left ventricular weight.(ABSTRACT TRUNCATED AT 250 WORDS)     

A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity

The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.     

Increased tail artery vascular responsiveness to angiotensin II in cold-treated rats

Chronic exposure of rats to cold for 1-3 weeks results in a mild form of hypertension. The renin-angiotensin system (RAS) has been implicated in this model of cold-induced hypertension. Previously we have characterized the vascular responsiveness in cold-acclimated animals, using aortic tissue, and recent studies have focused on the thermoregulatory responses of angiotensin II (AngII), utilizing the tail artery of the rat. Therefore in the current study we evaluated the vascular responsiveness of cold-treated rats to AngII in both aorta and tail artery at 2 and 4 weeks of cold exposure (5+/-2 degrees C). Systolic blood pressures were significantly elevated in cold-treated animals compared with control animals at both 2 and 4 weeks of cold exposure. At both of these time points body weights were reduced and ventricular weights were increased in cold-treated animals. After 2 weeks of cold exposure the vascular responsiveness of the aorta to AngII was significantly lower than that of controls. This vascular responsiveness to AngII was elevated and returned to control levels after 5 weeks of cold exposure. However, this pattern was not observed in the tail artery. The vascular responsiveness of tail artery rings from cold-treated rats to AngII was significantly greater than that of control animals during both 2 and 5 weeks of exposure to cold. The vascular contractile responses of both the aorta and tail artery to KCI in the cold-treated animals was not different from that of the control animals maintained at ambient room temperature, suggesting that the vascular smooth muscle contractile components were not altered by the cold exposure. Thus, the in vitro vascular reactivity to the receptor-mediated vasoconstrictor AngII was decreased in the sparsely innervated aorta and increased in the more densely innervated tail artery of the cold-treated animals when compared with controls. These results suggest that the increased responsiveness of AngII on the smooth muscle of the tail artery may play a role in adaptation to the cold and the maintenance of cold-induced hypertension.     

Changes of renal function and structure in rats exposed to cold

The kidney appears to play a crucial role in both initiating and maintaining the high blood pressure in cold-induced hypertension (CIH). The aim of the present study was to evaluate the changes of renal function and structure in rats exposed to cold for 2, 4 and 6 weeks. Systolic blood pressure increased significantly after 2 weeks of cold exposure and was maintained throughout the whole experiment. Upregulation of angiotensin type 1 receptor (AT₁R) expression was seen in the vascular zone and distal tubule after 4 and 6 weeks of cold exposure. This was accompanied by an increase in malondialdehyde (MDA) levels and decreases in superoxide dismutase (SOD), nitric oxide synthase (NOS) activities and nitric oxide (NO) content in kidney. Structural changes were also observed in glomeruli, tubules and arteries in cold-treated rats. These results suggest that upregulation of kidney AT₁R plays a critical role in the development of CIH, and its interaction with oxidative stress, NO and NOS may be involved in changes of renal function and structure.     

High Na intake increases renal angiotensin II levels and reduces expression of the ACE2-AT(2)R-MasR axis in obese Zucker rats

High sodium intake is known to regulate the renal renin-angiotensin system (RAS) and is a risk factor for the pathogenesis of obesity-related hypertension. The complex nature of the RAS reveals that its various components may have opposing effects on natriuresis and blood pressure regulation. We hypothesized that high sodium intake differentially regulates and shifts a balance between opposing components of the renal RAS, namely, angiotensin-converting enzyme (ACE)-ANG II-type 1 ANG II receptor (AT(1)R) vs. AT(2)-ACE2-angiotensinogen (Ang) (1-7)-Mas receptor (MasR), in obesity. In the present study, we evaluated protein and/or mRNA expression of angiotensinogen, renin, AT(1A/B)R, ACE, AT(2)R, ACE2, and MasR in the kidney cortex following 2 wk of a 8% high-sodium (HS) diet in lean and obese Zucker rats. The expression data showed that the relative expression pattern of ACE and AT(1B)R increased, renin decreased, and ACE2, AT(2)R, and MasR remained unaltered in HS-fed lean rats. On the other hand, HS intake in obese rats caused an increase in the cortical expression of ACE, a decrease in ACE2, AT(2)R, and MasR, and no changes in renin and AT(1)R. The cortical levels of ANG II increased by threefold in obese rats on HS compared with obese rats on normal salt (NS), which was not different than in lean rats. The HS intake elevated mean arterial pressure in obese rats (27 mmHg) more than in lean rats (16 mmHg). This study suggests that HS intake causes a pronounced increase in ANG II levels and a reduction in the expression of the ACE2-AT(2)R-MasR axis in the kidney cortex of obese rats. We conclude that such changes may lead to the potentially unopposed function of AT(1)R, with its various cellular and physiological roles, including the contribution to the pathogenesis of obesity-related hypertension.     

17beta-estradiol downregulates tissue angiotensin-converting enzyme and ANG II type 1 receptor in female rats

Estrogens have been implicated in both worsening and protecting from cardiovascular disease. The effects of 17beta-estradiol (E2) on the cardiovascular system may be mediated, at least in part, by its modulation of local tissue renin-angiotensin systems (RAS). We assessed two critical components, angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (AT(1)R), in the heart, lung, abdominal aorta, adrenal, kidney, and brain in four groups of female Wistar rats (n = 5-6/group): 1) sham ovariectomized, 2) ovariectomized (OVX) treated with subcutaneous vehicle, 3) OVX treated with 25 mug/day (regular) E2 subcutaneously, and 4) OVX treated with 250 mug/day (high) subcutaneous E2 for 2 or 5 wk. After 2 wk, plasma ACE activity was not altered by OVX, but it was 34-38% lower in OVX + regular E2 and OVX + high E2 rats compared with sham OVX rats, and these decreases were no longer present after 5 wk. After 5 wk, OVX alone increased ACE activity and binding densities, and AT(1)R binding densities by 15-100% in right ventricle, left ventricle (LV), kidney, lung, abdominal aorta, adrenal and several cardiovascular regulatory nuclei in the brain. These effects were, for the most part, prevented by regular E2 replacement and were reversed to decreases by high E2 treatment. This regulation of tissue ACE and AT(1)R is significant as the activity of these tissue RAS contributes to the pathogenesis and/or progression of hypertension, atherosclerosis, and LV remodeling after myocardial infarction.     

Diabetes-induced stimulation of the renin-angiotensin system in the rat brain cortex

Cerebrovascular disease is a threat to people with diabetes and hypertension. Diabetes can damage the brain by stimulating the renin-angiotensin system (RAS), leading to neurological deficits and brain strokes. Diabetes-induced components of the RAS, including angiotensin-converting enzyme (ACE), angiotensin-II (Ang-II), and angiotensin type 1 receptor (AT1R), have been linked to various neurological disorders in the brain. In this study, we investigated how diabetes and high blood pressure affected the regulation of these major RAS components in the frontal cortex of the rat brain. We dissected, homogenized, and processed the brain cortex tissues of control, streptozotocin-induced diabetic, spontaneously hypertensive (SHR), and streptozotocin-induced SHR rats for biochemical and Western blot analyses. We found that systolic blood pressure was elevated in SHR rats, but there was no significant difference between SHR and diabetic-SHR rats. In contrast to SHR rats, the heartbeat of diabetic SHR rats was low. Western blot analysis showed that the frontal cortexes of the brain expressed angiotensinogen, AT1R, and MAS receptor. There were no significant differences in angiotensinogen levels across the rat groups. However, the AT1R level was increased in diabetic and hypertensive rats compared to controls, whereas the MAS receptor was downregulated (p < 0.05). These findings suggest that RAS overactivation caused by diabetes may have negative consequences for the brain's cortex, leading to neurodegeneration and cognitive impairment.     

Aldosterone acts centrally to increase brain renin-angiotensin system activity and oxidative stress in normal rats

Aldosterone acts upon mineralocorticoid receptors in the brain to increase blood pressure and sympathetic nerve activity, but the mechanisms are still poorly understood. We hypothesized that aldosterone increases sympathetic nerve activity by upregulating the renin-angiotensin system (RAS) and oxidative stress in the brain, as it does in peripheral tissues. In Sprague-Dawley rats, aldosterone (Aldo) or vehicle (Veh) was infused for 1 wk via an intracerebroventricular (ICV) cannula, while RU-28318 (selective mineralocorticoid receptor antagonist), Tempol (superoxide dismutase mimetic), losartan [angiotensin II type 1 receptor (AT(1)R) antagonist], or Veh was infused simultaneously via a second ICV cannula. After 1 wk of ICV Aldo, plasma norepinephrine was increased and mean arterial pressure was slightly elevated, but heart rate was unchanged. These effects were ameliorated by ICV infusion of RU-28318, Tempol or losartan. Aldo increased expression of AT(1)R and angiotensin-converting enzyme (ACE) mRNA in hypothalamic tissue. RU-28318 minimized and Tempol prevented the increase in AT(1)R mRNA; RU-28318 prevented the increase in ACE mRNA. Losartan had no effect on AT(1)R or ACE mRNA. Immunohistochemistry revealed Aldo-induced increases in dihydroethidium staining (indicating oxidative stress) and Fra-like activity (indicating neuronal excitation) in neurons of the hypothalamic paraventricular nucleus (PVN). RU-28318 prevented the increases in superoxide and Fra-like activity in PVN; Tempol and losartan minimized these effects. Acute ICV infusions of sarthran (AT(1)R antagonist) or Tempol produced greater sympathoinhibition in Aldo-treated than in Veh-treated rats. Thus aldosterone upregulates key elements of brain RAS and induces oxidative stress in the hypothalamus. Aldosterone may increase sympathetic nerve activity by these mechanisms.     

Hypertension during chronic exposure to cold: comparison between Sprague-Dawley and Long-Evans strains.

It is now well established that chronic exposure of rats to cold (5-6 degrees C) induces an elevation of systolic, diastolic, and mean blood pressures and cardiac hypertrophy within 3 weeks. Since rats of the Long-Evans (LE) strain are known to be resistant to the induction of deoxycorticosterone salt induced hypertension, their cardiovascular responses to chronic exposure to cold were compared with those of rats of the Sprague-Dawley (SD) strain. The results of these studies revealed clear differences between the LE and SD strains of rats. Thus, rats of the SD strain had a significant elevation in their blood pressure; a significantly increased urinary output of norepinephrine and epinephrine; a significantly greater dipsogenic responsiveness to acute administration of angiotensin II, and significant increases in weights of the heart, kidneys, adrenals, and brown adipose tissue compared with their warm-adapted controls. All of these changes are characteristic of rats acclimated to cold. In contrast, rats of the LE strain appear to be less responsive to cold in that blood pressure failed to rise as sharply and to attain as high a level. Furthermore, urinary outputs of norepinephrine and epinephrine were significantly lower in cold-treated rats of the LE strain compared with cold-treated rats of the SD strain, but dipsogenic responsiveness to angiotensin II was unchanged. Although increases in the weight of the previously mentioned organs were also observed in cold-treated rats of the LE strain compared with their warm-adapted controls, weights of the heart and interscapular brown adipose tissue of both groups were significantly less than those of counterparts of the SD strain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combination of direct renin inhibition with angiotensin type 1 receptor blockade improves aldosterone but does not improve kidney injury in the transgenic Ren2 rat

Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT(1)R) blockade. This is important as, even with contemporary use of AT(1)R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination of direct renin inhibition with AT(1)R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT(1)R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP and serum aldosterone, but did not result in greater improvement in markers of glomerular and tubular injury (i.e. β-NAG) compared to either intervention alone. Further, combination therapy did not improve markers of oxidative stress and podocyte and proximal tubule integrity in this transgenic model of RAAS-mediated kidney damage despite greater reductions in serum aldosterone and BP levels.     

