Blood Pressure Lowering Activity Research Articles

MANP: a novel particulate guanylyl cyclase A receptor/cGMP activator for resistant hypertension: preliminary first in human clinical trial results

MANP is a novel natriuretic peptide developed at the Mayo Clinic following its discovery from a familial frameshift mutation of the atrial natriuretic peptide (ANP) gene (NPPA) [1,2]. MANP possesses the 28 amino acid (AA) core structure of ANP with a novel 12 AA extended C-terminus resulting in a 40 AA peptide. MANP activates the particulate guanylyl cyclase A (pGC-A) receptor with equal potency to ANP and is highly resistant to degradation by neprilysin. In vivo, MANP has greater and longer lasting blood pressure (BP) lowering, natriuretic and aldosterone suppressing actions than ANP [3]. In animal models of hypertension, MANP potently reduces BP and enhances renal function while in experimental hypertensive heart failure, MANP has more potent renal and aldosterone suppressing actions than the cyclic guanylyl monophosphate (cGMP)-activating therapeutic agent nitroglycerin [4]. In vivo administered subcutaneously, MANP activates plasma cGMP 10-fold greater than ANP with a 4-fold greater half-life [3,4]. Based upon its potent cGMP mediated cardiorenal actions and studies which suggest that human hypertension may represent a relative natriuretic peptide deficiency state, MANP is being developed for treatment of severe resistant hypertension.

A new monoterpene glucoside and complete assignments of dihydroflavonols of Pulicaria jaubertii: potential cytotoxic and blood pressure lowering activity

One new monoterpene glucoside and five dihydroflavonols were isolated for the first time from the aerial parts of Pulicaria jaubertii and identified as p-menthane-2-O-β-D-glucopyranoside [1], dihydroquercetin (taxifolin) [2], 7,3′-di-O-methyltaxifolin [3], 3′-O-methyltaxifolin [4], 7-O-methyltaxifolin (padmatin) [5] and 7-O-methyl-dihydrokampferol (7-O-methylaromadenderin) [6]. The structures of these compounds were unambiguously assigned on the basis of NMR spectroscopic data (1H, 13C, DEPT, HSQC, HMBC) and MS analysis. 2D-NMR methods required revision of assignments of H-6 and H-8 for dihydroflavonol compounds. Possible cytotoxic activity as well as blood pressure (BP) lowering activity were tested. The alcoholic extract showed cytotoxic activity against prostate carcinoma (PC-3), breast carcinoma (MCF-7) and hepatocellular carcinoma (HepG-2) human cell lines with IC50 19.1, 20.0 and 24.1 μg, respectively. The higher dose levels of the alcoholic extract significantly reduced normal BP of rats in a dose-dependent manner.

Effects of Add-on Therapy Consisting of a Selective Mineralocorticoid Receptor Blocker on Arterial Stiffness in Patients with Uncontrolled Hypertension.

Aldosterone plays an important role in the pathogenesis of atherosclerosis; however, the significance of mineralocorticoid receptor blockade for atherosclerosis has not been fully elucidated. In this study, the effect of add-on eplerenone on the degree of arterial stiffness was examined in patients with uncontrolled hypertension. Forty-seven uncontrolled hypertensive patients who had previously been treated with anti-hypertensive drugs were examined retrospectively. Thirty-two patients received add-on therapy consisting of eplerenone (Group E) and 15 patients received add-on therapy with a Calcium channel blocker (CCB) or an increased dose of CCB (Group C) in addition to their baseline medications. Both the systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were significantly decreased at two and 12 months in Group C. In contrast, neither the SBP nor DBP values were significantly changed at two months and eventually decreased at 12 months in Group E. The degree of arterial stiffness, as evaluated according to the cardio-ankle vascular index (CAVI), did not improve at either two or 12 months in Group C, whereas the CAVI values improved as early as at two months and the improvement was sustained at 12 months in Group E. The extent of change in the CAVI was not associated with the level of changes in the SBP or DBP values in Group E. Treatment with eplerenone added to the patient's baseline medications improves the degree of arterial stiffness as early as at two months after the beginning of treatment, independent of the blood pressure-lowering actions of these drugs in patients with uncontrolled hypertension.

Protective role of dairy and its constituents on vascular function independent of blood pressure-lowering activities.

