UMLS:C0004135 - FACTA Search

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The present study was performed to determine the angiotensin II (ANG II) dependence of stop-flow pressure (SFP) tubuloglomerular feedback responses in hypertensive transgenic rats [strain name: TGR(mRen2)27] harboring the mouse ren-2 renin gene. SFP feedback responses to increases in late proximal perfusion rate were assessed in pentobarbital-anesthetized male ren-2 transgenic rats during control conditions and after administration of the AT1 receptor antagonist, L-158,809 (1 mg/kg iv). During control conditions, increases in late proximal perfusion rate elicited flow-dependent decreases in SFP. The magnitude of the maximal SFP feedback response to a late proximal perfusion rate of 40 nl/min averaged 16.1 +/- 1.4 mmHg (n = 7), a value higher than that normally observed in normotensive rats. Administration of L-158,809 decreased mean arterial blood pressure (174 +/- 6 vs. 117 +/- mmHg, P < 0.01, n = 10) and attenuated the magnitude of the maximal SFP feedback response by 84 +/- 4% (16.1 +/- 1.4 vs. 2.6 +/- 0.5 mmHg, P < 0.01, n = 7). In contrast, mechanical reduction of renal arterial pressure from 179 +/- 5 to 113 +/- 1 mmHg (P < 0.01, n = 7) attenuated the magnitude of the maximal SFP feedback response by only 43 +/- 5% (14.4 +/- 1.9 vs. 7.9 +/- 0.7 mmHg, P < 0.01, n = 7), indicating that approximately one-half of the attenuation of SFP feed-back responses elicited by AT1 receptor blockade was due to removal of the stimulatory effect of ANG II on the sensitivity of the tubuloglomerular feedback mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:ANG II dependence of tubuloglomerular feedback responsiveness in hypertensive ren-2 transgenic rats. 777 10

Experiments in inbred strains of normotensive and hypertensive rats have clearly demonstrated circadian rhythms in blood pressure and heart rate. Pre- and postsynaptic signal transduction processes in vitro can, but need not, vary with circadian time, greatly depending on the strain of rats investigated. These data highlight the notion of a strain-dependent, and thus genetic, regulation of the cardiovascular system. Obviously, circadian rhythms in blood pressure cannot be explained by single biochemical parameters, but results from both in vitro and in vivo studies give first evidence that the vascular nitric oxide-cGMP system may be involved in the circadian regulation of blood pressure in WKY and SHR rats. In secondary hypertensive TGR and in their normotensive controls, SPRD, the guanylyl cyclase system does not seem to play a role in circadian blood pressure regulation. In neither of the four strains studied did aortic adenylyl cyclase show any time-dependent variation. Because vascular tissue was taken from the thoracic aorta of the rats, a contribution of adenylyl cyclase to circadian blood pressure regulation in small resistance arteries cannot be ruled out. Further studies in different parts of the vascular tree are needed to definitely answer that question. No data are available on time-dependent variation in the activity of phospholipase C, the second messenger pathway of vascular alpha-adrenoceptors and angiotensin II AT1-receptors, both of which mediate vasoconstriction. Future research into this system will be helpful in identifying mechanisms involved in blood pressure regulation in SPRD and TGR.
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PMID:Signal transduction in animal models of normotension and hypertension. 885 34

TGR(mREN2)27 is a transgenic rat harboring the murine Ren-2 gene and exhibit fulminant hypertension and marked heart hypertrophy. In order to study the role of angiotensin II in the increase of cardiac mass, these animals were treated with antihypertensive and non-antihypertensive doses of the angiotensin II receptor AT1 antagonist Telmisartan for 9 weeks. All doses led to significant reductions of heart hypertrophy detected by the evaluation of the diameter of cardiac muscle bundles. We conclude from this study that cardiac hypertrophy in TGR(mREN2)27 is characterized by an increased volume of cardiomyocytes and an unchanged amount of fibrous tissue and that angiotensin II plays an important role in the mechanisms leading to this phenotype.
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PMID:Reduction of cardiac hypertrophy in TGR(mREN2)27 by angiotensin II receptor blockade. 897 60

