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Query: UMLS:C0004135 (ATM)
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Regulation of the gene expression of type-1 angiotensin II receptor (AT1) by treatment with manidipine, a calcium channel blocker, or delapril, an angiotensin converting enzyme inhibitor, for one week was assessed in the adrenal gland, heart, kidney, and brain from spontaneously hypertensive rats (SHR). Tissue AT1 receptor messenger RNA (mRNA) content was measured by reverse transcriptase-polymerase chain reaction. Treatment with manidipine (3 mg/kg/day) or delapril (30 mg/kg/day) lowered systolic blood pressure (SBP) significantly (p < 0.01) (delta SBP; -73 mmHg or -67 mmHg, respectively). Although delapril markedly increased plasma renin activity (PRA), manidipine did not alter PRA. AT1 receptor mRNA content in the adrenal gland was significantly (p < 0.01) decreased by treatment with manidipine or delapril. In contrast, cardiac AT1 receptor mRNA content was significantly (p < 0.01) increased by treatment with either agent. There was no significant change in renal and brain AT1 receptor mRNA contents. These findings suggest that although the expression of AT1 receptor gene depends on the circulating renin-angiotensin system (RAS), it is regulated independently in a tissue-specific manner via the local RAS in each tissue of SHR.
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PMID:Regulation of the gene expression of type-1 angiotensin II receptor in spontaneously hypertensive rats. 134 80

ISOFORMS OF ANGIOTENSIN II RECEPTORS: So far, three isoforms of angiotensin II receptors have been identified by complementary DNA cloning, all with seven transmembrane domain structures. AT1A and AT1B are the most common isoforms. They are coupled to phospholipase C through Gq/G11 proteins and to a calcium channel, and negatively coupled to adenyl cyclase. AT2 is only remotely related to the AT1 family. KNOWN STRUCTURAL DETAILS OF ANGIOTENSIN II RECEPTORS: Ligand-binding domains are being defined in the space surrounded by transmembrane helices. Coupling to Gq seems to involve the second cytosolic loop. Receptor proteins undergo transition to a low-affinity form, which is desensitized and internalized. CHROMOSOME LOCATION: In the rat, AT1A, AT1B and AT2 are located on chromosomes 17, 2 and X, respectively. SIGNALING PATHWAY: Studies with receptors are revealing several different pathways of angiotensin signaling that modulate protein tyrosine phopsphorylation.
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PMID:Molecular biology of angiotensin II receptors: an overview. 776 96

Biological actions of natriuretic peptide (NP) are determined by the condition of the receptor as well as that of the hormone. Although we previously demonstrated in hypertensive rats the up-regulation of NP-A receptor that mediates various biological actions of NPs, the pathophysiologic significance of NP-C receptor, another subtype thought to be related to clearance of NPs and possibly to biological actions, remains unknown. In the present study, we determined NP-C receptor messenger RNA (mRNA) level in the aortic tissue of stroke-prone spontaneously hypertensive rats (SHR-SP/Izm) and in cultured aortic smooth muscle cells by ribonuclease protection assay. The aortic NP-C receptor mRNA level in SHR-SP/Izm was significantly lower than that in the control WKY/Izm. Oral administration of an angiotensin (Ang) II receptor (AT1) antagonist, TCV-116, but not a calcium channel blocker, manidipine, reversed the down-regulated NP-C receptor mRNA in SHR-SP/Izm to the level in WKY/Izm, whereas the latter was more potent in decreasing the blood pressure. In cultured aortic smooth muscle cells, the NP-C receptor was the predominant subtype. Ang II decreased the NP-C receptor mRNA level in a dose-dependent manner, but this effect was reversed by an AT1 antagonist, CV-11974. Neither the NP-A nor NP-B receptor mRNA level was altered by Ang II. These findings indicate that vascular NP-C receptor is down- regulated via Ang-II-mediated mechanism in SHR-SP/Izm. The phenomenon, together with the up-regulation of the NP-A receptor, may play an important role in counteracting hypertension by enhancing the action of NPs.
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PMID:Angiotensin II-dependent down-regulation of vascular natriuretic peptide type C receptor gene expression in hypertensive rats. 860 80

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.
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PMID:Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats. 876 77

Blood pressure and heart rate were measured by telemetry in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) to investigate the contribution of angiotensin II to the reflex tachycardia resulting from exaggerated hypotension caused by a high dose of a calcium channel blocker. Pre-treatment with TCV-116, an angiotensin II AT1 receptor antagonist, or enalapril partially attenuated the reflex tachycardia induced by manidipine, but TCV-116 had almost no effect on the sinus tachycardia induced by isoproterenol. The suppressive effects of TCV-116 against the reflex tachycardia tended to be more obvious in WKY than in SHR, though the difference was not statistically significant. Concurrent administration of propranolol almost completely inhibited both the reflex tachycardia and the sinus tachycardia in SHR and WKY, indicating that the sympathetic nervous system contributes to both types of tachycardia. We demonstrated that angiotensin II may be involved in the reflex tachycardia induced by calcium channel blockers probably via activation of some component of the sympathetic nervous system other than postsynaptic factors at the sinus node.
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PMID:Role of angiotensin II in reflex tachycardia during hypotension caused by a calcium channel blocker. 878 49

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.
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PMID:The renin-angiotensin system and vascular hypertrophy. 883 52

Angiotensin-converting enzyme inhibitors improve arterial stiffness independently of blood pressure reduction. Since we have recently shown that in hypertensive individuals the A1166C polymorphism of the angiotensin II type 1 receptor (AT1-R) is an independent determinant of aortic stiffness, we designed the present study to assess the influence of this polymorphism on the changes of aortic stiffness after chronic treatment with the angiotensin-converting enzyme inhibitor perindopril and the calcium channel blocker nitrendipine. Forty perindopril- and 42 nitrendipine-treated hypertensive individuals were studied. We evaluated aortic stiffness by measuring the carotid-femoral pulse wave velocity. Carriers of the AT1-RC allele showed higher baseline values of pulse wave velocity than AA homozygotes (P < .05). In the perindopril group, a threefold greater reduction in pulse wave velocity was observed in carriers of the C allele than in AA homozygotes (-2.85 +/- 0.62 versus -0.94 +/- 0.32 m/s, respectively; P < .001), whereas in the nitrendipine group, pulse wave velocity decreased only in AA homozygotes and not in AT1-R C carriers (-1.38 +/- 0.35 versus +0.04 +/- 0.60 m/s, respectively; P < .01). These results indicate that according to the AT1-R A1166C genotype, an angiotensin-converting enzyme inhibitor and a calcium channel blocker affect pulse wave velocity in opposite ways. Since some evidence shows that increased pulse wave velocity may enhance cardiovascular risk, it might be useful for physicians to consider the AT1-R genotype when prescribing an angiotensin-converting enzyme inhibitor or calcium channel blocker to a hypertensive individual.
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PMID:Influence of the angiotensin II type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine on arterial stiffness in hypertensive individuals. 895

After a 4-week placebo baseline period, 29 Chinese elderly hypertensive patients were randomized, double-blind, to 12 weeks of treatment with either losartan potassium (n = 19), an angiotensin II antagonist at the AT1 receptor, or felodipine (n = 10), a calcium channel blocking agent. Of these 29 patients 12 had coexisting non-insulin-dependent diabetes mellitus. At week 12, the mean reductions (95% confidence intervals) in mean arterial pressure were similar in both groups: losartan -18 (range -22 to -14) mm Hg; felodipine -19 (range -25 to -11) mm Hg. In the whole group, the 24-hour urinary albumin excretion was reduced by 27% with losartan as compared with no change in the felodipine-treated group (p = 0.03; analysis of variance). In the diabetic group, losartan treatment reduced the urinary albumin excretion by 24% as compared with 11% in the felodipine-treated group. In the non-diabetic patients, the urinary albumin excretion fell by 29% in the losartan-treated group, but increased by 14% in the felodipine-treated group (p < 0.001; repeated-measures analysis of variance). Plasma sodium increased to a similar extent in both groups. The fasting plasma triglyceride level declined by 25% (p < 0.001 within group) with losartan, but was not significantly reduced in the felodipine-treated group. For comparable reductions in blood pressure, a greater reduction in albuminuria was seen with losartan than with felodipine treatment in Chinese hypertensive patients with or without non-insulin-dependent diabetes mellitus. Long-term studies are required to examine whether these antiproteinuric effects of losartan can be translated to renoprotection.
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PMID:Antihypertensive and anti-albuminuric effects of losartan potassium and felodipine in Chinese elderly hypertensive patients with or without non-insulin-dependent diabetes mellitus. 905 57

The objective of this study was to determine the effect of angiotensin I (Ang I) treatment in vivo on two major Ca-transport systems-the L-type voltage dependent calcium channel (L-VDCC) and the Na/Ca exchanger in rat heart. For our experiments we used four groups of rats, treated differently with saline, Ang I, the ACE inhibitor enalapril and/or combination of both for 6 days, every 24 h. We observed an increase in the activity, and also in mRNA expression of the Na/Ca exchanger, after repeated administration of Ang I in vivo. The maximal binding capacity of Ca-antagonist PN 200-110, which binds to the alpha 1 subunit of the L-VDCC was elevated from 0.8-1.85 pg/mg protein. mRNA expression of the voltage-dependent calcium channels of L-type system was also upregulated by Ang I administration, but not when enalapril was applied simultaneously with Ang I. These results demonstrate that in vivo application of the Ang I significantly modulates not only the activity, but also expression of the Na/Ca exchanger and the L-VDCC in rat hearts through angiotensin II (Ang II). Since in the in vitro experiments on the isolated cardiomyocytes, Ang II (100 nM) increased the calcium uptake after depolarization, and the AT1 receptor agonist losartan prevented this increase, we assume that this regulation might involve the AT1 receptors.
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PMID:Angiotensin I modulates Ca-transport systems in the rat heart through angiotensin II. 922 Mar 59

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States, and accounts for 35% of all the patients with ESRD entering a dialysis program; 63% of patients with diabetic nephropathy have type II diabetes mellitus. Hypertension is a major risk factor for renal disease and is common in people with diabetes mellitus. Strategies for preventing the progression of renal failure in patients with diabetes mellitus include glycemic control, and control of blood pressure. Blocking the renin-angiotensin system (RAS) slows the progression of established diabetic nephropathy in type I diabetes mellitus, and inhibiting angiotensin II formation retards or impedes the progression from microalbuminuria to established diabetic nephropathy (macroproteinuria) in people with type I diabetes mellitus. The situation could be the same for people with type II diabetes mellitus. The ability of RAS blockade using irbesartan, an AT1 angiotensin II receptor antagonist, to slow the progression in renal failure has been compared with that of the calcium channel blocker amlodipine and placebo in a pilot study. The results suggest that blockade of the RAS, in this case with irbesartan, is at least equivalent to calcium channel blockers with respect to antihypertensive efficacy, but provides better renoprotective benefits.
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PMID:Renoprotection and renin-angiotensin system blockade in diabetes mellitus. 943 77


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