Greater intakes of dairy are frequently associated with reduced risk of cardiovascular disease. These observational studies have served as the basis for controlled interventions aimed at defining the cardioprotective mechanisms of dairy. Understanding these relationships is of public health importance because most of the US population fails to meet dietary recommendations for dairy, suggesting that many individuals could lower their cardiovascular disease risk by relatively simple dietary modification. Clinical studies investigating the acute ingestion of dairy or its constituents, including short-term (≤2 week) supplementation studies or those assessing postprandial responses, have largely shown benefits on vascular function without concomitant improvements in blood pressure. Chronic interventions have been less conclusive, with some showing benefits and others indicating a lack of improvement in vascular function regardless of blood pressure changes. Vasoprotective activities of dairy are likely mediated through improvements in nitric oxide bioavailability, oxidative stress, inflammation, and insulin resistance. Future controlled studies are needed to determine if these health benefits are mediated directly by dairy or indirectly by displacing other dietary components that otherwise impair vascular health.

Protein kinase G Iα oxidation paradoxically underlies blood pressure lowering by the reductant hydrogen sulfide.

Dysregulated blood pressure control leading to hypertension is prevalent and is a risk factor for several common diseases. Fully understanding blood pressure regulation offers the possibility of developing rationale therapies to alleviate hypertension and associated disease risks. Although hydrogen sulfide (H2S) is a well-established endogenous vasodilator, the molecular basis of its blood-pressure lowering action is incompletely understood. H2S-dependent vasodilation and blood pressure lowering in vivo was mediated by it catalyzing formation of an activating interprotein disulfide within protein kinase G (PKG) Iα. However, this oxidative activation of PKG Iα is counterintuitive because H2S is a thiol-reducing molecule that breaks disulfides, and so it is not generally anticipated to induce their formation. This apparent paradox was explained by H2S in the presence of molecular oxygen or hydrogen peroxide rapidly converting to polysulfides, which have oxidant properties that in turn activate PKG by inducing the disulfide. These observations are relevant in vivo because transgenic knockin mice in which the cysteine 42 redox sensor within PKG has been systemically replaced with a redox-dead serine residue are resistant to H2S-induced blood pressure lowering. Thus, a primary mechanism by which the reductant molecule H2S lowers blood pressure is mediated somewhat paradoxically by the oxidative activation of PKG.

Cardiovascular inhibitory properties of <i>Lens culinaris</i>

In present study, we report the blood pressure lowering, vasodilatory and cardio-depressant activities of Lens culinaris. The crude extract of L. culinaris induced dose-dependent (3-30 mg/kg) fall in the arterial pressure of rats under anesthesia. When tested in rat aortic ring preparations, L. culinaris at concentration range of 0.03-5.0 mg/mL relaxed high K+ (80 mM) and phenylephrine (1 ?M)-induced contractions, like that caused by verapamil. In isolated guinea-pig atria, L. culinaris caused inhibition of atrial force and rate of spontaneous contractions, similar to that exhibited by verapamil. These data indicate that L. culinaris exhibits blood pressure lowering potential, mediated possibly through Ca++ channel blockade mechanism.

Bovine Peptic Casein Hydrolysate Ameliorates Cardiovascular Risk Factors in a Model of ApoE-deficient Mice but not Overweight, Mildly Hypercholesterolaemic Men

Associations have been shown between consumption of bovine dairy and decreased prevalence of metabolic related disorders. Milk peptides may promote both angiotensin-I- converting enzyme (ACE) inhibition for blood pressure (BP) lowering and insulin action for better glycaemic control. Less is known of other metabolic parameters. The aim of this study was to investigate effects of dairy peptic casein hydrolysate (CH) on markers of cardiovascular disease (CVD) risk in (1) an apolipoproteinE (ApoE) - deficient mouse model of high-fat fed hypercholesterolaem- ia, and, (2) a clinical study of moderate overweight and hypercholesterolaemia. In Trial 1, ApoE-deficient mice were supplemented with high dose CH (~1g/kg body weight) in a randomised, 9-wk, parallel design intervention, and blood and tissue samples harvested. In Trial 2, 24 mildly hypercholesterolaemic men were supplemented with lower dose CH (~0.1g/kg body weight, 10g/day, 3-wks) and matched whey protein control (WP, 10g/day, 3-wks) in a randomised, 9-wk, cross-over design intervention. Diets were separated by a 3-wk washout. Fasting blood and urine samples were collected, and blood pressure (BP) measured weekly. Clinical trial registration number, ACTRN 12611001013954. In ApoE-deficient mice, administration of CH significantly inhibited circulating total cholesterol concentrations by 37% (TC, P<0.01) and decreased aorta atherosclerotic lesion score by 25% (P<0.01). In the clinical study there were no significant differential effects of CH supplementation on CV markers, including serum lipids (TC, LDL-C, HDL-C, triglyceride), glucose and BP. Whilst high dose bovine peptic CH attenuated CVD risk in a murine ApoE deficient model of aggressive hypercholesterolaemia, no evidence of amelioration of risk by supplementation with a lower dose of CH in an overweight population of mildly hypercholesterolaemic men was found.

