title: Dual ECE/NEP inhibition on cardiac and neurohumoral function during the transition from hypertrophy to heart failure in rats.
abstract: CGS 26303 is a vasopeptidase inhibitor that simultaneously inhibits endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). We compared the effects of chronic treatment with CGS 26303 to the selective inhibition of angiotensin-converting enzyme (ACE) and NEP during the transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF) in hypertensive rats. LV geometry and function were assessed in Dahl salt-sensitive rats placed on a high-salt diet from age 6 weeks (hypertensive rats) and in control rats fed a low-salt diet. The hypertensive rats were randomized into groups that received no treatment or were treated with an ACE inhibitor (temocapril), an ECE/NEP inhibitor (CGS 26303), or a NEP inhibitor (CGS 24592) from the LVH stage (11 weeks) to the CHF stage (17 weeks). All treatments decreased the systolic blood pressure equally and significantly improved LV fractional shortening. Both temocapril and CGS 26303 ameliorated LV perivascular fibrosis, reduced mRNA levels of types I and III collagen, and decreased the heart weight/body weight ratio. CHF rats had increased plasma ET-1 levels compared with control rats. Only CGS 26303 reduced ET-1 to normal levels. ET-1 levels were found to correlate with heart/body weight, right ventricle/body weight and perivascular fibrosis ratios. During the transition to CHF, CGS 26303 produces effects that are comparable to temocapril and superior to CGS 24592. The beneficial effects of CGS 26303 are likely caused in part by the greater reduction of plasma ET-1. Dual ECE/NEP inhibitor may provide a new strategy for the treatment of human heart failure.
authors.affiliation: Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki, Chuo, Kobe, 650-0017, Japan. emoto@med.kobe-u.ac.jp
authors.forename: Noriaki
authors.initials: N
authors.lastname: Emoto
authors.forename: Sunu Budhi
authors.initials: SB
authors.lastname: Raharjo
authors.forename: Daiji
authors.initials: D
authors.lastname: Isaka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Masuda
authors.forename: Suko
authors.initials: S
authors.lastname: Adiarto
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokoyama
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002303:Cardiac Output, Low / Q000209:etiology*; D006332:Cardiomegaly / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology*; D003094:Collagen / Q000235:genetics; D004452:Echocardiography; D019332:Endothelin-1 / Q000235:genetics; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D018377:Neurotransmitter Agents / Q000097:blood / Q000378:metabolism*; D063065:Organophosphonates / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D013777:Tetrazoles / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; C086164:CGS 24592; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D018377:Neurotransmitter Agents; D063065:Organophosphonates; D012333:RNA, Messenger; D013777:Tetrazoles; D013841:Thiazepines; C089987:CGS 26303; D010649:Phenylalanine; D009320:Atrial Natriuretic Factor; C055603:temocapril hydrochloride; D003094:Collagen; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes