cardiovascular-agents and omapatrilat

Although there has been substantial progress in the treatment of congestive heart failure over the last several decades, it is clear that heart failure continues to burden our aging population. As the epidemic of heart failure grows, there remains an unmistakable need for novel diagnostic and therapeutic options in its management. In this article, we review recent innovations in the management of congestive heart failure, highlighting several recent clinical trials.

Topics: Age Factors; Biomarkers; C-Reactive Protein; Cardiovascular Agents; Heart Failure; Humans; Natriuretic Peptide, Brain; Neurotransmitter Agents; Pyridines; Thiazepines

Omapatrilat is a dual angiotensin converting enzyme and neutral endopeptidase inhibitor. It is another a new class of drugs, which are effective in the treatment of patients with hypertension and heart failure also accompanying diabetes. They are producing difference endocrine changes, vasodilatation, diuresis, natriuresis and they have anti hypertrophic activity on tissues, reduce sympathetic tone. Omapatrilat produces beneficial effects in experimental animals and in clinical studies. The overall safety with omapatrilat appears to be good. Angioedema is a rare but potentially life threatening side-effects of endopeptidase inhibitors. Treatment with omapatrilat has a higher tendency towards preventing death and worsening heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Agents; Heart Failure; Humans; Hypertension; Pyridines; Thiazepines

Topics: Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Diabetic Angiopathies; Humans; Hypertension; Pyridines; Renin-Angiotensin System; Thiazepines

Current thinking views the progression of heart failure as the result of sustained activation of vasoconstrictor neurohormones. In this model, the sustained synthesis of vasoconstrictor neurohormones leads to disease progression through alterations in cardiomyocyte structure and function, which affects myocardial contractility, cardiac metabolism, and cellular growth. Ultimately, these events induce irreversible adverse ventricular remodeling through myocyte cell loss and progressive myocardial fibrosis. In the past decade, several landmark clinical trials tested the neurohormonal hypothesis, by targeting the activation of both the beta-adrenergic and the renin-angiotensin-aldosterone systems. Although the observed decrease in mortality using this strategy in heart failure populations was encouraging, morbidity and mortality levels remained elevated, and it has now been shown that several other humoral interactions are at play and potentially deserve antagonizing, or in the case of vasodilator neurohormones, deserve stimulation. It is known a family of vasodilator neurohormones - the natriuretic peptides - that have natriuretic, vasodilatory, and antiproliferative effects, endogenously inhibit the renin-angiotensin system. These peptides are degraded primarily by a neutral endopeptidase (NEP), an endothelial cell-surface zinc metallopeptidase, which shares a similar structure and catalytic site with the angiotensin converting enzyme (ACE). NEPs have broad substrate specificity, encompassing atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide, but also bradykinin and adrenomedullin. The recognition that ACE and NEP enzymes had related structures, led to the design and development of a class of molecules with a dual inhibitory effect on ACE and NEP, referred to as vasopeptidase inhibitors. Preliminary clinical trials in heart failure with vasopeptidase inhibitors have become available and show promising results. Thus, the combined inhibition of ACE and NEP, by attenuating excessive vasoconstriction and enhancing vasodilator substances, holds promise as a valuable option in heart failure treatment for the near future.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Agents; Cardiovascular System; Clinical Trials as Topic; Drug Evaluation, Preclinical; Enzyme Inhibitors; Heart Failure; Humans; Protease Inhibitors; Pyridines; Renin-Angiotensin System; Thiazepines

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Hypertension; Neprilysin; Pyridines; Thiazepines

Vasopeptidase (VP) inhibitors are novel molecules that co-inhibit neutral endopeptidase 24.11 (NEP), which degrades natriuretic peptides and angiotensin-converting enzyme (ACE). We review the biology of the natriuretic peptide system and a recent study of the role for the natriuretic peptide system in the mechanism of action of omapatrilat (the most clinically advanced VP inhibitor). This study compared the cardiorenal and humoral actions of omapatrilat with those of ACE inhibition. The actions of omapatrilat were further defined in the presence and absence of a natriuretic peptide receptor antagonist. This investigation provided insight into a unique new pharmacologic agent that has beneficial renal actions in experimental mild heart failure that exceed those seen with ACE inhibition alone and that are linked to the natriuretic peptide system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiovascular Agents; Heart Failure; Humans; Kidney; Neprilysin; Pyridines; Thiazepines

