Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Hypertensive transgenic (TGR(mRen-2)27) (abbreviated to TG) rats (n = 6) and their normotensive Sprague-Dawley (SD) control strain (n = 7) were chronically instrumented for the measurement of cardiac haemodynamics. The hypertension in TG rats (mean blood pressure 181 +/- 9 mmHg) was entirely attributable to a reduction in total peripheral conductance (TG rats = 169 +/- 7, SD rats = 292 +/- 15 microliters min-1 mmHg-1 100g-1) since cardiac index was not different in the two strains (TG rats = 30.5 +/- 1.2, SD rats = 29.5 +/- 1.6 ml min-1 100g-1). 2. In other animals instrumented for the assessment of regional haemodynamics, the extent of peripheral vasoconstriction was similar in renal, mesenteric and hindquarters vascular beds in the TG rats (reduction in vascular conductance relative to SD rats = 42%, 46% and 49%, respectively). 3. During an 8 h observation period with saline infusion, or following injection of losartan (10 mg kg-1) in SD rats there was no hypotension or regional vasodilation. With infusion of the endothelin antagonist, SB 209670 (10 micrograms kg-1 min-1), there was a slight hypotension, but no significant vasodilation; co-administration of losartan and SB 209670 caused a similar profile of effect, although the hypotension was increased. 4. With the same experimental protocol in TG rats, losartan caused a biphasic, progressive fall in mean arterial blood pressure accompanied by renal, mesenteric and hindquarters vasodilation. Although the response to SB 209670 was not biphasic, its hypotensive and vasodilator effects were not different from those of losartan after 8 h. In the combined presence of losartan and SB 209670, mean arterial blood pressure (116 +/- 5 mmHg) was significantly lower than with SB 209670 (132+/-4 mmHg) or losartan(136 +/- 6 mmHg) alone, and renal, mesenteric and hindquarters vascular conductances (61 +/- 3, 90+/-14 and 52+/-4 [kHz nmHg-1]103, respectively) were higher than the corresponding values following either SB 209670 (49 +/- 4, 52 +/- 4 and 34 +/- 3 [kHz mmHg- 1]103, respectively) or losartan (43 +/- 5, 59 +/- 13 and 35+/-4 [kHz mmHg-1]103, respectively) alone. These results indicate the maintenance of hypertension inTG rats is dependent upon renal, mesenteric and hindquarters vasoconstriction, mediated by angiotensinII (AII) and endothelin (ET). Since we found that plasma ET-1 levels in TG rats (12.06+/-2.87 pmol 1-1)were lower than in SD rats (21.53 +/- 3.94 pmol 1-1), then it is possible that locally-generated, rather than circulating ET-l contributes to the widespread vasoconstriction in TG rats.
 ...
PMID:Haemodynamic effects of losartan and the endothelin antagonist, SB 209670, in conscious, transgenic ((mRen-2)27), hypertensive rats. 856 54

We have previously established a transgenic rat model termed TGR(hET-2)37 overexpressing the human endothelin-2 (ET-2) gene with high renal transgene expression. This renal overexpression is of pathophysiological interest because a long-term activated paracrine renal endothelin system has been implicated in chronic renal failure due to progressive glomerular injury. Therefore, our aim in the present study was to analyze renal transgene expression in detail and address the question of whether transgene expression causes phenotypic and functional changes in the kidney. We used reverse transcription-polymerase chain reaction and in situ hybridization techniques for transgene expression analysis. Tissue ET-2 concentrations were measured with a specific radioimmunoassay. For histological evaluation of renal tissue, all samples were subjected to hematoxylin-eosin and periodic acid-Schiff staining. Renal tissue ET-2 concentrations were significantly increased in TGR(hET-2)37 rats. Using in situ hybridization, we found that the human ET-2 gene was almost exclusively expressed within the glomeruli. The glomerular transgene expression resulted in a significantly increased glomerular injury score and likewise in a significantly increased protein excretion, whereas glomerular filtration rate was not altered. Blood pressure was similar in TGR(hET-2)37 rats and age-matched controls, suggesting that the local changes in the kidney were correlated with paracrine endothelin actions. In conclusion, our study revealed that the major renal expression site of the human ET-2 transgene in TGR(hET-2)37 rats was within the glomeruli and caused the development of glomerulo-sclerosis with significantly increased protein excretion that is independent of blood pressure. We suggest that TGR(hET-2)37 rats are a new monogenetic animal model for study of the paracrine renal endothelin system and its involvement in renal pathophysiology.
Hypertension 1996 Aug
PMID:Characterization of the renal phenotype of transgenic rats expressing the human endothelin-2 gene. 870 81