Genetic AT1A receptor deficiency attenuates cold-induced hypertension

The aim of this study was to test our hypotheses that AT1A receptors play a role in the pathogenesis of cold-induced hypertension (CIH) and in the cold-induced increase in drinking responses to ANG II. Two groups of wild-type (WT) and two groups of AT1A receptor gene knockout (AT1A-KO) mice were used (6/group). Blood pressures (BP) of the four groups were similar during the control period at room temperature (25 degrees C). After the control period, one group of WT and one group of AT1A-KO mice were exposed to cold (5 degrees C), while the remaining groups were kept at 25 degrees C. BP of the cold-exposed WT group elevated significantly within 1 wk of exposure to cold and increased gradually to a maximum level by week 5. However, there was only a slight increase in BP of the cold-exposed AT1A-KO group. The maximal cold-induced increase in BP (DeltaBP) is significantly less in AT1A-KO group (11 +/- 3 mmHg) than in WT group (49 +/- 6 mmHg), indicating that AT1A receptor deficiency attenuates cold-induced elevation of BP. Interestingly, both WT and AT1A-KO mice developed cardiac and renal hypertrophy to the same extent. AT1A-KO caused a significant increase in urine and plasma levels of nitric oxide (NO), indicating that the renin-angiotensin system inhibits NO formation probably via AT1A receptors. Cold exposure inhibited endothelial NO synthase protein expressions and decreased urine and plasma levels of NO, which may be mediated partially by AT1A receptors. AT1A-KO completely abolished the cold-induced increase in drinking responses to ANG II. We conclude that 1) AT1A receptors play an essential role in the pathogenesis of CIH but not cardiac hypertrophy; 2) the role of AT1A receptors in CIH may be mediated partially by its inhibitory effect on the NO system; and 3) cold-induced increase in drinking response to ANG II is mediated by AT1A receptors.     

Altered expression of angiotensin AT1a and vasopressin V1a receptors and nitric oxide synthase mRNA in the brain of rats with renovascular hypertension.

Previous studies revealed that the brain angiotensinergic, vasopressinergic and nitrergic systems are involved in regulation of blood pressure and that their function is altered in various forms of hypertension. The purpose of our investigation was to determine whether expression of AT1a angiotensin receptors (AT1aR) mRNA, V1a vasopressin receptors (V1aR) mRNA and neuronal nitric oxide synthase (NOS1) mRNA is altered in the brain of rats with the renovascular hypertension. Eight male Sprague Dawley (SD 2K,1C) rats were subjected to constriction of the left renal artery in order to produce the renovascular hypertension whereas nine SD rats underwent the sham surgery. In both groups blood pressure was determined before and after the surgery. Four weeks after the surgery the brain fragments were harvested for determination of mRNA expression. Competitive PCR method was applied for relative quantitative analysis of V1aR mRNA, AT1aR mRNA and NOS1 mRNA in the preoptic, diencephalic, mesencephalopontine, medullary and cerebellar fragments of the brain. Blood pressure was significantly higher in the 2K,1C than in the sham operated rats. In the preoptic, mesencephalopontine and medullary regions AT1aR mRNA expression was significantly lower in the 2K,1C rats than in the sham operated rats. The 2K,1C rats manifested also significantly higher expression of V1aR mRNA and NOS1 mRNA in the preoptic brain region in comparison to the sham operated rats. The study provides evidence for significant changes of expression of AT1aR mRNA, V1aR mRNA and NOS1 mRNA in the specific brain regions of rats with the renovascular hypertension.     