Angiotensin-converting enzyme inhibition is not an effective antianginal therapy. Experimental data suggest that broader vasopeptidase inhibition may decrease the magnitude of demand-induced myocardial ischemia. A randomized, double-blind, placebo controlled parallel study evaluated omapatrilat, an inhibitor of angiotensin-converting enzyme and neutral endopeptidase. The primary objective was to compare maximum duration of exercise at peak plasma concentrations. Exercise treadmill studies were performed in 348 patients who had chronic angina at baseline and after 4 weeks of therapy with 80 mg/day omapatrilat or placebo. Safety data were collected and reported for all patients. Treadmill exercise duration at peak was significantly prolonged in the omapatrilat group compared with the placebo group (76.6 +/- 84.2 vs 28.7 +/- 82.2 seconds difference from baseline, p <0.001). Similar statistically significant increases were seen in time to onset of level III/IV angina and time to onset of >/=0.1-mV ST-segment depression (p <0.001). The significant improvements in exercise duration and measurements of myocardial ischemia were not sustained 20 to 28 hours after dosing. Omapatrilat was generally well tolerated in this predominantly normotensive population. The incidence of serious adverse events was 5.2% in the 2 groups. Thus, omapatrilat, an investigational vasopeptidase inhibitor, is effective in prolonging exercise duration and parameters of demand-induced myocardial ischemia in patients who have chronic angina at peak concentrations. The data confirm the proof of principle that broader vasopeptidase inhibition beyond angiotensin-converting enzyme inhibition is required to alleviate symptoms of chronic angina.

Topics: Angina Pectoris; Angiotensin II; Angiotensin III; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Agents; Chronic Disease; Double-Blind Method; Exercise Tolerance; Female; Humans; Male; Middle Aged; Neprilysin; Pyridines; Thiazepines

Vasopeptidase inhibition (VPI), a therapeutic strategy by dual inhibition of both ACE and neutral endopeptidase 24.11, has not shown a prognostic benefit over ACE inhibition in chronic severe heart failure (CHF). Nevertheless, the effects of early treatment by VPI on cardiac remodelling have not been well assessed. We analysed the effects of early chronic VPI (50 mg/kg/day Omapatrilat) on cardiac remodelling and neurohumoral function during the progression of rapid ventricular pacing-induced heart failure in rabbits (early left ventricular dysfunction [ELVD]: 10 days at 330 bpm, CHF: further 10 days at 360 bpm). VPI-treated animals (ELVD-VPI n = 6; CHF-VPI n = 8) and placebo treated animals (ELVD n = 6; CHF n = 7) were compared with control rabbits (CTRL n = 5). LV fractional shortening (FS) and enddiastolic diameter (LVEDD) were assessed by echocardiography (12 MHz probe). LV BNP- and LV IL-6 gene expression was analysed quantitatively by real time PCR. Neurohumoral function was assessed by ANP, cGMP, plasma renin activity (PRA) and Aldosterone. In ELVD, LVEDD and atrial mass were significantly increased (both p < 0.05). This increase was markedly attenuated by VPI (both p < 0.05 vs. placebo). CHF was associated with a further increase in atrial mass and an increase in LV mass (both p < 0.05), which was again attenuated by VPI (atrial mass, p < 0.05 vs. untreated). LV BNP mRNA was significantly increased in CHF (p < 0.05 vs. control), and chronic VPI completely abolished this increase in ELVD and significantly attenuated it in CHF (p < 0.05 vs. CHF-placebo). Beyond that, the increase of cGMP was augmented by chronic VPI (p < 0.05 vs. placebo in CHF) in heart failure and that of Aldosterone was attenuated (p < 0.05 vs. placebo in ELVD), whereas PRA was temporarily increased (p < 0.05 vs. placebo in ELVD). Combined inhibition of ACE and NEP by VPI significantly inhibits early cardiac remodelling and LV BNP gene expression. If initiated early enough, it may slow down cardiac remodelling and represents a promising therapeutic strategy in progressive heart failure.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiomegaly; Cardiovascular Agents; Disease Models, Animal; Gene Expression Regulation; Heart Failure; Male; Natriuretic Peptide, Brain; Neprilysin; Pyridines; Rabbits; Renin; Renin-Angiotensin System; RNA, Messenger; Tachycardia; Thiazepines; Ventricular Dysfunction, Left; Ventricular Remodeling