Primary human hypertension is a polygenic disorder. It is the prevalent cause of cardiovascular disease leading to cardiac failure, stroke, chronic renal failure and, ultimately to death. Several genes are involved in cardiovascular control mechanisms and their genetics are complex. Experimental models which are well defined are needed to clarify the role of individual genes. The generation of the hypertensive transgenic rat line TGR (mREN2)27 bearing the murine Ren-2 gene cloned from the DBA/2J mouse strain provides a monogenic model of hypertension in which the genetic basis (the additional renin gene) is known. These rats develop severe hypertension, which reaches 200 mm Hg and higher at 8 weeks of age in the heterozygous animal. Homozygous rats develop even higher blood pressures than heterozygous animals, which is paralleled by a higher mortality rate in homozygous rats. Animals develop pathomorphologic alterations which are characteristic for systemic hypertension. The transgenic rats are characterized by unchanged or even suppressed concentrations of active renin, angiotensin I (ANG I), ANG II, and angiotensinogen compared to transgene-negative littermates. In contrast, plasma levels of inactive renin (prorenin) are much higher in TGR (mREN)27 rats than in control animals. In the kidneys, renin is suppressed, probably mediated through negative feedback inhibition, in other tissues, especially in the adrenal gland, murine Ren-2 mRNA is expressed at very high levels. The cascade of pathophysiologic events which finally lead to hypertension is not fully understood in this rat model. Treatment with ACE inhibitors or angiotensin II receptor antagonists such as losartan is extremely efficient, which could mean that hypertension in this model is mediated through ANG II. Since the the renin-angiotensin system (RAS) in the kidneys is suppressed, other ANG II generating sites must be considered. This favors the concept of extrarenal RASs in this model.
 ...
PMID:The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects. 873 83

Transgenic techniques represent powerful tools for the study of gene-related mechanisms of diseases such as hypertension, which results from a complex interaction between genetic and environmental factors. The renin-angiotensin system, a biochemical cascade in which renin functions as the key enzyme in the formation of the effector peptide angiotensin II, plays a major role in the regulation of blood pressure. The renin gene, therefore, represents an important candidate gene for hypertension. Because rats are more suited than mice for a number of experimental settings often employed in cardiovascular research, we modified the transgenic technique to generate the transgenic rat strain TGR(mREN2)27 harboring the murine Ren-2 gene. These transgenic rats develop fulminant hypertension at an early age despite low levels of renin in plasma and kidney. In addition, high expression of the transgene in a number of extrarenal tissues is associated with increased local formation of angiotensin II. Thus the TGR(mREN2)27 rat represents a model of hypertension with a defined genetic background. Studies on the transgenic rat may not only provide new insights into pathophysiological mechanisms of hypertension in this animal model but also offer the unique possibility to investigate the function and regulation of renin-angiotensin systems in extrarenal tissues. The aim of this review is to compile the knowledge that has been accumulated to date on this transgenic rat and to discuss possible mechanisms responsible for its hypertensive phenotype.
 ...
PMID:Physiological characterization of the hypertensive transgenic rat TGR(mREN2)27. 876 74