Human eNOS gene delivery attenuates cold-induced elevation of blood pressure in rats

We previously showed that chronic cold exposure inhibits endothelial nitric oxide synthase (eNOS) expression and decreases nitric oxide (NO) production. The aim of the present study was to evaluate the possible role of the NO system in the development of cold-induced hypertension (CIH) by testing the hypothesis that adenoviral delivery of human eNOS gene increases NO production and attenuates CIH in rats. The effect of in vivo delivery of adenovirus carrying human eNOS full-length cDNA (rAdv.heNOS) on CIH was tested using four groups of Sprague-Dawley rats (6 rats/group). Blood pressure (BP) did not differ among the four groups during the control period at room temperature (24 degrees C). Two groups of rats received intravenous injection of rAdv.heNOS (1 x 10(9) plaque-forming units/rat), and the other two groups received the same dose of rAdv.LacZ to serve as controls. After gene delivery, one rAdv.heNOS-treated group and one rAdv.LacZ-treated group were exposed to cold (6 degrees C) while the remaining groups were kept at 24 degrees C. We found that the BP of the rAdv.LacZ group increased significantly within 1 wk of exposure to cold and reached a peak level at week 5 (152.2 +/- 6.4 mmHg). In contrast, BP (118.7 +/- 8.4 mmHg) of the cold-exposed rAdv.heNOS group did not increase until 5 wk after exposure to cold. The rAdv.heNOS increased plasma and urine levels of NO significantly in cold-exposed rats, which indicates that eNOS gene transfer increased NO production. Notably, rAdv.heNOS decreased plasma levels of norepinephrine and plasma renin activity in cold-exposed rats, which suggests that eNOS gene transfer may decrease the activities of the sympathetic nervous system and the renin-angiotensin system. Immunohistochemical analysis showed that the transferred human eNOS was expressed in both endothelium and adventitia of mesenteric arteries. We conclude that 1) eNOS gene transfer attenuates CIH by increasing NO production and inhibiting the sympathetic nervous system and the renin-angiotensin system; and 2) the NO system appears to mediate this nongenetic, nonpharmacological, nonsurgical model of hypertension.     

Vaccarin administration ameliorates hypertension and cardiovascular remodeling in renovascular hypertensive rats

Sympathetic overdrive, activation of renin angiotensin systems (RAS), and oxidative stress are vitally involved in the pathogenesis of hypertension and cardiovascular remodeling. We recently identified that vaccarin protected endothelial cell function from oxidative stress or high glucose. In this study, we aimed to investigate whether vaccarin attenuated hypertension and cardiovascular remodeling. Two‐kidney one‐clip (2K1C) model rats were used, and low dose of vaccarin (10 mg/kg), high dose of vaccarin (30 mg/kg), captopril (30 mg/kg) were intraperitoneally administrated. Herein, we showed that 2K1C rats exhibited higher systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), left ventricular mass/body weight ratio, myocardial hypertrophy or fibrosis, media thickness, and media thickness to lumen diameter, which were obviously alleviated by vaccarin and captopril. In addition, both vaccarin and captopril abrogated the increased plasma renin, angiotensin II (Ang II), norepinephrine (NE), and the basal sympathetic activity. The AT1R protein expressions, NADPH oxidase subunit NOX‐2 protein levels and malondialdehyde (MDA) content were significantly increased, whereas superoxide dismutase (SOD) and catalase (CAT) activities were decreased in myocardium, aorta, and mesenteric artery of 2K1C rats, both vaccarin and captopril treatment counteracted these changes in renovascular hypertensive rats. Collectively, we concluded that vaccarin may be a novel complementary therapeutic medicine for the prevention and treatment of hypertension. The mechanisms for antihypertensive effects of vaccarin may be associated with inhibition of sympathetic activity, RAS, and oxidative stress.     

