Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:The hypertensive Ren-2 transgenic rat TGR (mREN2)27 in hypertension research. Characteristics and functional aspects. 873 83

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.
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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 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.
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PMID:Cardiorenal consequences of dual angiotensin converting enzyme and neutral endopeptidase 24.11 inhibition in transgenic rats with an extra renin gene. 889 43

Soluble guanylyl cyclase activity and its stimulation by diethylamineNONOate was measured in aortae from hypertensive TGR(mREN2)27 rats (TGR) and Sprague-Dawley controls. Superoxide dismutase was added in vitro to evaluate the contribution of oxidative breakdown of nitric oxide (NO) by superoxide anions. Expression of soluble guanylyl cyclase was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Basal and stimulated soluble guanylyl cyclase activity was significantly reduced in TGR rats, addition of superoxide dismutase had no effect. Expression of soluble guanylyl cyclase subunits was not different between strains. The independent contribution of hypertension and the overactive renin-angiotensin system to soluble guanylyl cyclase subsensitivity was assessed after normalization of TGR's blood pressure by the Ca(2+)-channel blocker amlodipine or the angiotensin converting enzyme-inhibitor enalapril. Soluble guanylyl cyclase activity in TGR was slightly increased by amlodipine and almost completely restored by enalapril. In conclusion, TGR showed desensitized vascular soluble guanylyl cyclase, depending on their overactive renin-angiotensin system.
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PMID:Contribution of the renin-angiotensin system to subsensitivity of soluble guanylyl cyclase in TGR(mREN2)27 rats. 1096 40

Multiple indirect lines of evidence point at a cardioprotective role for enhanced bradykinin formation. In particular, the inhibition of angiotensin-converting enzyme, also known as kininase II, can protect against cardiac ischemia, putatively via accumulation of bradykinin. To address whether an increase in kinin formation is sufficient to protect against cardiac ischemia, we studied transgenic rats harboring the human tissue kallikrein gene TGR(hKLK1) under the control of the metallothionein promoter, which drives expression of the transgene in various organs including the heart. We subjected the isolated hearts from transgenic rats and their transgene negative littermates to ex vivo regional cardiac ischemia and reperfusion. During the experiment, the hearts were treated with either vehicle or the specific bradykinin type 2 receptor antagonist HOE 140 (10-9 M). In the transgenic rats, overflow of nucleotide breakdown products upon reperfusion was significantly less (455 +-54 nmol/min/g in transgene negative rats vs. 270+-57 nmol/min/g in the transgenic rats, P.
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PMID:Increased kallikrein expression protects against cardiac ischemia. 1102 68

It is still a controversial issue whether different classes of antihypertensive drugs are equally effective in the regression of cardiac hypertrophy and associated complications. The present study compared the effects of prolonged treatment with the Ca2+-channel blocker amlodipine and the ACE inhibitor enalapril, respectively, in TGR(mREN2)27 rats (TGR), an animal model of renin-dependent hypertension. TGR were divided into three groups and received either amlodipine, enalapril or drinking water without addition, Sprague-Dawley rats (SPRD) served as normotensive control group. Cardiovascular parameters were monitored by radiotelemetry, and drug doses were titrated until 24-h blood pressure was reduced to approximately 140/90 mmHg in both active treatment groups. After 8 weeks of treatment left ventricular (LV) hypertrophy was completely reversed in both treatment groups despite a tenfold increase in plasma angiotensin II in amlodipine-treated TGR. In untreated TGR LV catecholamines were depleted, and beta1-adrenergic stimulation of adenylyl cyclase was blunted. Treatment of TGR with enalapril prevented both the depletion of tissue catecholamines and the desensitisation of LV beta1-adrenoceptors. Amlodipine had no effect on cardiac adrenergic signal transduction. Basal activity of LV soluble guanylyl cyclase was not different between TGR and SPRD, but its sensitivity to stimulation by nitric oxide was slightly reduced in TGR. Treatment had no effect on basal and stimulated guanylyl cyclase activity. The present study in an animal model of renin-dependent hypertension suggests that blood pressure reduction per se is sufficient for a regression of cardiac hypertrophy. However, beta-adrenergic desensitisation was prevented only in the enalapril-treated group, supporting a blood pressure-independent contribution of the renin-angiotensin system to the regulation of beta-adrenergic signal transduction.
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PMID:Normalisation of blood pressure in hypertensive TGR(mREN2)27 rats by amlodipine vs. enalapril: effects on cardiac hypertrophy and signal transduction pathways. 1119 27

