One-clip Renovascular Hypertensive Rats Research Articles

Electroacupuncture Improves Baroreflex and γ-Aminobutyric Acid Type B Receptor-Mediated Responses in the Nucleus Tractus Solitarii of Hypertensive Rats.

Electroacupuncture (EA) has been reported to benefit hypertension, but the underlying mechanisms are still unclear. We hypothesized that EA attenuates hypertension, in part, through modulation of γ-aminobutyric acid (GABA) receptor function in the nucleus tractus solitarii (NTS). In the present study, the long-term effect of EA on GABA receptor function and expression was examined in the NTS of two-kidney, one-clip (2K1C) renovascular hypertensive rats. EA (0.1–0.4 mA, 2 and 15 Hz) was applied at Zusanli (ST36) acupoints overlying the deep fibular nerve for 30 min once a day for two weeks. The results showed that long-term EA treatment improved blood pressure (BP) and markedly restored the baroreflex response in 2K1C hypertensive rats. The increased pressor and depressor responses to microinjection of GABAB receptor agonist and antagonist into the NTS in the hypertensive rats were blunted by the EA treatment. Moreover, EA treatment attenuated the increased GABAB receptor expression in the NTS of hypertensive rats. In contrast, EA had no significant effect on the GABAA receptor function and expression in the NTS of 2K1C hypertensive rats. These findings suggest that the beneficial effects of EA on renovascular hypertension may be through modulation of functional GABAB receptors in the NTS.

Chronic infusion of berberine into the hypothalamic paraventricular nucleus attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway

BackgroundBerberine (BBR), a Chinese traditional herbal medicine, has many pharmacologic benefits such as anti-inflammation and anti-oxidation. It is widely used in clinical treatment of cardiovascular diseases such as hypertension. However, the mechanism of how BBR attenuates hypertension through affecting central neural system is not clear. PurposeThis study was designed to determine whether chronic infusion of BBR into the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway. MethodsTwo-kidney, one-clip (2K1C) renovascular hypertensive rats were randomly assigned and treated with bilateral PVN infusion of BBR (2μg/h) or vehicle (artificial cerebrospinal fluid) via osmotic minipumps for 28 days. Results2K1C rats showed higher mean arterial pressure (MAP) and PVN Fra-like activity, plasma levels of norepinephrine (NE), PVN levels of NOX2, NOX4, Erk1/2 and iNOS, and lower PVN levels of copper/zinc superoxide dismutase (Cu/Zn-SOD). Chronic infusion of BBR reduced MAP, PVN Fra-like activity and plasma levels of NE, reduced NOX2, NOX4, Erk1/2, iNOS and induced Cu/Zn-SOD in the PVN. ConclusionsThese results suggest that BBR attenuates hypertension and sympathoexcitation via the ROS/Erk1/2/iNOS pathway in 2K1C renovascular hypertensive rats.

Exercise training attenuates renovascular hypertension partly via RAS- ROS- glutamate pathway in the hypothalamic paraventricular nucleus.

Exercise training (ExT) has been reported to benefit hypertension; however, the exact mechanisms involved are unclear. We hypothesized that ExT attenuates hypertension, in part, through the renin-angiotensin system (RAS), reactive oxygen species (ROS), and glutamate in the paraventricular nucleus (PVN). Two-kidney, one-clip (2K1C) renovascular hypertensive rats were assigned to sedentary (Sed) or treadmill running groups for eight weeks. Dizocilpine (MK801), a glutamate receptor blocker, or losartan (Los), an angiotensin II type1 receptor (AT1-R) blocker, were microinjected into the PVN at the end of the experiment. We found that 2K1C rats had higher mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These rats also had excessive oxidative stress and overactivated RAS in PVN. Eight weeks of ExT significantly decreased MAP and RSNA in 2K1C hypertensive rats. ExT inhibited angiotensin-converting enzyme (ACE), AT1-R, and glutamate in the PVN, and angiotensin II (ANG II) in the plasma. Moreover, ExT attenuated ROS by augmenting copper/zinc superoxide dismutase (Cu/Zn-SOD) and decreasing p47phox and gp91phox in the PVN. MK801or Los significantly decreased blood pressure in rats. Together, these findings suggest that the beneficial effects of ExT on renovascular hypertension may be, in part, through the RAS-ROS-glutamate pathway in the PVN.

