Circulation , 98 — PubMed Google Scholar. Kidney Int , 60 — PubMed Article Google Scholar. Circulation , — Hypertension , 24 — Hypertension , 22 — Nussberger J: Circulating versus tissue angiotensin II. Google Scholar. Hypertension , 38 — Hypertension , 30 — Importance of mannose 6-phosphate receptors. Arterioscler Thromb Vasc Biol , 21 — Hypertension , 37 — J Clin Invest , 98 — Am J Hypertens , 15 — J Hypertens , 20 — Local production of angiotensin I. Hypertension , 29 — J Clin Invest , — This is the first report on the existence of a cell-surface pro renin receptor contributing to local angiotensin generation.
Am J Physiol , :HH Human AGT protein from the left ventricle of vehicle and valsartan treated rats averaged [1. Cardiac chymase protein averaged 1. Figure 3. Normalization of blood pressure by valsartan-treatment produces a robust and selective increase in the human sequence of Ang- in the left ventricular tissue of TGR hAGT L rats. Figure 4. Comparative concentrations of left ventricular content of Ang II as determined by Mass Spectroscopy in normal Sprague Dawley SD rats and transgenic rats expressing the human angiotensinogen gene randomized to either treatment with vehicle or the AT 1 -R receptor antagonist valsartan.
Figure 5. Treatment with vehicle or valsartan did not change the expression of these gene transcripts. Valsartan treatment had no effect on the enzymatic activity of these enzymes Table 2. Similar significant correlations were found for plasma hAng- with plasma Ang I 0. Cardiac chymase activity correlated with cardiac ACE2 activity Table 3. Table 3. The creation of a rat expressing the human AGT gene in its genome allows for exploring non-renin mechanisms of excess Ang II activity as rat renin shows no catalytic activity for the human AGT protein 2.
The collective characterization of the hemodynamic, biochemical, and rat and human expressions of renin angiotensin system components in the blood and cardiac tissue of rats expressing the human AGT gene offers new insights into the biological importance of alternate Ang II generating pathways whereby shorter sequences of the AGT substrate lead to chronic hypertension and cardiac hypertrophy through non-canonical renin angiotensin biotransformation pathways.
While the identity of the enzyme cleaving the human AGT sequence in these transgenic rats remains to be fully identified, and it was not the object of this investigation, we showed previously that kallikrein or a kallikrein-like enzyme does cleave Ang- from AGT 21 , The demonstration of higher cardiac hAng- values during valsartan treatment suggest a potential for increased intracellular incorporation of Ang- from the circulation or the interstitial spaces as demonstrated by us in neonatal cardiac myocytes 23 or alternatively, increased expression or activity of an AGT-cleaving protease.
Further work will be necessary to explain the factor s accounting for the selective increase in cardiac hAng- content following blockade of AT 1 -R. Experimental models for the study of primary hypertension have yielded important information as to the diverse nature of the blood pressure regulatory mechanisms that contribute to blood pressure elevation Too often, however, these studies highlight an overarching acceptance of renin as the primary pathway initiating the biochemical cascade leading to chronic Ang II pathological actions.
While the humanization of rats with both the AGT and renin genes 25 reiterated the importance of renin mechanisms to chronic disordered blood pressure regulation, these studies did not exclude whether similar activation of hypertensive mechanisms may be initiated by increased expression of AGT alone. Global deficiency or reduction of AGT gene expression impairs survival and is associated with marked alterations in systemic and renal homeostasis 1.
Likewise, AGT overexpression is associated with hypertension and renal tubular damage 26 , While the studies in mice implicate AGT expression as a source for altered structural and functional regulation of homeostatic mechanisms, no studies have addressed the pathogenetic role of Ang II-derived hypertensive actions in conditions in which renin does not initiate the substrate's hydrolysis.
While tissue Ang II synthesis is now generally accepted, a vigorous debate persists regarding the site within the tissue at which the peptide is formed 28 — Cardiac Ang I and Ang II concentrations in vehicle treated transgenic rats are several orders of magnitude higher than those reported in normal and genetically hypertensive rats 31 — While this study does not directly answer the question of whether cardiac Ang II was formed intracellularly, increases in cardiac hAng- content and chymase immuno-reactive fluorescence are in keeping with the idea that the elevated Ang II demonstrated in the heart of these transgenic rats is from intracellular formation.
Previous studies from this laboratory did document increased Ang- uptake in neonatal cardiomyocytes from SHR 23 and internalization of mast cell released chymase in isolated adult cardiac fibroblasts through a dynamin-dependent mechanism The hemodynamic response to a 2-week treatment with valsartan is in keeping with past studies reporting a significant antihypertensive effect of the drug at the doses employed here We now show that blockade of AT 1 -R triggers an increase in plasma Ang I and Ang II concentrations in the absence of parallel elevations in rat and human levels of circulating Ang- The absence of changes in circulating Ang- may be interpreted to be related to the observation that rat renin which was significantly elevated in treated rats does not catalyze rat or human Ang- 8.
Numerous studies demonstrate an intracellular Ang II expression of local origin [see 37 for review] and consensus is emerging regarding the existence of an intracellular cardiac RAS that functions independently from the circulating RAS 28 , 38 , With both methods, a trend for reduced cardiac Ang II content did not reach statistical significance.
These data are in keeping with similar findings from previous studies where blockade of AT 1 -R failed to alter cardiac Ang II content 32 , 33 , 35 , As reviewed recently 41 — 43 , clinical trials of RAS inhibitors failed to show a large benefit in cardiac outcomes beyond what can be attributed to the blood pressure lowering effect of these drugs. This discrepancy, as noted by Kumar et al. Ang- processing into biologically active peptides is mediated by ACE in the circulation 44 and chymase in cardiac and renal tissues 10 , 20 , In keeping with previous studies, chymase has been visualized in human 46 , dog 47 , 48 , and enlarged rat myocytes from volume overload due to an aorto-caval fistula 21 , Confocal microscopy using an antibody directed to the human chymase CMA-1 demonstrated the presence of strong chymase immunofluorescence in rats expressing the human AGT gene.
The enrichment of chymase in the heart of TGR hAGT L rats coincides with the concurrent finding of high chymase activity using Ang- as a substrate Taken together with the heightened Ang II in hearts of transgenic when compared to control SDs, these findings substantiate the view that Ang forming-chymase is central to the conversion of Ang- to Ang II.
In summary, rats expressing the human AGT gene are hypertensive and are characterized by a RAS profile with higher circulating and cardiac levels of human Ang- Treatment with valsartan results in augmented concentrations of circulating Ang I and Ang II as well as increased cardiac human but not rat Ang- Both here and in the previously published study 9 the hypertension and cardiac dysfunction characterized in a humanized model of hypertension is validated through the confirmation that expression of the human AGT gene does not alter circadian blood pressure mechanisms as the more pronounced hypertension and tachycardia, observed during the night hours, reflects the augmented locomotor activity of nocturnal animals.
Moreover, we show that cardiac chymase enzymatic activity is several orders of magnitude greater than ACE or ACE activities. Given the existence of a robust vast literature dealing with chymase contribution to the pathogenesis of diseases of the heart and blood vessels 50 , 51 , controversy as to its role in mediating Ang II-derived pathology is perplexing.
Limitations in terms of experimental design, the presence of high concentrations of endogenous protease inhibitors in interstitial fluid and dismissing the fact that chymase can be sourced from either degranulation of mast cells or gene translation in myocytes, fibroblast and endothelial cells has contributed to discard this noncanonical pathway of Ang II production as a critical mechanism contributing to adverse cardiac remodeling.
The void has been further aggravated by a slow pace in the development of specific chymase inhibitors, a fact that may be finally circumvented by the promising findings of recent experimental studies 45 and a published clinical trial 52 , The datasets generated for this study are available on request to the corresponding author. CF and JVa designed the study. CF wrote the manuscript, analyzed the data, and prepared the figures.
SA and KW performed the enzymatic assays, analyzed the data and contribute to manuscript writing. Ability of Kallikrein to generate angiotensin II-like pressor substance and a proposed kinin-angiotensin enzyme system.
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Jpn Heart J ; Differences in tissue angiotensin II-forming pathways by species and organs in vitro. Angiotensin II is a very powerful hormone that can act directly on blood vessels, causing them to become narrow, or constrict, to increase blood pressure.
It has another important function as well—stimulating the release of aldosterone. Aldosterone is a hormone that helps increase blood pressure by causing the kidneys to retain both salt and water, which over time increases the amount of fluid in the body. This increase, in turn, raises blood pressure. Aside from the blood vessels, angiotensin II can also bind to receptors located in different areas of the body.
It regulates blood pressure by sending messages to the brain and the kidneys to help raise blood pressure.
Angiotensin II stimulates an area in the brain called the "thirst center" to help increase blood pressure. This thirst center is located in a part of the brain called the hypothalamus. When the thirst center is told by angiotensin II that the blood pressure is too low, it creates a sensation of thirst. Drinking water, then, increases the fluid volume in the body and raises blood pressure.
Angiotensin II also stimulates the body's " fight-or-flight response " to help increase blood pressure. This response, which is usually activated during stressful situations, causes the heart to pump more quickly and forcefully to increase the circulating volume and the blood pressure.
Thirst is not the only message from the brain in response to low blood pressure. Angiotensin II also tells the hypothalamus to increase the production of a protein called antidiuretic hormone. This hormone travels from the brain to the kidneys and tells the kidneys to reabsorb water from the urine.
Angiotensin II also acts directly on the kidneys to further help increase blood pressure and blood flow by telling the kidneys to:. As a long-term regulator of blood pressure, the classical RAS pathway has a constant baseline level of activity, and actually works much like the gas pedal of a car. Constant pressure on the gas pedal is required to keep the car moving forward, even when you just want to go at the same speed.
If you need to, though, you can press the pedal down suddenly in order to quickly speed up. Likewise, constant activity in the classical RAS pathway keeps blood pressure steady over the long term, but sudden bursts of action are possible when a quick response is required.
The classical RAS pathway is known to be an important factor in heart disease. One heart disease that is common in the United States is chronic high blood pressure, also known as hypertension.
Some people with hypertension have no identifiable cause. This is referred to as primary, or essential, hypertension. Other people have hypertension due to secondary causes. Secondary hypertension can be caused by hormonal imbalances in the classical RAS pathway. For example, a tumor in the adrenal gland can release excessive amounts of aldosterone and lead to fluid retention and high blood pressure.
Many scientific papers, conference presentations, and textbooks have been written about the importance of the classical RAS pathway in blood pressure regulation. This is an area of research still being pursued by scientists more than 50 years after the discovery of the system. The details of the renin-angiotensin-aldosterone system continue to be investigated and could help us further understand:.
For example, Black patients with high blood pressure often don't respond as well to ACE inhibitors as to other medicines. This is likely because African-Americans have a different level of activity in their renin-angiotensin-aldosterone system, which makes them less sensitive to drugs that work by blocking the system.
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