We determined effects of the vasopeptidase inhibitor (VPI) omapatrilat and angiotensin II type 1 receptor (AT(1)R) blocker (ARB) candesartan in rats during healing between day-2 and day-21 after reperfused myocardial infarction (RMI) on left ventricular (LV) remodeling and function, and regional matrix metalloproteinase (MMP)-9, tissue inhibitor of MMP (TIMP)-3, inducible-nitric-oxide-synthase (iNOS), oxidant-generating myeloperoxidase (MPO), and cytokines tumor-necrosis-factor (TNF)-alpha, interleukin (IL)-6 and IL-10, and transforming-growth-factor (TGF)-beta(1), and collagens. Compared to RMI-placebo, both agents reversed adverse LV remodeling and systolic and diastolic dysfunction, improved collagen remodeling, and normalized MMP-9 (activity, protein, and mRNA), TIMP-3 (protein and mRNA), and iNOS, MPO, TNF-alpha, IL-6, and TGF-beta(1) proteins, and improved MMP-9/TIMP-3 balance and IL-10 levels in previously ischemic zones. The results suggest that modulation of matrix proteases, oxidants, cytokines, and NOSs with omapatrilat and candesartan contribute to reversal of adverse collagen and LV remodeling and attenuation of LV dysfunction during healing after RMI.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Cardiovascular Agents; Cytokines; Extracellular Matrix; Humans; Isoenzymes; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardial Reperfusion; Myocardium; Nitric Oxide Synthase; Peroxidase; Protease Inhibitors; Pyridines; Random Allocation; Rats; Tetrazoles; Thiazepines; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-3; Ventricular Remodeling

Congestive heart failure (CHF) results in decreased cardiac sympathetic innervation.. The purpose of this study was to test the hypothesis that therapy with the vasopeptidase inhibitor omapatrilat (OMA) attenuates cardiac neuronal remodeling in CHF.. We induced CHF in dogs with rapid ventricular pacing for 5 weeks with (CHF+OMA group, n = 8) or without (CHF group, n = 10) concomitant OMA treatment (10 mg/kg twice daily). Cardiac catheterization and echocardiography were performed to determine cardiac structure and hemodynamic parameters. Myocardial nerve density was determined by immunocytochemical staining with anti-growth associated protein 43 (GAP43) and anti-tyrosine hydroxylase (TH) antibodies. Seven normal dogs were used as histologic controls.. In the CHF group, ascites developed in 3 dogs and 4 dogs died, compared with no ascites or death in the CHF+OMA group (P = .07). In the 6 CHF dogs that survived, all had atrial fibrosis, severely depressed left ventricular systolic function, and increased atrial and ventricular chamber size. OMA treatment decreased the atrial and ventricular chamber sizes and the degree of atrial fibrosis. Most CHF dogs showed severe myocardial denervation, although some showed normal or abnormally high nerve counts. OMA treatment prevented heterogeneous reduction of nerve density. The left ventricular TH-positive nerve densities were 128 +/- 170 microm(2)/mm(2), 261 +/- 185 microm(2)/mm(2), and 503 +/- 328 microm(2)/mm(2) (P < .05), and the atrial GAP43-positive nerve densities were 1,683 +/- 1,365 microm(2)/mm(2), 305 +/- 368 microm(2)/mm(2), and 1,278 +/- 1,479 microm(2)/mm(2) (P < .05) for the control, CHF, and CHF+OMA groups, respectively.. CHF results in heterogeneous cardiac denervation. Long-term OMA treatment prevented the reduction of nerve density and promoted beneficial cardiac structural remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiovascular Agents; Disease Models, Animal; Dogs; Heart Atria; Heart Failure; Heart Ventricles; Hypertrophy, Left Ventricular; Male; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue; Pyridines; Renin; Stroke Volume; Thiazepines; Ventricular Dysfunction, Left; Ventricular Pressure; Ventricular Remodeling