Role of the sympathetic nervous system in cold-induced hypertension in rats

Hypertension develops in rats exposed chronically to cold [6 +/- 2 degrees C (SE)] and includes both an elevation of mean arterial pressure and cardiac hypertrophy. Previous studies suggest that cold-exposed animals, at least initially, have a large sustained increase in the activity of their sympathetic nervous system, suggesting a failure of the baroreceptor system to provide sufficient negative feedback to the central nervous system. The present study was designed to investigate whether alterations in the activity of the sympathetic nervous system, including the baroreceptor reflex, occur during exposure to cold and whether they contribute to cold-induced hypertension. Twenty male rats were prepared with indwelling catheters in the femoral artery and vein. Ten of the rats were exposed to cold (6 +/- 2 degrees C) chronically, while the remaining 10 were kept at 26 +/- 2 degrees C. Withdrawal of arterial blood samples (less than 5 ml/kg), measurement of direct arterial pressures, and measurement of baroreflex function were carried out at 0800 h at intervals throughout the experiment. Norepinephrine and epinephrine concentrations in plasma were also determined at intervals throughout the experiment. Systolic, diastolic, and mean blood pressures of cold-exposed rats were increased to levels significantly above those of controls. The sensitivity of the baroreflex (delta heart period/delta mean arterial pressure) was decreased in the cold-treated group. The concentration of norepinephrine in plasma increased after 24 h of exposure to cold and remained elevated throughout the experiment, whereas the concentration of epinephrine in plasma increased initially but returned to control levels after 19 days of exposure to cold.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of high salt intake on brain AT1 receptor densities in Dahl rats

To assess effects of dietary salt on brain AT1 receptor densities, 4-wk-old Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats were fed a regular (101 mumol Na/g) or high (1,370 mumol Na/g)-salt diet for 1, 2, or 4 wk. AT1 receptors were assessed by quantitative in vitro autoradiography. AT1 receptor densities did not differ significantly between strains on the regular salt diet. The high-salt diet for 1 or 2 wk increased AT1 receptor binding by 21-64% in the Dahl S rats in the subfornical organ, median preoptic nucleus, paraventricular nucleus, and suprachiasmatic nucleus. No changes were noted in the Dahl R rats. After 4 wk on a high-salt diet, increases in AT1 receptor binding persisted in Dahl S rats but were now also noted in the paraventricular nucleus, median preoptic nucleus, and suprachiasmatic nucleus of Dahl R rats. At 4 wk on the diet, intracerebroventricular captopril caused clear decreases in blood pressure only in the Dahl S on the high-salt diet but caused largely similar relative increases in brain AT1 receptor densities in Dahl S and R on the high-salt diet versus regular salt diet. These data demonstrate that high salt intake rapidly (within 1 wk) increases AT1 receptor densities in specific brain nuclei in Dahl S and later (by 4 wk) also in Dahl R rats. Because the brain renin-angiotensin system only contributes to salt-induced hypertension in Dahl S rats, further studies are needed to determine which of the salt-induced increases in brain AT1 receptor densities contribute to the hypertension and which to other aspects of body homeostasis.     

Expression of the renin angiotensin system genes in the kidney and heart of ISIAH hypertensive rats

The content of mRNA of renin-angiotensin system (RAS) genes was measured in the kidney and heart of hypertensive ISIAH and normotensive WAG rats using the real-time PCR. A statistically significant decrease in the mRNA level of RAS genes was registered in the kidney of ISIAH rats, including Ren (by 45%), Ace (43%), AT1A (34%), COX-2 (50%). The level of myocardial expression of AT1A decreased by 28% while Ace expression increased by 80%. These results suggest reduction of renal RAS basal activity in the hypertensive ISIAH rats, and therefore this strain of rats may be referred to the group of models of low-renin hypertension. The ISIAH rats were also characterized by a two-fold increase in the connective tissue sodium concentration and also by a small (but statistically significant) increase in plasma sodium concentration (139 ± 0.3 mmol/l versus 136 ± 0.25 mmol/l in WAG rats). These results together with a tendency to a decrease of plasma aldosterone level also support existence of a classical low-renin hypertension in the ISIAH rats. It is suggested that altered function of renal ion channels represents a basis for the development of low renin hypertension in the ISIAH rats. In addition, impairments in renal system of NO synthesis may also contribute to the pathogenesis of arterial hypertension in the ISIAH rats.