Tissue- and Subtype-Specific Modulation of Angiotensin II Receptors by Chronic Treatment with Cyclosporin A, Angiotensin-Converting Enzyme Inhibitors and AT1 Antagonists

Regitz‐Zagrosek, Vera; Auch-Schwelk, Wolfgang; Hess, Benjamin; Klein, Uwe; Duske, Ellen; Steffen, Christian; Hildebrandt, Alfred G.; Fleck, Eckart

doi:10.1097/00005344-199507000-00011

Cited by 37 publications

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“…Some previous studies have showed subtypes of angiotensin receptors to be downregulated by their selective subtype-specific antagonists in other organs. 36,37 The present study for the first time showed the information regarding the interaction of mRNAs for AT 1 and AT 2 receptors and ACE to the extracellular matrix and vascular hypertrophy. In our study, all the treated SHR were given drugs between the ages of 10 to 20 weeks.…”

Section: Discussionmentioning

confidence: 57%

Interaction of mRNAs for Angiotensin II Type 1 and Type 2 Receptors to Vascular Remodeling in Spontaneously Hypertensive Rats

et al. 1998

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Abstract-We administered angiotensin II (Ang II) receptor type 1 (AT 1 ) blockade (losartan, 40 mg ⅐ kg Ϫ1 ⅐ d Ϫ1), type II receptor (AT 2 ) blockade (PD123319, 100 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ), or angiotensin-converting enzyme (ACE) inhibitor (enalapril, 30 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) to spontaneously hypertensive rats (SHR) from 10 to 20 weeks of age. Control SHR and Wister-Kyoto rats (WKY) received a placebo for the same period. At the end of treatment, losartan and enalapril were both found to have significantly reduced the arterial systolic blood pressure and the collagen concentration to the level of WKY, whereas PD123319 had no effect. Enalapril and PD123319 significantly reduced the media cross-sectional area of the aorta in comparison to that of untreated SHR, which was still larger than that of the WKY; however, losartan did not change it. Using reverse transcription-polymerase chain reaction, we next examined the mRNA expressions for ACE, AT 1 receptor, and AT 2 receptor in experimental animals. We observed significantly enhanced mRNA expression for AT 1 and AT 2 receptors and ACE in untreated SHR compared with WKY. The AT 1 mRNA level was also significantly decreased in the SHR treated with either losartan or enalapril, whereas the AT 2 mRNA level was significantly decreased in the SHR treated with either PD123319 or enalapril in comparison to untreated SHR. The level of ACE mRNA was significantly decreased only in the SHR treated with enalapril. These results indicate that AT 1 receptor, but not AT 2 receptor, plays a crucial role in the remodeling of matrix tissue, while AT 2 receptor may play a role in the development of hypertrophy of smooth muscle in aorta in SHR, and that the reduction of hypertrophy of smooth muscle does not fully account for the suppression of hypertension. (Hypertension. 1998;32:467-472.) Key Words: angiotensin II Ⅲ receptors, angiotensin Ⅲ hypertrophy, vascular Ⅲ collagen Ⅲ rats, inbred SHR L ong-term hypertension is reported to be associated with cardiovascular remodeling, which consists of cardiovascular hypertrophy and an increase in the extracellular matrix (especially collagen).1,2 In spontaneously hypertensive rats (SHR), both left ventricular hypertrophy and the properties of characteristic vascular resistance are already present early in life, based on the results of a comparison with normotensive Wister-Kyoto rats (WKY).3,4 Angiotensin-converting enzyme (ACE) inhibitors can lower the blood pressure in SHR mainly by reducing the production of angiotensin II (Ang II).5 Ang II is considered to act as a growth-promoting factor in aortic smooth muscle cells, 6,7 while it also increases collagen synthesis in smooth muscle cells.8 ACE inhibitors suppress such vascular remodeling in experimental models, possibly through blood pressure-independent mechanisms. 9,10 Recently, a selective Ang II receptor antagonist has been developed that inhibits the renin-angiotensin system (RAS) more specifically than ACE inhibitors. Two main Ang II receptor subtypes, AT 1 and AT 2 , have been identified, a...

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Section: Discussionmentioning

confidence: 57%

Interaction of mRNAs for Angiotensin II Type 1 and Type 2 Receptors to Vascular Remodeling in Spontaneously Hypertensive Rats

et al. 1998

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“…32 A loss of effect of Ang II would be consistent with a downregulation of AT 1 receptors, which is rather unexpected from a chronic treatment with a receptor antagonist but has been previously described. 33 This might be because of the increase in NO availability, 9,11 which has been shown to downregulate AT 1 receptor expression and number. 34,35 We tested the hypothesis that the diminished contractile effect of the peptides in the losartan-treated group could be caused by stimulation of AT 2 receptors.…”

Section: Discussionmentioning

confidence: 99%

Differential Effect of Chronic Antihypertensive Treatment on Vascular Smooth Muscle Cell Phenotype in Spontaneously Hypertensive Rats

et al. 2001

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The aim of this study was to investigate the effect of chronic losartan or captopril on vascular smooth muscle cell (VSMC) phenotype and vascular function in spontaneously hypertensive rats. Male 12-week-old rats were treated for 16 weeks with losartan (15 mg/kg per day) or captopril (60 mg/kg per day) in their drinking water. Systolic blood pressure, measured by the tail-cuff method, was reduced approximately 40 mm Hg in both treatment groups compared with a nontreated control group. Cell structure and proliferation studies were performed in VSMCs obtained from rat carotid arteries. Cells from the losartan-treated group showed a significant reduction in size, total protein content, and nucleus number, as well as proliferation after stimulation with 10% fetal calf serum and an increased percentage of cells in the G(1) phase compared with the control and captopril-treated groups. Functional studies were performed in isolated carotid arteries from these groups. Contractions elicited by 75 mmol/L KCl or 10(-)(7) mol/L norepinephrine and relaxations elicited by acetylcholine were similar in all groups. Concentration-response curves to angiotensin I or angiotensin II (10(-)(10) to 3x10(-)(7) mol/L) were almost abolished in the losartan-treated group and were not modified by preincubation with the angiotensin type 2 receptor antagonist PD 123,319. These results suggest that long-term losartan treatment significantly changes VSMC phenotype and proliferative status, apparently unrelated to blood pressure lowering or to endothelial function improvements.

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“…CsA has also been reported to elevate plasma angiotensin II levels ( Edwards et al ., 1994 ). Furthermore, long‐term treatment with CsA upregulates AT 1 receptors in vascular and renal tissue ( Iwai et al ., 1993 ; Regitz‐Zagrosek et al ., 1995 ) and increases vasoconstrictive effect of angiotensin II ( Auch‐Schwelk et al ., 1993 ; Takeda et al ., 1995 ).…”

Section: Discussionmentioning

confidence: 99%

Comparison of enalapril and valsartan in cyclosporine A‐induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high‐sodium diet

Lassila

Finckenberg

Père

et al. 2000

British J Pharmacology

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1 We compared the eects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT 1 receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). 2 SHR (8 ± 9 weeks old) on high-sodium diet were given CsA (5 mg 3 Blood pressure was recorded every second week by tail cu method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion. 4 CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial ®brosis. 5 Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive eect of enalapril. Urinary kallikrein excretion was similar in all groups. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology. 6 The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR.

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Tissue- and Subtype-Specific Modulation of Angiotensin II Receptors by Chronic Treatment with Cyclosporin A, Angiotensin-Converting Enzyme Inhibitors and AT1 Antagonists

Cited by 37 publications

References 0 publications

Interaction of mRNAs for Angiotensin II Type 1 and Type 2 Receptors to Vascular Remodeling in Spontaneously Hypertensive Rats

Interaction of mRNAs for Angiotensin II Type 1 and Type 2 Receptors to Vascular Remodeling in Spontaneously Hypertensive Rats

Differential Effect of Chronic Antihypertensive Treatment on Vascular Smooth Muscle Cell Phenotype in Spontaneously Hypertensive Rats

Comparison of enalapril and valsartan in cyclosporine A‐induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high‐sodium diet

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