Pharmacokinetics of subcutaneous delivery of M-ANP: an innovative designer anp-based guanylyl cyclase activating peptide for hypertension

Although mucocutaneous sites are the most frequently encountered sites of involvement, Kaposi Sarcoma (KS) may also occasionally involve the breast and the skeletal, endocrine, urinary and nervous systems.. Various imaging modalities may be used to delineate the extent of the disease by detecting unexpected sites of involvement. Herein, we report a case of classical type KS, in whom staging with 18F-FDG PET/CT imaging disclosed widespread disease and unexpected findings of bone and salivary gland involvement.Aunque el sarcoma de Kaposi (SK) se localiza comúnmente en mucosas y piel, ocasionalmente se pueden observar afectaciones de sistema esquelético, endocrino, urinario y nervioso. Diversos procedimientos de imagen se usan para determinar la extensión de la enfermedad, descubriendo localizaciones no sospechadas por la clínica. En este trabajo presentamos un SK clásico en el que la estadificación con 18F-FDG PET/TC identificó una inesperada afectación ósea y de glándula salivar.

Mechanistic view of renal protective action of calcium channel blockade.

Calcium channel blockers are one of the most useful antihypertensive agents because of their definite blood pressure lowering action. Although the antihypertensive effect of calcium channel blockers is attributed predominantly to the blockade of L-type calcium channels, recent studies demonstrate that the blockade of other subtypes of calcium channels, including T-type and N-type calcium channels, offers renal protective action because of their beneficial action on glomerular capillary pressure, renal fibrotic process, sympathetic nerve activity and aldosterone synthesis. It requires more extensive studies to clarify whether the ostensibly beneficial actions of these calcium channel blockers are available in a clinical setting.

Blood pressure lowering activity of a flavonoid and phytosterol rich extract of the sclerotia of Pleurotus tuberregium (Fr) Sing in salt-loaded rats

The sclerotia of Pleurotus tuberregium are eaten as food, and used in traditional health care, for the management of hypertension, yet there is scarcity of information in the literature regarding the nature of its effect on blood pressure indices. Thus, in this study, the ability of an aqueous extract of the sclerotia to moderate blood pressure indices and pulse rates were investigated in normal and sub-chronic salt-loaded rats. The normal and treatment control groups received a diet consisting 100% of commercial feed, while the test control, reference and test treatment groups received an 8% salt-loaded diet. The extract (at 100 and 200mg/kg body weight) and moduretics (at 1mg/kg body weight) were orally administered daily. The normal and test control groups orally received appropriate volumes of water. The extract was screened for bioactive components using gas chromatography coupled with flame ionization detector. The flavonoids were the major components (52.82mg/kg), and consisted of thirty-eight known flavonoids (mainly 29.03% kaempferol and 20.84% quercetin). The most abundant of the seven phytosterols and the twelve glycosides detected were sitosterol (98.16%) and amygdalin (37.56%), respectively. Compared to test control and corresponding values on day 0, the extract dose-dependently lowered the systolic, diastolic, pulse and mean arterial pressures of the salt-loaded rats; while producing a mixed effect on the pulse rates. This result suggests that the sclerotia can moderate all the blood pressure indices, and supports the use of the sclerotia in traditional health care, for the management of hypertension.

PSS176 - The Blood Pressure-Lowering Action of the Reductant Hydrogen Sulfide Is Paradoxically Mediated by the Oxidative Activation of Protein Kinase G Iα

PSS176 - The Blood Pressure-Lowering Action of the Reductant Hydrogen Sulfide Is Paradoxically Mediated by the Oxidative Activation of Protein Kinase G Iα

Propranolol reduces cognitive deficits, amyloid and tau pathology in Alzheimer's transgenic mice

The efficacy of antihypertensive agents in Alzheimer's disease (AD) is controversial. It has been tested here whether some antihypertensive drugs might influence AD through mechanisms independent of blood pressure-lowering activity. The effects of treatment with the antihypertensive propranolol on cognition and AD-related markers have been studied in the Tg2576 mouse model of AD. Propranolol, at a lower dose than that used as antihypertensive (5 mg/kg, 6 wk), attenuated cognitive impairments shown by Tg2576 mice aged 9 months in the novel object recognition and fear conditioning tests. Propranolol was also able to counteract the increases in hippocampal levels of Aβ(42) present in Tg2576 mice. This effect was accompanied by an increased expression of insulin degrading enzyme. Changes in markers of synaptic pathology, as shown by decreases in phosphorylation of Akt and in the expression of BDNF in Tg2676 mice, were also counteracted by propranolol treatment. Tau hyperphosphorylation shown by Tg2576 mice was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to an increase of GSK3β phosphorylation (inactive form) and a decreased JNK1 expression. Overall, these data further strengthen the potential of propranolol as a therapeutic agent for AD.