The paper begins with a discussion of the goals of metabolic predictions in early drug research, and some difficulties toward this objective, mainly the various substrate and product selectivities characteristic of drug metabolism. The major in silico approaches to predict drug metabolism are then classified and summarized. A discrimination is, thus, made between 'local' and 'global' systems. In its second part, an evaluation of METEOR, a rule-based expert system used to predict the metabolism of drugs and other xenobiotics, is reported. The published metabolic data of ten substrates were used in this evaluation, the overall results being discussed in terms of correct vs. disputable (i.e., false-positive and false-negative) predictions. The predictions for four representative substrates are presented in detail (Figs. 1-4), illustrating the interest of such an evaluation in identifying where and how predictive rules can be improved.

Topics: Analgesics, Opioid; Cardiovascular Agents; Computer Simulation; Expert Systems; Galantamine; HIV Protease Inhibitors; Humans; Indinavir; Molecular Structure; Parasympathomimetics; Pyridines; Software; Thiazepines; Tramadol

To develop a sensitive and specific analytical method for the quantitative determination of omapatrilat (BMS-186716) and its metabolites (BMS-196087, 225308, 198433, and 253653) in human plasma.. Methyl acrylate (MA) was selected to react with BMS-186716, 196087, and 253653 to protect the free sulfhydryl groups. High pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to detect the analytes.. The method was validated over the concentration range of 0.2-250 microg/L for BMS-186716, 0.5-250 microg/L for BMS-196087, 1-250 microg/L for BMS-225308, 2-250 microg/L for BMS-198433, and 10-2500 microg/L for BMS-253653. The limit of quantitation was in turn 0.2, 0.5, 1, 2, and 10 microg/L, respectively. The extraction recovery was on average 60.5 %, 88.6 %, 76.3 %, 71.2 %, and 26.6 %, respectively. Inter- and intra-day precision of quality control samples (QC) was all within 15 % and accuracy was within 85 %--115 %. The analytes in human plasma were found to be stable after three cycles of freeze-thaw and for at least 6 h at room temperature (25 oC). No significant change was found in reconstituted reagent after 24 h at room temperature and results of long-term stability showed all the analytes in human plasma were stable for at least 3 months at -30 oC freezing condition.. This method is rapid, sensitive and specific for the pharmacokinetics study of omapatrilat and its metabolites.

Topics: Cardiovascular Agents; Chromatography, High Pressure Liquid; Humans; Mass Spectrometry; Pyridines; Thiazepines