It is admitted that low dose of angiotensin converting enzyme (ACE) inhibitors allows the regression of left ventricular hypertrophy (HVG) in experimental models where plasma renin activity (PRA) is high. The use of low dose of ramipril, an ACE inhibitor, make it possible to explore the place of cardiac renin-angiotensin system (RAS) in the regression of HVG independently of blood pressure (BP). Twenty rats TGR (mRen2) 27, heterozygous male, 10 weeks old were treated by daily oral gavage during 6 weeks by 10 micrograms/kg/jour ramipril or distilled water and compared to 10 normotensive Sprague Dawley (SD) rats. BP was measured. After the period of treatment, plasma, left kidney and the ventricles were removed. On each tissue samples and plasma, angiotensinogen (Aogen), the renin activity, angiotensins I (Ang I) and II (Ang II) were determined by radioimmuno assay and the activity of ACE was measured by fluorimetry. BP does not differ between treated and untreated groups during 6 weeks of treatment but is significantly higher compared to SD rats. PRA of untreated rats is high (36 +/- 5 ng Ang I/mL/h). However, treatment did not make it possible to decrease HVG. In plasma and kidney treatment's effect on SRA is confirmed by the increase in renin activity (plasma: 63 +/- 9 vs 36 +/- 5 ng Ang I/mL/h; kidney: 127 +/- 11 vs 92 +/- 7 micrograms Ang I/g/h) which is accompanied by an increase of Ang I rates (plasma: 297 +/- 31 vs 15 +/- 10 fmol/mL; kidney: 241 +/- 37 vs 160 +/- 12 fmol/g) and of the reduction in Aogen. An inhibition of ACE is perceptible with low dose of ramipril in heart (left ventricle: 1.7 +/- 0.1 vs 2.5 +/- 0.3 nmol HisLeu/min/mg protein), but it does not appear significant modifications of the other elements of the RAS in this tissue. The Ang II cardiac rates are probably not solely defined by cardiac ACE activity, other ways of synthesis being described. The absence of regression of the HVG in TGR (mRen2) 27 rat with low dose of ramipril could be related to the absence of effect on cardiac Ang II rates. In addition, the relation between high PRA rates and the effectiveness of low dose of ACE inhibitor in the HVG are not confirmed.
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PMID:[Effect of a non-antihypertensive dose of ramipril on the plasma and tissue renin-angiotensin system in 27 TGR (mRen2) rats]. 1157 8

Angiotensin-(1-12) [Ang-(1-12)], an alternate substrate for tissue angiotensin II (Ang II) formation, underscores the importance of alternative renin-independent pathway(s) for the generation of angiotensins. Since renin enzymatic activity is species-specific, a transgenic model of hypertension due to insertion of the human angiotensinogen (AGT) gene in Sprague Dawley rats allowed for characterizing the contribution of a non-renin dependent mechanism for Ang II actions in their blood and heart tissue. With this in mind, we investigated whether TGR(hAGT)L1623 transgenic rats express the human sequence of Ang-(1-12) before and following a 2-week oral therapy with the type I Ang II receptor (AT1-R) antagonist valsartan. Plasma and cardiac expression of angiotensins, plasma renin activity, cardiac angiotensinogen, and chymase protein and the enzymatic activities of chymase, angiotensin converting enzyme (ACE) and ACE2 were determined in TGR(hAGT)L1623 rats given vehicle or valsartan. The antihypertensive effect of valsartan after 14-day treatment was associated with reduced left ventricular wall thickness and augmented plasma concentrations of angiotensin I (Ang I) and Ang II; rat and human concentrations of angiotensinogen or Ang-(1-12) did not change. On the other hand, AT1-R blockade produced a 55% rise in left ventricular content of human Ang-(1-12) concentration and no changes in rat cardiac Ang-(1-12) levels. Mass-Spectroscopy analysis of left ventricular Ang II content confirmed a >4-fold increase in cardiac Ang II content in transgenic rats given vehicle; a tendency for decreased cardiac Ang II content following valsartan treatment did not achieve statistical significance. Cardiac chymase and ACE2 activities, significantly higher than ACE activity in TGR(hAGT)L1623 rats, were not altered by blockade of AT1-R. We conclude that this humanized model of angiotensinogen-dependent hypertension expresses the human sequence of Ang-(1-12) in plasma and cardiac tissue and responds to blockade of AT1-R with further increases in the human form of cardiac Ang-(1-12). Since rat renin has no hydrolytic activity on human angiotensinogen, the study confirms and expands knowledge of the importance of renin-independent mechanisms as a source for Ang II pathological actions.
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PMID:Activation of the Human Angiotensin-(1-12)-Chymase Pathway in Rats With Human Angiotensinogen Gene Transcripts. 3180 58