M-atrial natriuretic peptide and nitroglycerin in experimental acute hypertensive heart failure: differential actions of two cGMP activating therapeutics

Background Systemic hypertension is a common characteristic in acute heart failure (HF). This increasingly common phenotype is frequently associated with renal dysfunction and requires renal enhancing therapies. In a canine model of HF and acute hypertension we defined the cardiorenal actions of M-atrial natriuretic peptide (MANP), a novel particulate guanylyl cyclase A receptor activator (pGC-A) developed at the Mayo Clinic, and nitroglycerin (NTG), a soluble guanylyl cyclase (sGC) activator. Compared to native ANP, MANP has more sustained renal enhancing, blood pressure lowering and aldosterone inhibiting action. Based on the expression of the pGC-A receptor in the glomerulus, renal tubule and adrenal gland, compared to the more widespread expression of sGC in the renal vasculature, we hypothesized that MANP would have a more robust effect upon the glomerular filtration rate (GFR) and natriuretic actions and with greater aldosterone suppressing effects than sGC activation with NTG. To test these hypotheses, we used a canine model of combined HF and hypertension. Specifically, HF was induced by chronic (10 days) rapid right ventricular pacing (180 bmp), while hypertension was induced by continuous angiotensin II infusion (on day 11). We than characterized the cardiorenal and humoral actions of intravenous MANP (n=7), NTG (n=7), and vehicle (n=7) infusion. Results Mean arterial pressure (MAP) was reduced by both MANP (139±4 to 118±3 mmHg, p<0.05) and NTG (137 ±3 to 116±4 mmHg, p<0.05); similar findings were observed for reductions in pulmonary wedge pressure with MANP (12±2 to 6±2 mmHg, p<0.05) and NTG (12±1 to 6±1 mmHg, p<0.05). MANP enhanced renal function with significant increases in GFR (38±4 to 53±5 ml/min, p<0.05), renal blood flow (132±18 to 236±23 ml/ min, p<0.05), and natriuresis (11±4 to 689±37 mEq/min, p<0.05) with inhibition of aldosterone (32±3 to 23±2 ng/ dL, p<0.05), whereas NTG had no significant effect on these renal parameters or aldosterone activation.

Reply to Letter to the Editor: The proper blood pressure may impaire cardiovascular risk factors

We are very delighted about the international interest in ourpaper “Uncontrolled arterial hypertension in primary care –patient characteristics and associated factors” (Swiss MedWkly. 2012;142:w13693). We are especially delighted thatour work obviously is not only recognised by primary carephysicians, but also by specialists as the letter to the editorby Sait Demirkol [1] reflects.We are also thankful for the comment regarding the crosssectional design of our study. We agree with Demirkol andcolleagues that a cross sectional design can only show cor-relations but not prove any causality. This would only bepossible – as suggested by Demirkol et al. – by a followup. The data presented in our paper are derived from thebaseline-assessment of the CoCo trial, a randomised, con-trolled trial aiming at improving blood pressure control byusing a colour coded booklet for patients to note their bloodpressure measurements (Trials. 14 April 2010;11:38).It is our aim to follow the patients included in CoCo forat least one year. Therefore, we will be able – controlledfor the intervention – to analyse the influence of the de-tected risk factors for elevated blood pressure, namely age,smoking and a high body mass index over time. We arelooking forward to present these data soon.We agree with Demirkol and colleagues that patients withestablished cardiovascular diseases have a dysregulation ofvascular tone thus further promoting atherosclerosis. Asa consequence, blood pressure control by pharmacologic-al agents might differ depending on pleiotropic effects ofthese agents beyond blood pressure lowering, includinganti-oxidative and anti-inflammatory actions (Curr VascPharmacol. 2011 Mar;9(2):145–52, Clin Exp Hypertens.2012 Nov 30. [Epub ahead of print]). To investigate theeffect of various pharmacological agents was beyond thescope of the current study and unfortunately as stated inthe strengths and limitations section of our paper, co-mor-bidities were not systematically assessed. Therefore we arenot able to stratify for the factors: coronary artery disease,hypercholesterolemia or diabetes mellitus. Nevertheless,there is sufficient evidence that successful modification oflifestyle risk factors have a beneficial effect on blood pres-sure control irrespective of cardiovascular co-morbidities.Our cross-sectional results confirmed that the prevalence ofmodifiable cardiovascular risk factors is high in unselectedpatients with uncontrolled blood pressure thus demonstrat-ing the potential of successful lifestyle change programmesas mentioned by Demirkol and colleagues (Oman Med J.2012;27(6):511).