The imperatorin derivative OW1, a new vasoactive compound, inhibits VSMC proliferation and extracellular matrix hyperplasia

Chronic hypertension induces vascular remodeling. The most important factor for hypertension treatment is reducing the risk of cardiovascular disease. OW1 is a novel imperatorin derivative that exhibits vasodilative activity and antihypertensive effects in two-kidney one-clip (2K1C) renovascular hypertensive rats. It also inhibited vascular remodeling of the thoracic aorta in a previous study. Here, the inhibitory effects and mechanisms of OW1 on arterial vascular remodeling were investigated in vitro and in 2K1C hypertensive rats in vivo. OW1 (20μM, 10μM, 5μM) inhibited Ang II-induced vascular smooth muscle cells (VSMCs) proliferation and ROS generation in vitro. OW1 also reversed the Ang II-mediated inhibition of α-SMA levels and stimulation of OPN levels. Histology results showed that treatment of 2K1C hypertensive rats with OW1 (20, 40, and 80mg/kg per day, respectively for 5weeks) in vivo significantly decreased the number of VSMCs, the aortic cross-sectional area (CSA), the media to lumen (M/L) ratio, and the content of collagen I and III in the mesenteric artery. Western blot results also revealed that OW1 stimulated the expression of α-SMA and inhibited the expression of collagen I and III on the thoracic aorta of 2K1C hypertensive rats. In mechanistic studies, OW1 acted as an ACE inhibitor and affected calcium channels. The suppression of MMP expression and the MAPK pathway may account for the effects of OW1 on vascular remodeling. OW1 attenuated vascular remodeling in vitro and in vivo. It could be a novel candidate for hypertension intervention.

Antihypertensive and vascular remodelling effects of the imperatorin derivative OW1 in renovascular hypertension rats.

OW1 is a novel imperatorin derivative that exhibits vasodilator activity. In the present study, the antihypertensive effect of and inhibition of vascular remodelling by OW1 were investigated in two-kidney, one-clip (2K1C) renovascular hypertensive rats. Rats were subjected to the 2K1C procedure and treated with OW1 (40 or 80mg/kg per day) for 8weeks. Blood pressure was measured in conscious rats. Microalbumin (mALB) and total protein (U-TP) concentrations were determined in the urine, as were plasma concentrations of angiotensin (Ang) II, calcitonin gene-related peptide (CGRP) and angiotensin-converting enzyme 1 (ACE). The unclipped kidney was stained with haematoxylin and eosin and Masson trichrome, whereas aortic sections were stained with Masson trichrome. In addition, OW1-induced vasodilatation was evaluated in vitro in rat mesenteric and renal arteries. Immunohistochemical analysis was used to quantify collagen I and III expression. OW1 relaxed rat mesenteric and renal arterial rings in vitro. Treatment of 2K1C hypertensive rats with OW1 (40 and 80mg/kg per day) for 8weeks significantly decreased blood pressure. In addition, OW1 reduced plasma AngII and ACE concentrations and increased plasma CGRP concentrations. At 80mg/kg per day, OW1 decreased blood urea nitrogen, mALB and U-TP levels. Histological analysis revealed that OW1 reduced renal arteriolar thickness and relieved the structural hypertrophic arteries. Moreover, OW1 had an inhibitory effect on vascular remodelling and renal lesions in hypertensive rats. In conclusion, the results suggest that OW1 could potentially be a novel candidate for hypertension intervention.

GW24-e2451 Valsartan inhibit activation of Stat3 and expression of c-myc in Goldblatt rat

ObjectivesIn this study the change of signal transducer and activator of transcription 3 (Stat 3) and expression of c-myc in the developing of left ventricular hypertrophy (LVH) of Goldblatt rat,...

Sesamin exerts renoprotective effects by enhancing NO bioactivity in renovascular hypertensive rats fed with high-fat-sucrose diet

In the present study, we aimed to evaluate the protective effect of sesamin on kidney damage and renal endothelial dysfunction in two-kidney, one-clip renovascular hypertensive rats fed with a high-fat-sucrose diet (2K1C rats on HFS diet). Sesamin was intragastrically administered to 2K1C rats on HFS diet for eight weeks. Then, we measured the levels of serum hydrogen peroxide (H2O2), total antioxidant capability (T-AOC), renal malonaldehyde (MDA), total-erythrocuprein (T-SOD) and glutathione peroxidase (GSH-PX). The expressions of endothelial nitric oxide synthase (eNOS), nitrotyrosine and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47phox in the left and right renal cortexes were detected by Western blotting. Pathological changes in the left and right renal cortexes were observed by periodic acid-schiff staining (PAS) and Masson's staining. Treatment with sesamin (120 and 60mg/kg−1·d−1) in 2K1C rats on HFS diet improved renal function, corrected structural abnormalities, and attenuated renal oxidative stress. Furthermore, sesamin increased eNOS protein expression and reduced nitrotyrosine and p47phox protein expression. These results demonstrated that long-term treatment with sesamin had renoprotective effect and improved renal endothelial dysfunction via upregulation of eNOS expression and reduction of NO oxidative inactivation in both clipped and contralateral kidneys of 2K1C rats on HFS diet, and sesamin may have a favorably therapeutic value in treating chronic kidney disease in patients with hypertension and hyperlipemia.

Two-kidney, one-clip腎血管性高血圧ラットにおける一酸化窒素の役割

The relationship between blood pressure(BP) and nitric oxide(NO) in two-kidney, one-clip renovascular hypertensive rats (2K1C) was investigated. Although urinary NO2- + NO3-(NOx) excretion (UNOX V) increased 2 weeks after surgery (2W-2K1C), UNOX V decreased 4 weeks after surgery (4W-2K1C) compared with that of the control. UNOX V levels were restored 2 weeks after unclipping (U2K1C). BP and UNOX V did not change in 2K1C after treatment with L-arginine (Arg-2K1C). Aorta from 4W-2K1C and Arg-2K1C showed significantly decreased relaxation responses to acetylcholine(Ach), but Ach-induced relaxation of aorta in U2K1C returned to control-level responses. De-endothelialized aorta from 4W-2K1C, Arg-2K1C, and U2K1C had significantly decreased relaxation responses to lipopolysaccharide. These data suggest that: (1) transient increase of NO synthesis is accompanied by elevation of BP, but long-term elevation of BP decreases NO synthesis in endothelium and smooth muscle cells: (2) L-arginine supplement has no effect on the development of hypertension and on NO production by endothelium and smooth muscle cells in 2K1C.

Two-kidney,one-clip腎血管性高血圧ラットにおける血管内皮機能障害に及ぼす外因性一酸化窒素の影響

Previous studies have shown that hypertension causes endothelial dysfunction. To study the influence of exogenous nitric oxide(NO) on endothelial dysfunction produced by hypertension, we administered a non-depressor dose of nipradilol to two-kidney, one-clip renovascular hypertensive rats(2K1C). Sprague-Dawley rats underwent either sham surgery(G-1) or clipping of the left renal artery. From day seven, 2K1C were randomized into 3 groups, placebo treatment(G-2), nipradilol treatment(G-3,) and propranolol treatment(G-4). Urinary NO2- + NO3-(NOx) excretion (UNOx V) was measured 4 weeks after clipping, and then, acetylcholine(Ach), A23187, or sodium nitroprusside(SNP)-induced relaxation were measured in the aorta. Blood pressure was increased in G-2, G-3, and G-4 compared to G-1. UNOx V was lower in G-2, G-3, and G-4 compared to G-1, but UNOx V was higher in G-3 compared to G-2 and G-4. Although Ach or A23187-induced relaxation was significantly decreased in isolated artery from G-2, G-3, and G-4 compared with those from G-1. Ach- or A23187-induced relaxation was improved in G-3. SNP-induced relaxation did not differ among the 4 groups. These results suggest that exogenous NO from nipradilol reduces the endothelial dysfunction caused by hypertension without changing the blood pressure.

Sesamin improves endothelial dysfunction in renovascular hypertensive rats fed with a high-fat, high-sucrose diet

The present study was designed to evaluate the possible in vivo protective effects of sesamin on hypertension and endothelial function in two-kidney, one-clip renovascular hypertensive rats fed with a high-fat, high-sucrose diet (2K1C rats on HFS diet). Sesamin was orally administered for 8 weeks in 2K1C rats on HFS diet. Then, the serum malondialdehyde level was determined. The protein expression of endothelial nitric oxide synthase (eNOS), nitrotyrosine and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47 phox in aortas was detected by Western blotting. Vasorelaxation response to acetylcholine and nitroprusside, and functional assessment of nitric oxide (NO) bioactivity were also determined in aortic rings. Sesamin treatment reduced systolic blood pressure, improved vasodilatation induced by acetylcholine and enhanced NO bioactivity in the thoracic aortas. These changes were associated with increased eNOS, decreased malondialdehyde content, and reduced nitrotyrosine and p47 phox protein expression. All these results suggest that chronic treatment with sesamin reduces hypertension and improves endothelial dysfunction through upregulation of eNOS expression and reduction of NO oxidative inactivation in 2K1C rats on HFS diet.

Enhanced cardiac sympathetic afferent reflex involved in sympathetic overactivity in renovascular hypertensive rats

Sympathetic outflow is increased in hypertension. The aim of the present study was to investigate whether the cardiac sympathetic afferent reflex (CSAR) is enhanced in two-kidney one-clip (2K1C) renovascular hypertensive rats, and whether the enhanced CSAR contributes, in part, to the increased sympathetic outflow. Furthermore, the role of central angiotensin II type 1 (AT(1)) receptors in mediating the CSAR was determined. Under urethane and alpha-chloralose anaesthesia, the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in sinoaortic denervated and cervical vagotomized rats. The CSAR was evaluated by the response of RSNA and MAP to epicardial application of 1.0 nmol of capsaicin. Compared with sham-operated rats, the CSAR, baseline RSNA and plasma noradrenaline level were significantly enhanced in 2K1C rats. Intrapericardial administration of resiniferatoxin, which abolishes the CSAR because of the desensitization of transient receptor potential vanilloid 1-containing cardiac afferent fibres, decreased the RSNA and MAP. The enhanced CSAR in 2K1C rats was normalized by intracerebroventricular administration of the AT(1) receptor antagonist losartan. Intracerebroventricular administration of angiotensin II further potentiated the enhanced CSAR in 2K1C rats, a response which was abolished by pretreatment with losartan. These results indicate that the CSAR is enhanced in 2K1C rats and the enhanced CSAR contributes, in part, to the sympathetic activation and hypertension. Central AT(1) receptors are involved in the enhanced CSAR in 2K1C rats.

The combination of atenolol and amlodipine is better than their monotherapy for preventing end‐organ damage in different types of hypertension in rats

Combinations therapy is often used in hypertensive patients whether combination therapy is necessary for preventing end-organ damage is not known. The objective of this study was to determine in four different hypertensive animal models the necessity of adding the calcium channel blocker amlodipine to therapy with the ß-blocker atenolol to modulate end-organ damage. Spontaneously hypertensive rats, DOCA-salt hypertensive rats, two-kidney, one-clip renovascular hypertensive rats and Lyon genetically hypertensive rats were used to study this objective. These animal models have different sensitivities to atenolol and amlodipine. The dosages of therapy employed were 10 mg/kg atenolol alone, 1 mg/kg amlodipine, 10 mg atenolol + 1 mg/kg amlodipine and 5 mg/kg atenolol+0.5 mg/kg amlodipine. BP was continuously recorded in all animals. After determination of baroreflex sensitivity, rats were sacrificed for end-organ damage evaluation. The combination of amlodipine and atenolol had a synergistic inhibitory effect on blood pressure and blood pressure variability, and end-organ damage as compared with monotherapy with atenolol or amlodipine in all animal models. Baroreflex sensitivity also improved with the combination therapy more than with monotherapy. In conclusion, atenolol and amlodipine combination exerts a superior effect on blood pressure, blood pressure variability, baroreflex sensitivity and end-organ damage. The superior effect of the combination was observed in all four models of hypertension.