The transgenic rat TGR(mRen-2)27 develops severe hypertension with high adrenal renin and low kidney renin. The mechanism of suppressed kidney renin in these animals is still unclear. We investigated the effect of the angiotensin converting enzyme (ACE) inhibitor, perindopril on the renin-angiotensin system in plasma and tissues (adrenal gland and kidney), and the effect of mouse renin antibody on plasma and tissue renin activity before and after perindopril administration. Perindopril lowered blood pressure in the TGR(mRen-2)27 rats from 254.5 +/- 7.4 mm Hg to 154 +/- 7.8 mm hg (n = 8, P < .0001), while blood pressure in the untreated TGR (mRen-2)27 rats increased from 253.7 +/- 8.1 to 276.1 +/- 14.3 mm Hg during the study period. Perindopril significantly suppressed plasma angiotensin II (Ang II) from 19.4 +/- 2.5 pg/mL to 2.6 +/- 0.4 pg/mL, P < .0001, while markedly increasing plasma renin concentration (PRC) from 15.5 +/- 1.8 ng AngI/mL/h to 148.2 +/- 35.5 ng AngI/mL/h, P < .005 and kidney renin from 56.7 +/- 18.1 micrograms AngI/g/h to 827.4 +/- 79.1 micrograms AngI/g/h, P < .0001. However, adrenal renin was not increased. A mouse Ren-2 renin antibody at a 1:1000 dilution that suppresses purified mouse Ren-2 renin activity by 62.6 +/- 3.6% (n = 3, P < .0001) and does not suppress renin activity in plasma and kidney of the Sprague-Dawley rats, suppressed PRC in the untreated TGR(mRen-2)27 rats by 52.3 +/- 3.5% (n = 6, P < .0001). However, it only suppressed PRC in the perindopril treated TGR(mRen-2)27 rats by 7.0 +/- 2.4% (n = 6, P < .05). The antibody suppressed adrenal renin in both untreated and perindopril treated TGR(mREN-2)27 rats by 57.3 +/- 5.4% (n = 5, P < .0001) and 49.7 +/- 2.2% (n = 6, P < .0001), respectively. On the other hand, the mouse antibody suppressed kidney renin in the untreated TGR(mRen-2)27 rats by only 11.0 +/- 3.3% (n = 6, P < .05), and did not suppress kidney renin in the perindopril treated TGR(mRen-2)27 rats (n = 6, P < .0001), respectively. On the other hand, the mouse antibody suppressed kidney renin in the untreated TGR(mRen-2)27 rats by only 11.0 +/- 3.3% (n = 6, P < .05), and did not suppress kidney renin in the perindopril treated TGR(mRen-2)27 rats (n = 6, P < NS). The pH profile of renin activity in plasma confirmed the results of the antibody study. We conclude that in the TGR(mRen-2)27 rats adrenal renin is mainly mouse renin and kidney renin is mainly rat renin. The main sources of circulating renin in the TGR(mRen-2)27 rats are extra-renal tissues, including the adrenal glands, where mouse Ren-2 renin transcripts are highly expressed. The increased circulating renin in perindopril treated TGR(mRen-2)27 rats is rat renin derived from the kidney. The failure of adrenal renin to increase with perindopril suggests that at least in the basal state there is no feedback inhibition as there is in the kidney. The low kidney renin appears to be due to physiological rather than genetic factors.
 ...
PMID:Reversal of the suppressed kidney renin level in the hypertensive transgenic rat TGR(mRen-2)27 by angiotensin converting enzyme inhibition. 884 72

The cardiovascular consequences of neutral endopeptidase (NEP) inhibition with the NEP inhibitor ecadotril were evaluated by determining acute and long-term effects of the compound on hemodynamic, hormonal, renal, and structural parameters in hypertensive transgenic rats harboring a mouse renin gene (TGR (m(Ren2)27) and in normotensive controls (Sprague-Dawley rats, SDR). Acute administration of ecadotril (10 and 30 mg/kg, orally) produced a dose-dependent decrease in systolic blood pressure with a maximal effect of -23 mm Hg between 2 and 4 h after oral administration. The NEP activity in plasma was significantly inhibited and the plasma levels of atrial (ANP) and brain (BNP) natriuretic peptides and their second messenger, cyclic GMP, were distinctly raised after oral administration. In addition, ecadotril (10 and 30 mg/kg, orally) produced a dose-dependent increase in the urinary excretion of sodium and cyclic GMP. These effects were more pronounced in TGR (mRen2)27 than in the normotensive SDR without an activated natriuretic peptide system. In the long-term study, the systolic pressure in control TG (m(Ren2)27) rats increased from 213 +/- 5 to 255 +/- 7 mm Hg, whereas, in animals treated with ecadotril (30 mg/kg, orally twice daily), the blood pressure increased only from 213 +/- 5 to 227 +/- 6 mm Hg during the observation period of 13 weeks. The increases in heart weight and in kidney weight were also delayed. At the end of the study, cyclic GMP was elevated and ANP tended to be higher, whereas plasma renin activity had decreased. These data indicate a beneficial pharmacological profile of neutral endopeptidase inhibition that could prove useful in the treatment of cardiovascular diseases like hypertension.
 ...
PMID:Renal and antihypertensive effects of neutral endopeptidase inhibition in transgenic rats with an extra renin gene. 886 26

The first model of genetically engineered hypertension, the transgenic rat TGR (mREN2)27, provides a unique opportunity to study the behavioural effects of an altered brain renin-angiotensin system. The TGR (mREN2)27 rats, characterised by fulminant hypertension, show differences in both the peripheral and central angiotensin systems. The behaviour of male transgenic TGR (mREN2)27 and male Sprague-Dawley rats were determined by 4 behavioural tests. While on the elevated X-maze the TGR (mREN2)27 rat showed a greater 'anxiogenic' profile (fewer open arm entries) than the control Sprague-Dawley rats, this 'anxiogenic' profile increased further during a second exposure to the elevated X-maze 24 h later. In comparison the behaviour of the male Sprague-Dawley rats was not different between the two exposures to the elevated X-maze. Locomotor activity did not differ between either the TGR (mREN2)27 or Sprague-Dawley rats when placed in a 1 m2 open-field for 10 min. A short period of fluid-deprivation (3 h) reversed the 'anxiogenic' profile of the TGR (mREN2)27 on the elevated X-maze. Administration of captopril (20 mg . kg-1 body weight) in the drinking water of the TGR (mREN2)27 rats and Sprague-Dawley rats reversed the anxiogenic profile of the TGR (mREN2)27 rat on the elevated X-maze but did not alter the behaviour of the Sprague-Dawley rats.
 ...
PMID:Behaviour of the transgenic (mREN2)27 rat. 887 71

Transgenic rats, termed TGR(mREN2)27, which carry the mouse ren2d renin gene, develop fulminant hypertension. To evaluate the role of the circulating renin-angiotensin system (RAS) in hypertension of TGR(mREN2)27, we determined plasma levels of its components and their regulation by ether-stress. Plasma prorenin was elevated in prehypertensive and in adult heterozygous TGR(mREN2)27 (fourtyfold), when compared with Sprague Dawley (SD) controls, whereas plasma renin concentration (PRC) and angiotensin II were not in SD rats ether anesthesia increased PRC at day (11 a.m.; fivefold), but not at night (11 p.m.). Ether had no effect on PRC in TGR(mREN2)27. In contrast, ether increased plasma corticosterone levels at day and night in both strains to a similar degree. Our data indicate that plasma active renin is not a pathogenetic factor for hypertension in TGR(mREN2)27 and suggest a primary role of circulating prorenin. The lack of stimulation of PRC by ether in TGR(mREN2)27 probably reflects predominant extrarenal origin of renin.
 ...
PMID:Role of the circulating renin-angiotensin system in the pathogenesis of hypertension in transgenic rats. TGR(mREN2)27. 888 77

