Inactivation of substance P and its C-terminal fragments in rat plasma and its inhibition by Captopril

1981 ◽  
Vol 59 (6) ◽  
pp. 621-625 ◽  
Author(s):  
R. Couture ◽  
D. Regoli
Keyword(s):  
Substance P ◽  
Guinea Pig ◽  
Angiotensin Converting Enzyme ◽  
Free Acid ◽  
Biological Activities ◽  
Peptide Bond ◽  
Rat Plasma ◽  
Converting Enzyme ◽  
Metabolic Degradation

The metabolic degradation of substance P(SP), some of its C-terminal fragments, and some analogues by rat plasma has been evaluated from the disappearance of the biological activities of these peptides on the guinea pig isolated ileum. The experiments were performed by dissolving each peptide in saline and by adding 20% (v/v) of rat plasma for incubation at 37 °C for various periods of time.It was found that SP and octapeptide 4–11 are inactivated quite rapidly and at approximately the same rate whereas SP-free acid, heptapeptide 5–11, hexapeptide 6–11, and [D-Trp8]-SP are inactivated more slowly. The replacement of Phe7 by D-Trp does not protect the undecapeptide SP from inactivation.The degradation of SP and of all the C-terminal fragments was completely blocked by Captopril at a concentration of 10 μg/mL of plasma. Under these conditions, Captopril also slightly reduced the rate of inactivation of bradykinin and of SP-free acid.These results were interpreted as indicative of the presence in rat plasma of an endopeptidase that hydrolyses a peptide bond in the C-terminal pentapeptide sequence of SP. This endopeptidase is completely inactivated by Captopril, which thus appears to be not as specific for the angiotensin-converting enzyme as it was thought to be.

Structure–activity studies on substance P

1979 ◽  
Vol 57 (12) ◽  
pp. 1427-1436 ◽  
Author(s):  
R. Couture ◽  
A. Fournier ◽  
J. Magnan ◽  
S. St-Pierre ◽  
D. Regoli
Keyword(s):  
Blood Pressure ◽  
Substance P ◽  
Guinea Pig ◽  
Free Acid ◽  
Biological Activities ◽  
Intrinsic Activity ◽  
Guinea Pig Ileum ◽  
Rat Blood ◽  
Mesenteric Vein ◽  
Structure Activity

A complete series of analogues of substance P (SP) in which L-Ala was used to replace the natural residues one by one, and the C-terminal free acid SP, were synthesized and tested in order to study the relationships between chemical structure and biological activities. All compounds were tested for their hypotensive effect on the rat blood pressure and for their myotropic activities on the guinea pig ileum, the rabbit anterior mesenteric vein, and the rat vas deferens.The results indicate that the first five residues from the amino end and Gly9 can be replaced by L-Ala without change of hypotensive or myotropic activities, but the substitution of the residues from the carboxyl end (Met11, Leu10, Phe8, and Phe7) with L-Ala brings about variable losses of affinity. All analogues maintain full intrinsic activity in the guinea pig ileum; [Ala10]-SP and [Ala11]-SP maintain more than 80% of intrinsic activity in the mesenteric vein, the other analogues being full agonists; moreover, [Ala7]-SP and [Ala 8]-SP show a weaker hypotensive potency than all other compounds. The effect of SP is not modified by an inhibitor of the converting enzyme (YS 980), but that of SP free acid is either potentiated (rabbit mesenteric vein, rat vas deferens) or not modified (rat blood pressure, guinea pig ileum).The findings presented in this paper are discussed in terms of structure–activity relationships. However, no clear indication has emerged as to the identity of the active group(s) or on a possible distinction between the molecular sequences or groups involved in binding or in stimulation of receptors by SP.

scholarly journals Novel activity of angiotensin-converting enzyme. Hydrolysis of cholecystokinin and gastrin analogues with release of the amidated C-terminal dipeptide

1989 ◽  
Vol 262 (1) ◽  
pp. 125-130 ◽  
Author(s):  
P Dubreuil ◽  
P Fulcrand ◽  
M Rodriguez ◽  
H Fulcrand ◽  
J Laur ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Chloride Ion ◽  
Peptide Bond ◽  
Major Product ◽  
Enzyme Hydrolysis ◽  
Ion Concentration ◽  
Converting Enzyme ◽  
Rabbit Lung ◽  
Hydrolysis Of

ACE (angiotensin-converting enzyme; peptidyl dipeptidase A; EC 3.4.15.1), cleaves C-terminal dipeptides from active peptides containing a free C-terminus. We investigated the hydrolysis of cholecystokinin-8 [CCK-8; Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2] and of various gastrin analogues by purified rabbit lung ACE. Although these peptides are amidated at their C-terminal end, they were metabolized by ACE to several peptide fragments. These fragments were analysed by h.p.l.c., isolated and identified by comparison with synthetic fragments, and by amino acid analysis. The initial and major site of hydrolysis was the penultimate peptide bond, which generated a major product, the C-terminal amidated dipeptide Asp-Phe-NH2. As a secondary cleavage, ACE subsequently released di- or tri-peptides from the C-terminal end of the remaining N-terminal fragments. The cleavage of CCK-8 and gastrin analogues was inhibited by ACE inhibitors (Captopril and EDTA), but not by other enzyme inhibitors (phosphoramidon, thiorphan, bestatin etc.). Hydrolysis of [Leu15]gastrin-(14-17)-peptide [Boc (t-butoxycarbonyl)-Trp-Leu-Asp-Phe-NH2] in the presence of ACE was found to be dependent on the chloride-ion concentration. Km values for the hydrolysis of CCK-8, [Leu15]gastrin-(11-17)-peptide and Boc-[Leu15]gastrin-(14-17)-peptide at an NaCl concentration of 300 mM were respectively 115, 420 and 3280 microM, and the catalytic constants were about 33, 115 and 885 min-1. The kcat/Km for the reactions at 37 degrees C was approx. 0.28 microM-1.min-1, which is approx. 35 times less than that reported for the cleavage of angiotensin I. These results suggest that ACE might be involved in the metabolism in vivo of CCK and gastrin short fragments.

Inhibition of canine lung angiotensin converting enzyme by substance P

1982 ◽  
Vol 86 (2) ◽  
pp. 275-277 ◽  
Author(s):  
Pritam S. Verma ◽  
Richard G. Adams ◽  
Russell L. Miller
Keyword(s):  
Substance P ◽  
Angiotensin Converting Enzyme ◽  
Converting Enzyme

scholarly journals Substance P Increases Sympathetic Activity During Combined Angiotensin-Converting Enzyme and Dipeptidyl Peptidase-4 Inhibition

Hypertension ◽  
2014 ◽  
Vol 63 (5) ◽  
pp. 951-957 ◽  
Author(s):  
Jessica K. Devin ◽  
Mias Pretorius ◽  
Hui Nian ◽  
Chang Yu ◽  
Frederic T. Billings ◽  
...  
Keyword(s):  
Substance P ◽  
Angiotensin Converting Enzyme ◽  
Sympathetic Activity ◽  
Dipeptidyl Peptidase ◽  
Converting Enzyme ◽  
Dipeptidyl Peptidase 4
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