Dual ECE/NEP Inhibition on Cardiac and Neurohumoral Function During the Transition From Hypertrophy to Heart Failure in Rats

Abstract

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.

Antihypertensive effects of Ocimum basilicum L. (OBL) on blood pressure in renovascular hypertensive rats

“…Experimentally, the effects of ET inhibitors has been less convincing, with little effect on blood pressure, and variegated effects on hypertrophy, fibrosis or remodeling, depending probably on the models used. 15 ET-converting enzyme inhibitors, which oppose the production of ET, reduce cardiac remodeling and hypertrophy in animal models of heart failure 16 and in hypertension 17 to a greater degree than ACE inhibitors. 17 OBL also has an effect on platelets and lipid metabolism, but whether this could be related to possible inhibition of ET is unclear.…”

“…15 ET-converting enzyme inhibitors, which oppose the production of ET, reduce cardiac remodeling and hypertrophy in animal models of heart failure 16 and in hypertension 17 to a greater degree than ACE inhibitors. 17 OBL also has an effect on platelets and lipid metabolism, but whether this could be related to possible inhibition of ET is unclear. The effects of ET antagonists or convertase inhibitors on platelet function are ambiguous, possibly related to the opposite effects of endothelin-A and endothelin-B receptors.…”

Dual inhibition: a novel promising pharmacological approach for different disease conditions

“…Dual monoamine oxidase B inhibitors and adenosine A2A receptor antagonists Methylxanthines [26] and (E,E)-8-(4-phenylbutadien-1-yl)caffeine [27] Inflammation Dual cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) inhibitors Flavocoxid [28] and ML3000 (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-H-pyrrolizine-5-yl) acetic acid [29] Hypertension Dual inhibitors of neprilysin and angiotensin-converting enzyme BMS-182657, [30] MDL-100173 [31] and S21402 (RB105) {N-[2S,3R-(2-mercaptomethyl-1-oxo-3-phenylbutyl)-l-alanine]} [32] Dual inhibitors of the angiotensin II receptor and neprilysin LCZ696 [33] Dual inhibitors of angiotensin-converting and endothelin-converting enzymes CGS 26303 [34] and SLV 306 (Daglutril) [35] Dual vasopressin receptor (V1/V2) antagonists (RWJ-676070) [36] Thrombosis Dual-acting anticoagulant/antiplatelet inhibitors MC45301, MC45308, MC45350, and MC45403 derived from vitamin B6 (pyridoxine) [37] Microbial infections Dual inhibitors of type I and type II DNA topoisomerases Some novel indolyl quinoline analogs [38] Dual inhibitors of b-ketoacyl-[acyl carrier protein (ACP)] synthase II (FabF) and III (FabH) Platencin [39] Viral infections Dual inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase and RNase H Madurahydroxylactone derivatives [40] Dual inhibitors of 2A and 3C proteases encoded by human rhinoviruses (HRVs) LY343814 [41] Cancer Dual PI3K and mTOR inhibitors PI-103, [42] NVP-BEZ235, [43] WJD008 [44] and BAG956 [45] Dual topoisomerases I and II inhibitors Benzophenanthridine alkaloids, indolocarbazoles and lipophilic bis(naphthalimides), anthraquinones, pyridoindoles, indenoquinolones, acridines, TAS-103, leptosins (Leps) F and C, tafluposide (F 11782) and XR11576 [46][47][48][49][50] Dual inhibitors of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 NVP-AEE788 [51] Dual inhibitors of IkappaB kinase-2 (IKK2) and Fms-like tyrosine kinase 3 (FLT3) AS602868 [52] The new hybrids retain the potent and selective human AChEinhibitory activity of the parent 6-chlorotacrine, while exhibiting a significant in-vitr...…”

Dual Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibition

“…Furthermore, in this model of left ventricular hypertrophy and congestive heart failure, the benefits of dual ECE/NEP inhibition are thought in part to relate to a greater reduction in plasma ET-1 compared with RAS blockade alone. 15 The significant benefits of ECE/NEP inhibition in the absence of a BP response are very interesting. This likely relates to the nature of the 2K1C model, because other animal models treated with ECE/NEP inhibition show a fall in BP similar to that achieved with RAS inhibition.…”

“…This likely relates to the nature of the 2K1C model, because other animal models treated with ECE/NEP inhibition show a fall in BP similar to that achieved with RAS inhibition. 14,15 The Goldblatt model is one of RAS overactivity, and so to reduce BP effectively a greater degree of RAS inhibition is probably required than that achievable with ECE/NEP inhibition alone. It does leave us with the intriguing question: what is the mechanism for the cardioprotection seen with SLV388 if not BP lowering?…”