Cytochrome P45011B1 (11 beta-hydroxylase) was detected in the brain of male rats by in situ hybridization methods. Normal Sprague-Dawley rats were compared to the transgenic strain TGR(mRen2)27, characterized by the expression of the murine Ren-2d renin gene and the development of severe hypertension. Specific riboprobes were generated by in the vitro transcription of a 152 base-pair long cDNA template 35S-labeled riboprobes were hybridized to cryostat sections from adrenal glands and from two different levels of the brain using standard protocols and varying washing conditions. After exposure of the radiolabeled sections to X-ray film, the signals were quantified and compared. Following autoradiography and counterstaining, cytochrome P45011B1 mRNA was clearly localized in the zona fasciculata/reticularis of the adrenal cortex and in distinct layers of the cerebral cortex. High signal densities were obtained in the layers II-IV of the neocortex and in the layer II of the piriform cortex, although the concentrations of cytochrome P45011B1 mRNA were remarkably lower in the central nervous system as compared to adrenal glands. As revealed by the semi-quantitative analysis, there was a slight increase in adrenal 11 beta-hydroxylase mRNA in the transgenic rats, whereas the brain seems to express nearly the same amount of this enzyme in both strains. The cytochrome P45011B1 mRNA expression in distinct cells, probably nerve cells, and especially in regions with high densities of glucocorticoid receptors points to a possible function of brain derived corticosterone in receptor activation.
 ...
PMID:Expression of cytochrome P45011B1 mRNA in the brain of normal and hypertensive transgenic rats. 889 Dec 50

The cardiovascular consequences of mixed angiotensin converting enzyme and neutral endopeptidase (ACE/NEP) inhibition with alatriopril/alatrioprilat were compared with the consequences of endopeptidase (NEP) inhibition alone with (S)-thiorphan/ecadotril by determining the acute effects of the compounds on hemodynamic, hormonal, and renal parameters in hypertensive transgenic rats harboring an additional mouse renin gene (TGR(mRen2)27). Infusion of alatrioprilat and (S)-thiorphan in anesthetized TGR decreased blood pressure in a dose-dependent manner, but heart rate remained unchanged. The renal excretion of water, sodium, and cGMP also increased dose-dependently, with nearly the same maximal effects after infusion of (S)-thiorphan and alatrioprilat. At the end of infusion, plasma ANP and cGMP were elevated both after (S)-thiorphan and after alatrioprilat, whereas plasma renin activity increased only after alatrioprilat. The ACE inhibition effect was studied in ganglion-blocked rats receiving a continous infusion of angiotensin I. Alatrioprilat decreased the mean blood pressure dose-dependently, but about 30 times higher concentrations were needed to produce the same effects as the ACE inhibitor captopril. At a dose of 30 mg/kg p.o., ecadotril, the orally active prodrug of (S)-thiorphan, decreased the systolic blood pressure in conscious TGR by 22 mmHg for 6 h, whereas alatriopril (100 mg/kg p.o.) also reduced the systolic pressure in these rats with a maximal reduction of 22 mmHg. In addition, ecadotril and alatriopril significantly increased the urinary excretion of sodium. In contrast, ACE inhibition with captopril decreased the excretion of sodium dose-dependently in conscious TGR. In conclusion, combined ACE/NEP inhibition produced a comparable lowering of blood pressure and improvement in renal function as those with NEP inhibition in TGR. Dual ACE/NEP inhibition may therefore be useful in cardiovascular conditions such as hypertension or heart failure.
 ...
PMID:Cardiorenal consequences of dual angiotensin converting enzyme and neutral endopeptidase 24.11 inhibition in transgenic rats with an extra renin gene. 889 43


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>