1. Transgenic(TG) (mRen-2) rats overexpressing the mouse renin gene develop fulminant hypertension and cardiac hypertrophy. Since the activation of AT1 receptor by angiotensin II is involved in blood pressure regulation, cardiac performance and myocardial growth, we investigated the biological effects of angiotensin II and the regulation of the AT1 receptor in the heart and aorta of TGR (mRen-2)27 rats in comparison to control animals. 2. Contraction studies on isolated cardiac muscle strips reveal that angiotensin II exerts no positive inotropic effect on the left ventricular myocardium of both, transgenic and control rats. In contrast, angiotensin II leads via AT1 receptor activation in the left atrium of control rats to a significant contraction (130 +/- 5% of basal contraction) which is not detectable in left atrium preparations of the transgenic animals. Furthermore, AT1 receptor activation causes a profound contraction of aortic rings isolated from control rats amounting to 1.39 +/- 0.2 mN mg-1 wet weight, whereas aortic rings from TGR (mRen-2)27 rats contract only minimally upon angiotensin II stimulation (0.2 +/- 0.02 mN mg-1 wet weight). 3. These altered physiological responses of angiotensin II in the transgenic rats are in part due to a marked down-regulation of the AT1 receptor in atrial, ventricular and aortic tissue of these transgenic animals in comparison to control Sprague-Dawley rats, as shown by radioligand binding assays and quantitative polymerase chain reaction (PCR) experiments. The AT1 receptor density Bmax in the left atrium was 1.3 +/- 0.08 fmol mg-1 protein in control rats (KD 1.1 +/- 0.18 nmol l-1) and 0.94 +/- 0.15 fmol mg-1 protein (KD 2.1 +/- 0.3 nmol l-1. In the aorta Bmax values were 15.1 +/- 0.5 fmol mg-1 protein (KD 1.9 +/- 0.27 nmol l-1) for control rats and 11.3 +/- 0.76 fmol mg-1 protein (KD 1.9 +/- 0.27 nmol l-1) for the TGR(mRen-2)27 rats AT1 receptor mRNA was reduced in the transgenic animals to 46 +/- 3% in the left atrium, 50 +/- 11% in the left ventricle and 40 +/- 3% in the aorta, respectively. 4. Together, the AT1 receptor is down-regulated in TGR (mRen-2)27 rats in comparison to wildtype Sprague Dawley rats leading to a profoundly decreased response of cardiac and aortic tissue upon stimulation with angiotensin II.
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PMID:Down-regulation of aortic and cardiac AT1 receptor gene expression in transgenic (mRen-2) 27 rats. 914 97

The renin-angiotensin system plays an important role in the pathogenesis of cardiac hypertrophy and chronic heart failure as angiotensin II has been shown to induce cardiac hypertrophy and fibrosis. Besides these structural alterations, functional effects on cardiomyocytes have been reported in different mammalian species. Angiotensin II is known to produce a positive inotropic effect in some species, and differences in atrial and ventricular myocardium have been described. So far, the molecular events which govern angiotensin II-mediated changes in cardiac contractility are not completely understood. In order to study the dependency of the angiotensin II-induced positive inotropic effect on receptor density, we examined the effect of angiotensin II on cardiac function in atria, papillary muscles and isolated ventricular cardiomyocytes from adult Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats, which expressed the human angiotensin AT1 receptor (hAT1) specifically in the heart. In atrial myocardium from adult Sprague-Dawley rats, angiotensin II (30 micromol/l) produced an AT1-mediated positive inotropic effect (38.5% of control), whereas in papillary muscles and isolated ventricular myocytes, no inotropic response was observed. As shown by polymerase chain reaction (PCR) and radioligand binding, the human angiotensin AT1 receptor was exclusively expressed in transgenic animals, which markedly overexpressed the angiotensin AT1 receptor. However, in transgenic rats the positive inotropic effect in atrial preparations was similar to the controls, and neither in papillary muscles nor in isolated cardiomyocytes the increase in receptor density led to an inotropic effect induced by angiotensin II. These data suggest that the existence of functionally uncoupled receptors rather than the low density of receptors at the ventricular site is responsible for the inability of ventricular myocardium to respond to angiotensin II.
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PMID:Cardiac angiotensin II receptors: studies on functional coupling in Sprague-Dawley rats and TGR(alphaMHC-hAT1) transgenic rats. 922 12

1. We hypothesized that tissular renin-angotensin system (RAS) induces vascular hypertrophy in hypertensive Ren-2 transgenic rats (TGR; strain name TGR(mRen2)L27). This assumption was tested in cell cultures of vascular smooth muscle (VSMC) from both hypertensive TGR and control normotensive Sprague-Dawley (SD) rats. Planar cell surface area, protein synthesis, and protein content per cell were studied, the role for locally produced angiotensin II (AII) was evaluated and the possible pharmacological interference by different drugs was analysed. 2. By use of radioimmunoassay techniques, AII could be determined in TGR cultures (10.25 +/- 0.12 pg per 10(7) cells) while it could not be detected in SD ones. 3. Under serum-free conditions, VSMC from hypertensive TGR were hypertrophic when compared to SD VSMC, as they presented a higher protein content per cell (335 +/-18 and 288 +/- 7 pg per cell respectively; P<0.05) and increased mean planar cell surface area, as determined by image analysis (4,074 +/- 238 and 4,764 +/- 204 microm2, respectively; P < 0.05). 4. When exogenously added to cultured SD and TGR VSMC, AII (100 pM to 1 microM) promoted protein synthesis and protein content in a concentration-dependent manner without affecting DNA synthesis. Maximal effects were observed at 100 nM. At this concentration, AII effectively increased planar cell surface area in both SD and TGR cultures by approximately 20%. 5. Treatment of TGR cultures, in the absence of exogenous AII, with the angiotensin-converting enzyme inhibitor captopril or the angiotensin AT1 receptors antagonist losartan (100 nM to 10 microM) reduced planar cell surface area in a concentration-dependent manner. In addition, both captopril and losartan (10 microM), decreased protein synthesis by approximately 15%. 6. Treatment of SD VSMC, in the absence of exogenous AII, with both captopril and losartan had no effect either on planar cell surface area or protein synthesis. 7. Treatment with the Ca2+ antagonist nifedipine (100 nM to 10 microM) reduced cell size in both SD and TGR cultures. Maximal cell reduction reached by nifedipine averaged 906 +/- 58 and 1,292 +/- 57 microm2, in SD and TGR, respectively (P<0.05). In addition, nifedipine, nitrendipine and nisoldipine (all at 10 microM) decreased protein synthesis in both cell types by 15-25%. 8. We concluded that cultured VSMC from TGR are hypertrophic in comparison with those from SD. This cell hypertrophy can be the consequence of the expression of the transgene Ren-2 that activates a tissular RAS and locally produces AII, which acts in a paracrine, autocrine, or intracrine manner. Cell hypertrophy in TGR cultures could be selectively reduced by RAS blockade, while nifedipine decreased cell size and protein synthesis in both hypertrophic and non hypertrophic cells.
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PMID:Effects of captopril, losartan, and nifedipine on cell hypertrophy of cultured vascular smooth muscle from hypertensive Ren-2 transgenic rats. 925 25

Peptides produced by the renin-angiotensin system play a major role in the development and progression of various cardiovascular diseases. One of these peptides, angiotensin II, is a potent vasoconstrictor that exerts most of its effects through the human AT1 receptor. Following the discovery of a functional variation in the angiotensin-converting enzyme gene, research has identified other genetic variations in the renin-angiotensin system that may contribute to cardiovascular disorders. Of the described polymorphisms in the AT1-receptor gene, the A1166C transversion is associated with human essential hypertension. We have used the TGR(alpha MHC-h AT1) rat model, which overexpresses the human AT1 receptor in the myocardium, to study some of the associations between an increased AT1-receptor number and cardiovascular disorders. Our results suggest that under physiological conditions overexpression of the AT1 receptor causes no changes in cardiovascular structure; however, pressure and volume overload lead to hypertrophic growth in this model. While the AT1-receptor polymorphism may not cause cardiovascular disorders directly, it can perhaps contribute to a process that is started by other factors, such as increased activity or uptake by tissues of plasma renin, which leads to local activation of the renin-angiotensin system. Our data indicate that the AT1-receptor polymorphism is probably associated with an increased responsiveness to angiotensin II. Under basal conditions, this increased responsiveness does not seem to affect the heart, but it may exert adverse effects under loading or high-renin conditions.
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PMID:Is the A1166C polymorphism of the angiotensin II type 1 receptor involved in cardiovascular disease? 971 50