We have shown earlier that cardiomyocyte apoptosis continues at a high level late after myocardial infarction and contributes to adverse cardiac remodeling. Here we studied whether this process can be inhibited by the vasopeptidase inhibitor omapatrilat, a drug which causes simultaneous inhibition of both angiotensin converting enzyme and neutral endopeptidase. Our hypothesis was that omapatrilat-treated rats would have less cardiomyocyte apoptosis, and less adverse cardiac remodeling compared to rats treated with selective inhibitors of angiotensin converting enzyme, neutral endopeptidase or placebo. Myocardial infarction was produced by ligation of the left anterior descending coronary artery. Rats were randomized to receive omapatrilat, captopril, neutral endopeptidase inhibitor SQ-28603 or vehicle. Rats treated with omapatrilat and captopril had reduced cardiac BNP mRNA levels and less myocardial fibrosis by comparison with the vehicle-treated rats. However, omapatrilat was more effective than captopril in attenuating hypertrophy as measured by relative cardiac weight (3.0+/-0.2 vs. 3.8+/-0.2 mg/g, P<0.01) or by echocardiographically determined left ventricular mass (0.61+/-0.05 vs. 0.83+/-0.06 g, P<0.01). Myocardial apoptosis was elevated both in the infarction border zone (0.129+/-0.017%) and in the remote area (0.035+/-0.005%) still 4 weeks after myocardial infarction. Angiotensin converting enzyme inhibition proved to be important in the prevention of apoptosis since both omapatrilat and captopril reduced the number of apoptotic myocytes whereas selective neutral endopeptidase inhibitor SQ-28603 had no effect. In conclusion, myocardial apoptosis, remaining increased 4 weeks after myocardial infarction, was reduced by angiotensin converting enzyme inhibition. Vasopeptidase inhibition was more effective than selective angiotensin converting enzyme inhibition in preventing adverse cardiac remodeling after myocardial infarction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Blood Pressure; Body Weight; Cardiomyopathy, Hypertrophic; Cardiovascular Agents; Fibrosis; Male; Muscle Cells; Myocardial Infarction; Myocardium; Neprilysin; Organ Size; Pyridines; Rats; Rats, Wistar; Thiazepines; Ventricular Remodeling

Vasopeptidase inhibitors possess dual inhibitory actions on neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) and have beneficial effects on cardiac remodeling. However, the contribution of NEP inhibition to their effects is not yet fully understood. To address the role of cardiac NEP inhibition in the anti-remodeling effects of a vasopeptidase inhibitor, we examined the effects of omapatrilat on the development of cardiac remodeling in rats with left coronary artery ligation (CAL) and those on collagen synthesis in cultured fibroblast cells. In vivo treatment with omapatrilat (30 mg/kg/day for 5 weeks) inhibited cardiac NEP activity in rats with CAL, which was associated with a suppression of both cardiac hypertrophy and collagen deposition. In cultured cardiac fibroblasts, omapatrilat (10(-7) to approximately 10(-5) M) inhibited NEP activity and augmented the ANP-induced decrease in [3H]-proline incorporation. ONO-BB, an active metabolite of the NEP selective inhibitor ONO-9902, also augmented the ANP-induced response, whereas captopril, an ACE inhibitor, did not. The angiotensin I-induced increase in [3H]-proline incorporation was prevented by omapatrilat and captopril, but not by ONO-BB. The results suggest that vasopeptidase inhibitor suppressed cardiac remodeling in the setting of chronic heart failure, possibly acting through the direct inhibition of cardiac NEP. Vasopeptidase inhibitors may have therapeutic advantages over the classical ACE and NEP inhibitors alone with respect to the regression of cardiac fibrosis.

Topics: Animals; Cardiovascular Agents; Cells, Cultured; Collagen; DNA; Dose-Response Relationship, Drug; Fibroblasts; Fibrosis; Heart Failure; Male; Neprilysin; Proline; Protease Inhibitors; Pyridines; Rats; Rats, Wistar; Thiazepines; Time Factors; Ventricular Remodeling

Topics: Anticholesteremic Agents; Azetidines; Cardiovascular Agents; Cardiovascular Diseases; Directories as Topic; Drug Evaluation; Drug Industry; Ezetimibe; Humans; Internet; Ischemic Preconditioning, Myocardial; Nicorandil; Ontario; Product Surveillance, Postmarketing; Pyridines; Thiazepines

Topics: Cardiotonic Agents; Cardiovascular Agents; Double-Blind Method; Exercise; Heart Failure; Humans; Lisinopril; Pyridines; Randomized Controlled Trials as Topic; Thiazepines