A Novel Class of Oral Direct Renin Inhibitors: Highly Potent 3,5-Disubstituted Piperidines Bearing a Tricyclic P3–P1Pharmacophore

A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.

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Losartan

Characterization of the Specificity of Imidazoline I-1 Receptor Antibody for Subtype of Imidazoline Receptors In Vitro

Specific antibodies are essential in the study of receptor protein. Gene matching shows that Nischarin (NISCH) is a mouse homologue of human imidazoline receptor antisera-selective (IRAS) protein, a viable candidate for imidazoline I-1 receptor. However, selectivity of this antibody against imidazoline I-2 or imidazoline I-3 receptors remained obscure. At first, an intracerebroventricular (ICV) injection of anti-NISCH antibody blocked the blood pressure lowering action of rilmenidine (I-1 receptor agonist) in spontaneous hypertensive rat (SHR). However, the same injection of anti-NISCH antibody showed no effect in SHR treated with clonidine (α2 agonist). In order to clarify the selectivity of anti-NISCH antibody for each subtype of imidazoline receptors, this anti-NISCH antibody was subjected to the lysate of organs isolated from Wistar rats including cortex, hippocampus, cerebellum, and brain stem as central nervous tissues, and heart, liver, pancreas, skeletal muscle, kidney, prostate, and bladder as peripheral tissues. The results show that anti-NISCH antibody positively reacted with all tissues including heart, pancreas, skeletal muscle, kidney and bladder by Western blot analysis. Also, the blotting spots for anti-NISCH antibody show a concentration-dependent manner. Moreover, anti-NISCH antibody blocked the action of glucose uptake induced by 2-BFI (I-2 receptor agonist) in L6 cells. Taken together, the obtained data suggest that anti-NISCH antibody can be used not only for imidazoline I-1 receptor but also for I-2 and I-3 subtypes in immunoassays.

Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME

The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent. ANG II-dependent malignant hypertension was induced through dietary administration for 3 days of the natural xenobiotic indole-3-carbinol (I3C) in Cyp1a1-Ren-2 transgenic rats. Blood pressure (BP) was monitored by radiotelemetry and treatment with the sEH inhibitor [cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid (c-AUCB)] was started 48 h before administration of the diet containing I3C. In separate groups of rats, combined administration of the sEH inhibitor and the nonspecific NO synthase inhibitor [Nω-nitro-L-arginine methyl ester (L-NAME)] on the course of BP in I3C-induced and noninduced rats were evaluated. In addition, combined blockade of renin-angiotensin system (RAS) was superimposed on L-NAME administration in separate groups of rats. After 3 days of experimental protocols, the rats were prepared for renal functional studies and renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolites dihydroxyeicosatrienoic acids (DHETEs) were measured. Treatment with c-AUCB increased the renal EETs/DHETEs ratio, attenuated the increases in BP, and prevented the decreases in renal function and the development of renal damage in I3C-induced Cyp1a1-Ren-2 rats. The BP lowering and renoprotective actions of the treatment with the sEH inhibitor c-AUCB were completely abolished by concomitant administration of L-NAME and not fully rescued by double RAS blockade without altering the increased EETs/DHETEs ratio. Our current findings indicate that the antihypertensive actions of sEH inhibition in this ANG II-dependent malignant form of hypertension are dependent on the interactions of endogenous bioavailability of EETs and NO.

Direct renin inhibition – a promising strategy for renal protection?

Activation of the renin–angiotensin–aldosterone system (RAAS) plays a key role in the progression of chronic kidney disease (CKD). RAAS inhibitors, such as angiotensin converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs), decrease the rate of progression of diabetic and non-diabetic nephropathies and are first-line therapies for CKD. Although these agents are highly effective, current therapeutic strategies are unable to sufficiently suppress the RAAS and stop CKD progression. Aliskiren, the first in a new class of RAAS-inhibiting agents (direct renin inhibitors) has been approved to treat hypertension. Aliskiren exerts renoprotective, cardioprotective, and anti-atherosclerotic effects in animal models that appear to be independent of its blood pressure lowering activity. Early clinical studies using urinary protein excretion as a marker of renal involvement suggest a possibly novel role for aliskiren in treating CKD. This review discusses the antiproteinuric efficacy and safety of aliskiren and considers the evidence for its potential renoprotection.

Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin-angiotensin-aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension.