Triple vasopeptidase inhibition normalizes blood pressure in conscious, unrestrained, and spontaneously hypertensive rats.
BACKGROUND
CGS 35601 is a potent triple vasopeptidase inhibitor (VPI) of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin-converting enzyme (ECE). The aim of the study was to determine the effects of this VPI on the hemodynamic profile of conscious, instrumented, unrestrained spontaneously hypertensive rats (SHR), in comparison to selective inhibitors of ACE and ACE + NEP, than +ECE combined. Circulating plasma concentrations of vasoactive mediators and reactive oxygen species were measured.


METHODS
Old SHR male were instrumented (arterial catheter) and placed in a metabolic cage for daily hemodynamic measurements and blood samplings. Seven days after surgery, SHR received 1) saline vehicle; 2) increasing doses of the triple CGS 35601 (0.01, 0.1, 1, and 5 mg/kg/d, intra-arterially (i.a.) infusion for 5 d/dose) followed by a 5-day washout period; 3) benazepril (ACE inhibitor), ACE inhibitor + CGS 24592 (NEP inhibitor) and ACE inhibitor + NEP inhibitor + CGS 35066 (ECE inhibitor) (1 or 5 mg/kg/d i.a. infusion for 5 d/combination) followed by a 5-day washout period.


RESULTS
The lowest dose of CGS 35601 had no effect. Doses at 0.1, 1, and 5 mg/kg/d reduced mean arterial blood pressure by 10%, 22%, and 40%, respectively. Heart rate was unaffected in all groups. CGS 35601 decreased concentrations of angiotensin II (Ang II), endothelin-1 (ET-1), and pro-atrial natriuretic peptide (proANP), and increased those of big ET-1, atrial natriuretic peptide (ANP), bradykinin (BK), and hydrogen peroxide (H2O2) dose dependently.


CONCLUSIONS
The blood pressure-lowering effect of this triple VPI was superior to that of the other VPI in this preclinical rat model of hypertension. Further experiments are needed to assess triple VPI to other combinations in other models with regard to efficacy and angioedema. Only then it may constitute a first-in-class approach for the treatment of hypertension and other cardiovascular disorders.
Daull
Philippe
P
Laval Hospital Research Center, Quebec Heart and Lung Institute, Department of Medicine, Laval University, Ste-Foy, QC, Canada.
Benrezzak
Ouhida
O
Arsenault
Dominique
D
Pheng
Leng Hong
LH
Blouin
André
A
Cayer
Julie
J
Beaudoin
Myriam
M
Belleville
Karine
K
Sirois
Pierre
P
Nantel
François
F
Jeng
Arco Y
AY
Battistini
Bruno
B
D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D009320:Atrial Natriuretic Factor / Q000097:blood; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000097:blood; D000072396:Endothelin-Converting Enzymes; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D015260:Neprilysin / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000378:metabolism; D063065:Organophosphonates / Q000008:administration & dosage / Q000494:pharmacology; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D001572:Benzofurans; C086164:CGS 24592; C404932:CGS 35066; C511403:CGS 35601; D019332:Endothelin-1; D007211:Indoles; D063065:Organophosphonates; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D009569:Nitric Oxide; D010649:Phenylalanine; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes; C044946:benazepril