The pharmacodynamics and pharmacokinetics of omapatrilat, a member of a new class of cardiovascular compounds, the vasopeptidase inhibitors, were evaluated in subjects with hepatic cirrhosis (n = 10) and in healthy subjects (n = 10) matched for age, weight, gender and smoking history.. All subjects received omapatrilat 25 mg orally once daily for 14 days. Plasma renin and urinary atrial natriuretic peptide (ANP) levels were measured to assess the effect of omapatrilat on cirrhotic subjects. The effect of omapatrilat on blood pressure as well as changes in ANP and plasma renin levels were not altered by hepatic impairment. Pharmacokinetic parameters were determined from plasma omapatrilat concentrations.. There were no significant differences between the two subject groups with regard to log-transformed area under the curve or maximum observed plasma concentration. Systemic accumulation was similar in the two groups.. These results suggest, based on findings in otherwise healthy cirrhotic subjects, that no adjustment of standard dosing regimens is indicated for hypertensive patients with mild to moderate cirrhosis.

Topics: Administration, Oral; Area Under Curve; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Agents; Case-Control Studies; Female; Humans; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged; Pyridines; Renin; Thiazepines

Omapatrilat is a newly developed vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase and has potent antihypertensive efficacy. However, the specific effect of omapatrilat on cardiac function and left ventricular hypertrophy with hypertension remains controversial. Therefore, we investigated the effect of omapatrilat on blood pressure, cardiac hypertrophy, and cardiac function in spontaneously hypertensive rats (SHR). Studies were performed in SHR that received vehicle (n = 9), omapatrilat (n = 10), or fosinopril (ACE inhibitor, n = 7) by daily gavage for 56 days. Systolic blood pressure (SBP) and mean blood pressure (MBP) were measured by tail plethysmography. Left ventricular fractional shortening and left ventricular mass were measured by echocardiography at day 56. Omapatrilat and fosinopril significantly decreased SBP and MBP from day 1 through day 56, and omapatrilat markedly reduced SBP and MBP compared with fosinopril from day 21 to day 56. Although both omapatrilat and fosinopril decreased left ventricular mass and left ventricular mass-to-body weight ratio with increased LV fractional shortening, omapatrilat had a more potent effect on the reduction of left ventricular mass and improvement of cardiac function. This study shows that in SHR, omapatrilat mediated a potent and stable antihypertensive effect and a reduction in left ventricular mass with improvement of cardiac function, compared with ACE inhibition alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiovascular Agents; Endocardium; Fosinopril; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Pyridines; Rats; Rats, Inbred SHR; Thiazepines; Ventricular Function, Left

Omapatrilat is a member of the new drug class of vasopeptidase inhibitors that may offer benefit in the treatment of heart failure (HF) through simultaneous inhibition of angiotensin-converting enzyme and neutral endopeptidase. We examined the effects of omapatrilat in a placebo-controlled crossover study using a pacing model of HF. Seven sheep were paced sequentially at 180 bpm (mild HF) and then 225 bpm (severe HF) for 7 days each. Omapatrilat (0.005 mg/kg) or vehicle was administered by intravenous bolus on days 4 to 7 of each paced period. Omapatrilat lowered mean arterial and left atrial pressure and increased cardiac output acutely and chronically in both mild and severe HF (P<0.01 for all). Plasma atrial and brain natriuretic peptide and cGMP levels were stable acutely (P=NS), while brain natriuretic peptide increased after repeated dosing in severe HF (P<0.05). Plasma renin activity rose, whereas angiotensin II and aldosterone levels fell after acute and repeated dosing in both states (P<0.01 for all). Omapatrilat increased urinary sodium excretion by day 7 in both mild and severe HF (P<0.05). Effective renal plasma flow and glomerular filtration rate increased or were stable after omapatrilat in mild and severe HF after both acute and repeated dosing. Omapatrilat exhibited pronounced acute and sustained beneficial hemodynamic and renal effects in both mild and severe heart failure.