Adult Ren-2 gene transgenic rats, TGR(mRen-2)27, exhibit elevated circulating and kidney angiotensin II (Ang II) levels in the presence of severe hypertension. The aim of this study was to examine whether AT1 and AT2 receptors in the kidney and renal hemodynamic and tubular responses to blockade of these receptors were altered in the Ren-2 gene transgenic rats during the maintenance phase of hypertension. Renal AT1 and AT2 receptors were mapped by in vitro autoradiography (n=8), and the effects of blockade of these receptors on mean arterial pressure (MAP), heart rate (HR), and renal cortical (CBF) and medullary blood flows (MBF) were studied in anaesthetized, adult age-matched male homozygous TGR rats (n=12) and Sprague-Dawley (SD) rats (n=7). TGR rats showed higher basal MAP (P<0.001), heart and kidney weight (P<0.001), plasma renin activity (P<0.05) and plasma Ang II level (P<0.05), and CBF (P<0.05) and MBF (P<0.05) than SD rats. AT1 receptor binding was significantly increased in the glomeruli, proximal tubules, and the inner stripe of the outer medulla of TGR rats (P<0.01), while the AT2 receptor binding was low at all renal sites of TGR and SD rats. Immunohistochemistry revealed that this increased AT1 receptor labeling occurred mainly in vascular smooth muscle layer of intrarenal blood vessels including afferent and efferent arterioles, juxtaglomerular apparatus, glomerular mesangial cells, proximal tubular cells, and renomedullary interstitial cells (RMICs) in the transgenic rats. Blockade of AT1 receptors with losartan in TGR rats markedly reduced MAP to the normotensive level (P<0.001) without altering HR. Both CBF (P<0.005) and MBF (P<0.05) were significantly increased by losartan in the transgenic rats. By contrast, losartan only caused a smaller decrease in MAP and an increase in renal CBF in SD rats (P<0.05). PD 123319 was without any renal effect in both SD and TGR rats. These findings suggest that markedly increased AT1 receptors in renal vasculature, glomerular mesangial cells, and RMICs in the presence of fulminant hypertension and elevated circulating and tissue Ang II levels may play an important role in the maintenance of hypertension in the Ren-2 gene transgenic rats.
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PMID:Roles of AT1 and AT2 receptors in the hypertensive Ren-2 gene transgenic rat kidney. 993 Nov 28

This study investigated whether angiotensin II AT1-receptor blockade with losartan inhibits endothelium-monocyte interactions originating from long-term activation of the renin-angiotensin system in hypertensive transgenic rats [TGR(mRen2)27]. The number of circulating activated monocytes, monocytes adhered to thoracic aorta endothelium, and the extent of endothelial cell injury were compared in adult male transgenic (mRen2)27 and age-matched Hannover Sprague-Dawley (SD) rats after 12 days of continuous subcutaneous administration of saline (120 microl/24 h), losartan (10 mg/kg/24 h), or the vasodilator hydralazine (3 mg/kg/24 h). At the doses administered in this experiment, both losartan and hydralazine normalized mRen2 rat blood pressures equal to values in similarly treated SD rats. Compared with saline infusion, administration of either antihypertensive in mRen2 rats reduced (p<0.05) endothelial cell injury, but only losartan significantly (p<0.05) decreased the number of activated circulating and endothelium-adherent monocytes. Infusion of antihypertensives in SD rats had no effect on blood pressures, monocyte activity, or endothelial injury compared with saline administration. These findings suggest that the recruitment and infiltration of leukocytes into the subendothelium associated with renin-angiotensin system-induced hypertension is partly mediated by pressure-independent AT1-receptor pathways.
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PMID:Angiotensin II AT1-receptor blockade inhibits monocyte activation and adherence in transgenic (mRen2)27 rats. 1006 67

In acute experiments, intracranially applied angiotensin II and vasopressin elicit significant cardiovascular effects. The purpose of the present study was to find out whether chronic intrabrain elevation of these peptides, occurring in the renin transgenic TGR(mRen2)27 (TGR) rats, results in an alteration of the cardiovascular control. Mean arterial blood pressure (MAP) and heart rate responses to hypovolemia were examined in hypertensive TGR and normotensive Sprague-Dawley (SD) rats under control conditions and during blockade of central AT1 or V1 receptors. Both groups received cerebroventricular infusions of either 1) cerebrospinal fluid (series 1), 2) AT1 receptors antagonist (AT1ANT, series 2), or 3) V1 receptors antagonist (V1ANT, series 3). Blockade of AT1 and V1 receptors decreased MAP in TGR but not in SD rats. In SD rats, bleeding elicited a similar decrease of MAP in each series and a transient increase of heart rate in series 3. In TGR, hemorrhage caused bradycardia and decrease of MAP, which was greater than in SD rats. Hemorrhagic hypotension in TGR was abolished by V1ANT and bradycardia by V1ANT or AT1ANT. The results demonstrate remarkable differences in cardiovascular adjustment to hemorrhage in SD and TGR rats and provide evidence for enhanced involvement of central V1 and AT1 receptors in the regulation of blood pressure during hypovolemia in TGR. Central V1 vasopressin receptors play a crucial role in eliciting posthemorrhagic hypotension and bradycardia in this strain.
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PMID:Role of central AT1 and V1 receptors in cardiovascular adaptation to hemorrhage in SD and renin TGR rats. 1036 71

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