PROTECTIVE ROLE OF A NOVEL ERYTHROCYTE‐DERIVED DEPRESSING FACTOR ON BLOOD VESSELS OF RENOVASCULAR HYPERTENSIVE RATS

1. We have isolated a novel human erythrocyte-derived depressing factor (EDDF) that has a significant antihypertensive effect in various rat models of hypertension. The aim of the present study was to examine the mechanisms of action of EDDF on vascular function in two-kidney, one-clip (2K1C) renovascular hypertensive rats. 2. The EDDF was prepared from human erythrocytes. Experiments were performed in 18 male Wistar rats. The vascular ring perfusion assay and a two-photon laser scanning fluorescence microscope (TMP) were used to evaluate the vascular contractile response. The effects of EDDF on phenylephrine (PE)- and noradrenaline (NA)-induced vascular contraction were evaluated in 2K1C hypertensive rats. The proliferation and DNA synthesis in vascular smooth muscle cells (VSMC) were determined using the [3H]-TdR (thymidine) incorporation and 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Flow cytometry, reverse transcription-polymerase chain reaction and western blots were used to measure cell cycle and apoptotic profiles, platelet-derived growth factor (PDGF)-A expression and the activity of extracellular signal-regulated kinase (ERK)-1/2, as well as the expression of cyclin D1 and cyclin-dependent kinase (CDK) 4. 3. At 10(-5) g/mL, EDDF significantly decreased the PE- and NA-induced hypertensive vascular contraction. In addition, EDDF inhibited DNA synthesis in primary VSMC from 2K1C rats. The mRNA expression of PDGF-A in VSMC was twofold higher in 2K1C rats compared with control rats, whereas EDDF significantly inhibited the increment in PDGF-A mRNA expression. In addition, EDDF inhibited the phosphorylation of ERK1/2 and decreased the expression of cyclin D1 and CDK4; p21 (Cip1) levels were increased after treatment with EDDF. 4. In conclusion, EDDF inhibits VSMC proliferation in 2K1C rats through G0/G1 cell cycle arrest. The effects may be mediated, in part, by enhanced expression of p21 (Cip1) and the inhibition of ERK1/2 phosphorylation and the expression of cyclin D1/CDK4 and PDGF-A.

BLOOD PRESSURE VARIABILITY, CARDIAC BAROREFLEX SENSITIVITY and ORGAN DAMAGE IN EXPERIMENTALLY HYPERTENSIVE RATS

1. The present study was designed to investigate the haemodynamic features and morphological changes in experimentally hypertensive rat models. 2. Sprague-Dawley rats were used to prepare the experimentally hypertensive models, including two-kidney, one-clip renovascular hypertensive (2K1C) rats, deoxycorticosterone acetate salt hypertensive (DOCA) rats and N(G)-nitro-l-arginine methyl ester-induced hypertensive (l-NAME) rats. Six weeks after the induction of hypertension, 24 h blood pressure was recorded and blood pressure variability (BPV) expressed by 24 h (or 12 h in the daytime and night-time study) standard deviation of the variables was calculated. Then, cardiac baroreflex sensitivity (BRS) was determined and four endogenous factors (tumour necrosis factor-alpha, interleukin-1beta, angiotensin II and endothelin-1) were measured. Finally, morphological changes were examined. 3. It was found that an increase in BPV and a decrease in BRS were accompanied by an elevation of blood pressure in all three hypertensive models. The DOCA rats had the highest BPV, whereas the l-NAME rats had the lowest BRS. 4. Morphological changes were similar in DOCA and l-NAME rats and the cardiac changes were relatively slight in 2K1C rats. Tumour necrosis factor-alpha was increased in all the three models, especially in DOCA rats. Endothelin-1 was higher in DOCA rats and angiotensin II was increased in 2K1C rats and decreased in DOCA rats. 5. In conclusion, increased BPV and decreased BRS accompanied the elevation of blood pressure in all three hypertensive models. The DOCA rats had the highest BPV and the l-NAME rats had the lowest BRS. Obvious organ damage was seen in all three hypertensive models 6 weeks after the induction of hypertension.