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiovascular Agents; Cross-Over Studies; Cyclic GMP; Disease Models, Animal; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Injections, Intravenous; Kidney; Natriuretic Peptide, Brain; Pyridines; Renin; Sheep; Sodium; Thiazepines

Because part of the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors results from their protective effects on cardiac bradykinin (BK) metabolism, the purpose of this study was to define the metabolism of BK in normal and failing human hearts and to compare the effect of omapatrilat, a vasopeptidase inhibitor (VPI), which simultaneously inhibits both neutral endopeptidase (NEP) and ACE, with that of an ACE inhibitor. Exogenous BK at a nanomolar concentration was incubated alone, in the presence of an ACE inhibitor (ramiprilat, 36 nM), or in the presence of a VPI (omapatrilat, 61 nM) with left ventricular membranes prepared from normal donor hearts (n = 7), and hearts from patients with an ischemic (n = 11) or dilated (n = 12) cardiomyopathy (DCM). The half-lives calculated for BK alone (199 +/- 60, 224 +/- 108, and 283 +/- 122 s; P = NS) exhibited similar values for normal, ischemic, and DCM heart tissues, respectively. Ramiprilat significantly increased the half-life of BK (P <.01), but the effect was similar for the three kinds of tissues (297 +/- 104, 267 +/- 157, and 407 +/- 146 s, respectively; P = NS). The potentiating effect of the VPI omapatrilat on the kinetic parameter of BK (478 +/- 210, 544 +/- 249, and 811 +/- 349 s, respectively) was greater than that of the ACE inhibitor (P <.01). Moreover, omapatrilat had a more important potentiating effect with DCM than normal heart membranes (P <.05). These results show that not only ACE but also and mainly NEP play an important role in the degradation of BK in human heart membranes. Omapatrilat, a VPI, has a greater protective effect on BK metabolism than that of a pure ACE inhibitor. Thus, inhibition of both ACE and NEP with omapatrilat could be more cardioprotective than ACE inhibition alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Cardiomyopathy, Dilated; Cardiovascular Agents; Female; Half-Life; Heart; Humans; Male; Membranes; Middle Aged; Myocardial Ischemia; Myocardium; Neprilysin; Peptidyl-Dipeptidase A; Protease Inhibitors; Pyridines; Ramipril; Thiazepines

Angiotensin-converting enzyme (ACE) inhibition as well as neutral endopeptidase (NEP) inhibition was demonstrated to influence hemodynamics in various cardiac disease states. However, specific effects of chronic combined ACE and NEP inhibition on left ventricular (LV) and myocyte geometry and function remain unclear. In this study, a dual-acting metalloprotease inhibitor (DMPI), which possesses both ACE and NEP inhibitory activity, was used in a rapid-pacing model of LV dysfunction. LV and myocyte geometry and function were examined in control dogs (n = 6), in dogs with pacing-induced LV dysfunction (216 +/- 2 beats/min, 28 days, n = 7), and in dogs with DMPI treatment during rapid pacing (10 mg/kg p.o., b.i.d., n = 6). With chronic rapid pacing, LV end-diastolic volume increased (84 +/- 4 vs. 49 +/- 3 ml), and LV ejection fraction decreased (38 +/- 3% vs. 68 +/- 3%) compared with control (p < 0.05). DMPI concomitantly administered during long-term rapid pacing did not change LV ejection fraction (35 +/- 3%), but LV end-diastolic volume was reduced (70 +/- 5 vs. 84 +/- 4 ml; p < 0.05) when compared with rapid pacing only. With long-term rapid pacing, myocyte cross-sectional area was decreased (278 +/- 5 vs. 325 +/- 5 microm2), and resting length increased (178 +/- 2 vs. 152 +/- 1 microm) when compared with control (p < 0.05). With DMPI concomitantly administered during rapid pacing, myocyte cross-sectional area (251 +/- 5 microm2) and resting length (159 +/- 4 microm) were reduced when compared with rapid pacing only (p < 0.05). Myocyte velocity of shortening decreased from control values with long-term rapid pacing (39.3 +/- 3.9 vs. 73.2 +/- 5.9 microm/s; p < 0.05) but improved with DMPI treatment during rapid pacing when compared with rapid pacing only (58.9 +/- 6.7 microm/s; p < 0.05). Myocyte velocity of shortening with beta-adrenergic-receptor stimulation (25 nM isoproterenol) was reduced from controls with rapid pacing (125 +/- 12 vs. 214 +/- 30 microm/s; p < 0.05) but was improved with DMPI treatment during rapid pacing when compared with rapid pacing only (178 +/- 12 microm/s; p < 0.05). In a model of rapid pacing-induced LV failure, concomitant DMPI treatment significantly reduced the degree of LV dilation with no apparent effect on LV pump function. At the level of the LV myocyte, long-term DMPI treatment with rapid pacing improved myocyte performance and beta-adrenergic response. Thus the improvement in isolated myocyte contractile function was

