Converting enzyme inhibition and blood pressure regulation

1976 ◽  
Vol 6 (4) ◽  
pp. 538-542 ◽  
Author(s):  
A. Clifford Barger
Keyword(s):  
Blood Pressure ◽  
Enzyme Inhibition ◽  
Blood Pressure Regulation ◽  
Pressure Regulation ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibition

Brain angiotensin receptors and sympathoadrenal regulation during insulin-induced hypoglycemia

2001 ◽  
Vol 280 (4) ◽  
pp. R1162-R1168 ◽  
Author(s):  
René H. Worck ◽  
Dennis Staahltoft ◽  
Thomas E. N. Jonassen ◽  
Erik Frandsen ◽  
Hans Ibsen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Enzyme Inhibition ◽  
Blood Pressure Response ◽  
Pressure Response ◽  
Angiotensin Receptors ◽  
Converting Enzyme ◽  
Reflex Regulation ◽  
Conscious Rats ◽  
Converting Enzyme Inhibition

Simultaneous blockade of systemic AT1 and AT2 receptors or converting enzyme inhibition (CEI) attenuates the hypoglycemia-induced reflex increase of epinephrine (Epi). To examine the role of brain AT1 and AT2 receptors in the reflex regulation of Epi release, we measured catecholamines, hemodynamics, and renin during insulin-induced hypoglycemia in conscious rats pretreated intracerebroventricularly with losartan, PD-123319, losartan and PD-123319, or vehicle. Epi and norepinephrine (NE) increased 60-and 3-fold, respectively. However, the gain of the reflex increase in plasma Epi (Δplasma Epi/Δplasma glucose) and the overall Epi and NE responses were similar in all groups. The ensuing blood pressure response was similar between groups, but the corresponding bradycardia was augmented after PD-123319 ( P < 0.05 vs. vehicle) or combined losartan and PD-123319 ( P < 0.01 vs. vehicle). The findings indicate 1) brain angiotensin receptors are not essential for the reflex regulation of Epi release during hypoglycemia and 2) the gain of baroreceptor-mediated bradycardia is increased by blockade of brain AT2 receptors in this model.

scholarly journals Novel mechanism of inhibition of human angiotensin-I-converting enzyme (ACE) by a highly specific phosphinic tripeptide

2011 ◽  
Vol 436 (1) ◽  
pp. 53-59 ◽  
Author(s):  
Mohd Akif ◽  
Sylva L. Schwager ◽  
Colin S. Anthony ◽  
Bertrand Czarny ◽  
Fabrice Beau ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Active Site ◽  
Phenyl Group ◽  
Blood Pressure Regulation ◽  
Pressure Regulation ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Structural Determinants ◽  
Dual Inhibitor ◽  
Angiotensin I Converting Enzyme

Human ACE (angiotensin-I-converting enzyme) has long been regarded as an excellent target for the treatment of hypertension and related cardiovascular diseases. Highly potent inhibitors have been developed and are extensively used in the clinic. To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zinc metallopeptidase (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and ECE-1 (endothelin-converting enzyme-1). In the present paper, we show the first structures of testis ACE [C-ACE, which is identical with the C-domain of somatic ACE and the dominant domain responsible for blood pressure regulation, at 1.97Å (1 Å=0.1 nm)] and the N-domain of somatic ACE (N-ACE, at 2.15Å) in complex with a highly potent and selective dual ACE/ECE-1 inhibitor. The structural determinants revealed unique features of the binding of two molecules of the dual inhibitor in the active site of C-ACE. In both structures, the first molecule is positioned in the obligatory binding site and has a bulky bicyclic P1′ residue with the unusual R configuration which, surprisingly, is accommodated by the large S2′ pocket. In the C-ACE complex, the isoxazole phenyl group of the second molecule makes strong pi–pi stacking interactions with the amino benzoyl group of the first molecule locking them in a ‘hand-shake’ conformation. These features, for the first time, highlight the unusual architecture and flexibility of the active site of C-ACE, which could be further utilized for structure-based design of new C-ACE or vasopeptidase inhibitors.

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