Increase in adrenomedullin gene expression in the left atrium and ventricle in the two-kidney one-clip renovascular hypertensive rats

The 2-kidney 1-clip rat model was set up by clipping the left renal artery. At 5 weeks after clipping, there was an increase in preproadrenomedullin mRNA levels in both the left atria and the left ventricle. Adrenomedullin (AM) contents, however, increased in the left ventricle but decreased in the left atrium. These changes were not observed at 2 weeks after clipping. There were no changes in AM or preproadrenomedullin mRNA levels in the thoracic aorta and the mesenteric artery, and in plasma AM levels at 2 weeks or 5 weeks after clipping. We concluded that there was an increase in the secretion of AM in the left ventricle and the left atria in the 5 week renovascular hypertensive rat. The lack of change in plasma AM level suggests a paracrine function for the peptide in this setting.

Changes in cardiac adrenomedullin concentration in renovascular hypertensive rats.

We assessed changes in tissue and plasma adrenomedullin levels in two-kidney, one-clip renovascular hypertensive rats. Four weeks after clipping, adrenomedullin concentrations were significantly higher in the cardiac ventricles and lower in the left atrium than the respective values in sham-operated rats. The left ventricular adrenomedullin concentration significantly correlated with systolic blood pressure and the degree of cardiac hypertrophy. No difference was noted in the adrenomedullin concentrations of the adrenal gland, aorta, lung, kidneys, or plasma between the two groups. These findings indicate possible involvement of cardiac adrenomedullin in this model of hypertension.

Degree of renal artery stenosis alters nitric oxide regulation of renal hemodynamics.

Endothelium-derived nitric oxide (EDNO) maintains RBF in normal kidneys and to the nonclipped kidney of two-kidney, one-clip (2K, 1C) renovascular hypertensive rats. However, in clipped kidneys with severe renal stenosis, EDNO has been reported not to influence RBF, and it was suggested that low perfusion diminishes the stimulus of shear stress for EDNO synthesis. It was hypothesized that lesser degrees of renal artery stenosis would allow greater renal perfusion and, hence, a greater role for EDNO in maintaining RBF in the clipped kidney. The renal response to EDNO synthesis inhibition was studied with 10 mg/kg body wt N omega-nitro-L-arginine methyl ester (L-NAME). Four weeks after clipping, rats had different degrees of (functional) renal artery stenosis as determined by the ratio (R) of RBF (per gram kidney weight) in the nonclipped to clipped kidney. Stenosis was classified as either mild (R < or = 1.25) or moderate (R > or = 1.30). Both groups were similarly hypertensive (146 +/- 3 versus 148 +/- 6 mm Hg, respectively) and responded to L-NAME with a 42 mm Hg rise in blood pressure. In 2K,1C rats with mild renal artery stenosis, the renal response to L-NAME was similar in both nonclipped and clipped kidneys. RBF decreased by 17 to 19% (P < 0.005) and renal vascular resistance (RVR) increased by 59 to 63% (P < 0.005). When renal perfusion pressure was controlled, the decrease in RBF was exaggerated 3.6-fold in the nonclipped but only 2.3-fold in the clipped kidney, whereas the RVR increased proportionally.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of interleukin 1β in the integrative mechanisms and the maintenance of body fluid homeostasis in conscious rats

Changes in the central ANF-system of renovascular hypertensive rats. The central atrial natriuretic peptides (ANF)-system was investigated in volume-dependent one-kidney, one-clip (1K1C) and renin-dependent two-kidney, one-clip (2K1C) renovascular hypertensive rats by radio-immunological measurement of ANF concentration in 18 selected brain areas. Significant changes were found in nine brain areas of 1K1C and in eight brain areas of 2K1C hypertensive rats. Except unidirectional changes in the organum vasculosum laminae terminalis and the supraoptic nucleus, ANF concentration was changed in the opposite direction in all other brain areas, with an activation of the central ANF system in 1K1C and an inhibition in 2K1C hypertension. The localization of the alterations (circumventricular organs, anteroventral third ventricle region, hypothalamo hypophyseal system, brain stem) implies major differences in the central regulation of blood pressure and electrolyte and fluid homeostasis between these two models. The activation of the central ANF system in 1K1C hypertension may be a compensatory mechanism to prevent further increments in blood pressure and plasma volume. In contrast, the depression of the central ANF system in 2K1C hypertension may promote the elevation of the blood pressure.

Rat angiotensin II (type 1A) receptor mRNA regulation and subtype expression in myocardial growth and hypertrophy.

Two subtypes of angiotensin II (Ang II) receptors (AT1 and AT2) are distinguished by using the respective specific antagonists. In the present study, we report the regulation of cardiac AT1 type A (AT1A) receptor mRNA levels and the expression pattern of AT1 and AT2 receptors in the growth of the heart and the development and regression of cardiac hypertrophy. The ventricular AT1A mRNA level and the density of Ang II receptors at the neonatal period were significantly increased (3.5-fold and 2.5-fold, respectively) and then downregulated with maturation. The cardiac hypertrophy established in spontaneously hypertensive rats or two-kidney one-clip renovascular hypertensive rats resulted in substantial increases in ventricular AT1A mRNA levels (threefold) and Ang II receptor densities (twofold) as compared with those in respective control rats, whereas the receptor affinity was similar. The proportion of AT1 and AT2 subtypes in the specific Ang II binding in ventricular membranes prepared from normal adult rats was nearly equal. This proportion did not change significantly in the development of myocardial hypertrophy. The regression of cardiac hypertrophy by the normalization of elevated blood pressure completely reversed the increased levels of AT1A mRNA and the receptor density to the control level. Thus, AT1 and AT2 receptors are present in rat ventricular myocardium, and their expression is developmentally regulated and upregulated in response to hypertrophic change. Ang II action exerted through the increased number of Ang II receptors may contribute to the growth of the heart and thus to the maintenance of established hypertrophy as one of the hormones involved in hypertrophy development.

Central Depressor Effects of Amino Acids in Conscious Normotensive and Two-Kidney, One-Clip Renovascular Hypertensive Rats.

The circulatory effects of intracisternal injections of amino acids were investigated in conscious normotensive control rats (NCR) and in two-kidney, one-clip renovascular hypertensive rats (RHR). Arterial pressure was measured with an indwelling catheter connected to a pressure transducer. Heart rate was counted from the arterial pulse. The intracisternal injection of glycine, gamma-aminobutyric acid (GABA), taurine, serine, alanine, and sarcosine decreased blood pressure by an average of 16-30 mmHg in NCR and by an average of 32-55 mmHg in RHR. Both absolute and percent changes of depressor effects by GABA, taurine, serine, and alanine were larger in RHR than in NCR. All these amino acids also showed similar bradycardiac effects in both NCR and RHR, when compared in absolute values. The percent change of bradycardia induced by taurine and sarcosine was larger in RHR than in NCR. However, the degree of bradycardia by serine was larger in NCR than in RHR. These results suggest that serine, alanine, and sarcosine in addition to glycine, GABA, and taurine, play important roles in blood pressure control in conscious normotensive rats via central neural mechanisms and that the hypertension in renovascular hypertensive rats may involve a central abnormality.