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Agents; Dogs; Enzyme Inhibitors; Female; Hormones; Male; Metalloendopeptidases; Myocardial Contraction; Myocardium; Neprilysin; Peptidyl-Dipeptidase A; Pyridines; Receptors, Adrenergic, beta; Thiazepines; Ventricular Dysfunction, Left

A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cardiovascular Agents; Cyclic GMP; Enzyme Inhibitors; Heart Failure; Hypertension; Macaca fascicularis; Neprilysin; Pyridines; Rats; Renin; Sodium; Thiazepines

As it is extremely unstable in blood, the thiol compound BMS186716 was stabilized by the addition of methyl acrylate (MA) to blood samples. The blood samples were then kept in ice for 10-15 min for completion of the Michael addition reaction to occur between the thiol group of BMS186716 and MA, after which the plasma was separated by centrifugation under refrigeration. For sample analysis, the standard and quality control samples were prepared by spiking blank plasma with the BMS186716-MA adduct. After addition of the internal standard, BMS 188035-MA, each sample was acidified with HCI and then extracted with methyl tert.-butyl ether. Each reconstituted extract was injected into a high-performance liquid chromatography-positive ion electrospray ionization mass spectrometric system. The electrospray condition was chosen to enhance the [M+NH4]+ signal at the expense of the [M+H]+ signal. Monitoring the [M+NH4]+ signal, a lower limit of quantitation of 2.5 ng/ml was achieved, with 0.5 ml plasma. We have thus shown that a sulfhydryl compound (BMS186716) in blood can successfully be stabilized by reacting it with MA and that the adduct produced is adequately stable in blood and plasma to allow the development of a rugged quantitative bioanalytical method.

Topics: Acrylates; Animals; Antihypertensive Agents; Cardiovascular Agents; Chromatography, High Pressure Liquid; Dogs; Drug Stability; Mass Spectrometry; Metalloendopeptidases; Pyridines; Thiazepines

During method development in support of non-clinical studies in animal models, BMS-186716 was found to be extremely unstable in blood and plasma. Stabilization of the compound was achieved by reacting the compound with methyl acrylate (MA) in blood, from which the plasma was then prepared. While the resulting BMS-186716-MA adduct was found to be stable in dog plasma, and hence it was used as the basis for the method developed for analysis of dog plasma samples, the BMS-186716-MA adduct was found to be unstable in rat plasma as it was readily hydrolyzed to BMS-186716-acrylic acid (AA) by native esterases found in rat plasma. Although the finding of the instability of BMS-186716-MA in rat plasma was not the result of prospective planning, we were able to successfully develop a quantitative bioanalytical method using BMS-186716-AA as the analyte instead of the originally planned BMS-186716-MA analyte. The standard and quality-control (QC) samples were prepared by spiking blank plasma with BMS-186716-MA, and then allowing them to stand at room temperature for 1 h to convert BMS-186716-MA to BMS-186716-AA. After adding the internal standard BMS-188035-AA, each sample was acidified with HCl and then extracted with methyl tert.-butyl ether. The reconstituted extract was injected into a HPLC-electrospray ionization mass spectrometric system for detection by positive ion electrospray ionization. A lower limit of quantitation (LLQ) of 5 ng/ml was achieved, using 0.1 ml plasma and a standard curve range of 5-5000 ng/ml.

Topics: Acrylates; Animals; Cardiovascular Agents; Chromatography, High Pressure Liquid; Esterases; Hydrolysis; Mass Spectrometry; Pyridines; Rats; Reference Standards; Sensitivity and Specificity; Thiazepines