Radioligand binding reveals chymase as the predominant enzyme for mediating tissue conversion of angiotensin I in the normal human heart

2001 ◽  
Vol 102 (1) ◽  
pp. 15-21 ◽  
Author(s):  
Sidath D. KATUGAMPOLA ◽  
Anthony P. DAVENPORT
Keyword(s):  
Angiotensin Ii ◽  
Left Ventricle ◽  
Human Heart ◽  
Radioligand Binding ◽  
At1 Receptor ◽  
Cathepsin G ◽  
At2 Receptor ◽  
Angiotensin I ◽  
Human Left Ventricle ◽  
Angiotensin Type

We investigated the binding characteristics of angiotensin receptors and used this assay to determine the predominant enzyme capable of converting angiotensin I in the human left ventricle. In homogenates of human left ventricle, 125I-[Sar1,Ile8]angiotensin II bound with sub-nanomolar affinity, with a corresponding KD of 0.42±0.09nM, a Bmax of 11.2±2.3fmolċmg-1 protein and a Hill slope of 1.04±0.04. The rank order of inhibitory potency of competing ligands for the 125I-[Sar1,Ile8]angiotensin II binding site was CGP42112 > angiotensin II⩾ angiotensin III = angiotensin I > losartan. The angiotensin type II (AT2) receptor predominated in the human left ventricle over the angiotensin type I (AT1) receptor, with an approximate AT1/AT2 receptor ratio of 35:65. No specific 125I-angiotensin IV binding sites could be detected in the human left ventricle. Using competitive radioligand binding assays, we were able to demonstrate that the chymase/cathepsin G enzyme inhibitor chymostatin was more potent than the angiotensin-converting enzyme (ACE) inhibitor captopril at inhibiting the conversion of angiotensin I in the human left ventricle. Aprotonin (an inhibitor of cathepsin G but of not chymase) had no effect on angiotensin I conversion, suggesting that the majority of the conversion was mediated by chymase. Thus, although the current therapies used for the renin-angiotensin system have focused on ACE inhibitors and AT1 receptor antagonists, the left ventricle of the human heart expresses mainly AT2 receptors and the tissue-specific conversion of angiotensin I occurs predominantly via chymase rather than ACE.

scholarly journals Angiotensin II Dilates Bovine Adrenal Cortical Arterioles: Role of Endothelial Nitric Oxide

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3319-3324 ◽  
Author(s):  
Kathryn M. Gauthier ◽  
David X. Zhang ◽  
Erik M. Edwards ◽  
Blythe Holmes ◽  
William B. Campbell
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Receptor Activation ◽  
At1 Receptor ◽  
Internal Diameter ◽  
No Production ◽  
At2 Receptor ◽  
Angiotensin Type

Abstract Adrenal steroidogenesis is modulated by humoral and neuronal factors and blood flow. Angiotensin II (AII) stimulates adrenal cortical aldosterone and cortisol production and medullary catecholamine release. However, AII regulation of adrenal vascular tone has not been characterized. We examined the effect of AII on diameters of cannulated bovine adrenal cortical arteries. Cortical arteries (average internal diameter = 230 μm) were constricted with U46619 and concentration-diameter responses to AII (10−13 to 10−8 mol/liter) were measured. In endothelium-intact arteries, AII induced dilations at low concentrations (maximum dilation = 25 ± 6% at 10−10 mol/liter) and constrictions at high concentrations (maximum constriction = 25 ± 18% at 10−8 mol/liter). AII constrictions were blocked by the angiotensin type 1 (AT1) receptor antagonist, losartan (10−6 mol/liter). AII dilations were enhanced by losartan (maximal dilation = 48 ± 8%), abolished by endothelial cell removal or N-nitro-l-arginine (L-NA, 3 × 10−5 mol/liter) and inhibited by the angiotensin type 2 (AT2) receptor antagonist, PD123319 (10−6 mol/liter, maximal dilation = 18 ± 4%). In a 4,5-diaminofluorescein diacetate nitric oxide (NO) assay of isolated cortical arteries, AII stimulated NO production, which was abolished by PD123319, L-NA, or endothelial cell removal. Western immunoblot of arterial homogenates and endothelial and zona glomerulosa cell lysates revealed 48-kD and 50-kD bands corresponding to AT1 and AT2 receptors, respectively, in all three and a 140-kD band corresponding to endothelial NO synthase in endothelial cells and arteries. Our results demonstrate that AII stimulates adrenal cortical arterial dilation through endothelial cell AT2 receptor activation and NO release and AT1 receptor-dependent constriction.

scholarly journals Intracrine angiotensin II functions originate from noncanonical pathways in the human heart

2016 ◽  
Vol 311 (2) ◽  
pp. H404-H414 ◽  
Author(s):  
Carlos M. Ferrario ◽  
Sarfaraz Ahmad ◽  
Jasmina Varagic ◽  
Che Ping Cheng ◽  
Leanne Groban ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Functional Significance ◽  
Vascular Remodeling ◽  
Human Heart ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Extended Form ◽  
Angiotensin I ◽  
Angiotensin System ◽  
Ras Genes

Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1–12) [Ang-(1–12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1–12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions.

scholarly journals Interaction between Angiotensin Type 1, Type 2, and Mas Receptors to Regulate Adult Neurogenesis in the Brain Ventricular–Subventricular Zone

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1551 ◽  
Author(s):  
Maria Garcia-Garrote ◽  
Ana Perez-Villalba ◽  
Pablo Garrido-Gil ◽  
German Belenguer ◽  
Juan A. Parga ◽  
...  
Keyword(s):  
Adult Neurogenesis ◽  
Subventricular Zone ◽  
Functional Dependence ◽  
Renin Angiotensin System ◽  
At1 Receptor ◽  
Receptor Expression ◽  
At2 Receptor ◽  
Angiotensin Type

The renin–angiotensin system (RAS), and particularly its angiotensin type-2 receptors (AT2), have been classically involved in processes of cell proliferation and maturation during development. However, the potential role of RAS in adult neurogenesis in the ventricular-subventricular zone (V-SVZ) and its aging-related alterations have not been investigated. In the present study, we analyzed the role of major RAS receptors on neurogenesis in the V-SVZ of adult mice and rats. In mice, we showed that the increase in proliferation of cells in this neurogenic niche was induced by activation of AT2 receptors but depended partially on the AT2-dependent antagonism of AT1 receptor expression, which restricted proliferation. Furthermore, we observed a functional dependence of AT2 receptor actions on Mas receptors. In rats, where the levels of the AT1 relative to those of AT2 receptor are much lower, pharmacological inhibition of the AT1 receptor alone was sufficient in increasing AT2 receptor levels and proliferation in the V-SVZ. Our data revealed that interactions between RAS receptors play a major role in the regulation of V-SVZ neurogenesis, particularly in proliferation, generation of neuroblasts, and migration to the olfactory bulb, both in young and aged brains, and suggest potential beneficial effects of RAS modulators on neurogenesis.

scholarly journals The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer.

1995 ◽  
Vol 92 (23) ◽  
pp. 10663-10667 ◽  
Author(s):  
M. Nakajima ◽  
H. G. Hutchinson ◽  
M. Fujinaga ◽  
W. Hayashida ◽  
R. Morishita ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Gene Transfer ◽  
At1 Receptor ◽  
At2 Receptor ◽  
Gain Of Function ◽  
Growth Effects ◽  
Function Study

Analysis of responses to angiotensin peptides in the hindquarters vascular bed of the cat

1995 ◽  
Vol 268 (6) ◽  
pp. H2418-H2425
Author(s):  
E. A. Garrison ◽  
J. A. Santiago ◽  
S. Y. Osei ◽  
P. J. Kadowitz
Keyword(s):  
Angiotensin Ii ◽  
Perfusion Pressure ◽  
Enzyme Inhibitor ◽  
Similar Efficacy ◽  
At1 Receptor ◽  
Angiotensin I ◽  
Response Curves ◽  
Angiotensin Iv ◽  
Angiotensin Peptides ◽  
Vascular Bed

Responses to angiotensin I, II, III, and IV, des-Asp1-angiotensin I, and (p-amino-Phe6)-angiotensin II were compared in the hindquarters vascular bed of the cat. The peptides produced dose-related increases in perfusion pressure, and dose-response curves to all six peptides were parallel. Des-Asp1-angiotensin I, angiotensin I, II, and III produced similar increases in perfusion pressure and were approximately 300-fold more potent than (p-amino-Phe6)-angiotensin II, 100-fold more potent than angiotensin IV, 30-fold more potent than norepinephrine, and 10-fold more potent than U-46619. The time courses of the response to des-Asp1-angiotensin I, angiotensin I, II, and III were similar, and responses were not altered by a time-delay coil. DuP-532, an AT1 receptor antagonist, reduced responses to the six angiotensin peptides. PD-123,319 did not alter responses to the angiotensin peptides. The angiotensin-converting enzyme inhibitor captopril reduced responses to angiotensin I and des-Asp1-angiotensin I. These results show that des-Asp1-angiotensin I as well as angiotensin I, II, III, and IV have similar efficacy and that responses to the peptides and (p-amino-Phe6)-angiotensin II are mediated by AT1 receptors. These results suggest that AT2 receptors have little role in modulating responses and that angiotensin IV has a lower affinity for the AT1 receptor than does angiotensin II or III. The results also indicate that complete rapid local conversion of the substrates into active peptides occurs near the site of action within the hindquarters vascular bed.

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