Decreased stroke volume−brachial pulse pressure ratio in patients with type 2 diabetes over 50 years: the role of peripheral neuropathy.

BACKGROUND AND AIMS: To document the stroke volume to pulse pressure ratio (SV/PP, an index of total arterial compliance) and its correlates in patients with type 2 diabetes (T2DM) aged over 50 years whose peripheral neuropathy and silent myocardial ischemic (SMI) status were known. METHODS AND RESULTS: A total of 360 patients with T2DM aged ≥ 50 years, without cardiac history or symptom, left ventricular systolic dysfunction, dilatation and hypokinesia, were retrospectively enrolled. The SV/PP was calculated from echocardiographic left ventricular measurements and brachial blood pressure at rest. Peripheral neuropathy was defined as the presence of any two or more of the following: neuropathic symptoms, decreased distal sensation, or decreased or absent ankle reflexes. SMI was defined as an abnormal stress myocardial scintigraphy and/or stress echocardiography. A low SV/PP ratio (<0.53 ml/m²/mmHg, first tertile) was associated with age, creatinine clearance, 24 h urinary albumin excretion rate, peripheral neuropathy, hypertension, serum total cholesterol and triglycerides levels (p < 0.05-0.0001). In multivariate analysis, age (OR 1.1 [1.0-1.2], p < 0.01), triglycerides (OR 1.5 [1.2-2.0], p = 0.01) and peripheral neuropathy (OR 2.2 [1.2-3.9], p = 0.009) were independently associated with a low SV/PP. The patients with peripheral neuropathy had lower SV (p < 0.01) and higher PP (p < 0.05) than those without, and only lower SV after adjustment for age and nephropathy. Similar results were obtained in the patients with and without SMI. CONCLUSION: Peripheral neuropathy was independently associated with decreased SV/PP, mainly through decreased SV, in patients with T2DM over 50 years.

Endothelin receptors blockade blunts hypoxia-induced increase in PAP in humans.

BACKGROUND: Activation of the endothelin-1 (ET-1) pathway may be involved in hypoxia-induced pulmonary vasoconstriction, increase in pulmonary pressure and high altitude pulmonary oedema. Thus, we investigated the effect of the ETA/ETB receptor antagonist, bosentan, on pulmonary artery systolic pressure (PASP) in healthy subjects (n = 10). DESIGN: We used a double-blind, placebo-controlled, randomized, cross-over design to study the effects of a single oral dose of bosentan (250 mg) on PASP after 90-min-exposure to normobaric hypoxia (FiO(2) = 0.12). We measured PASP and cardiac output by echocardiography, systolic arterial blood pressure, arterial O(2) saturation (SaO(2)), and blood gases at rest and during a sub-maximal exercise. RESULTS: PASP in normoxia at rest was 23.5 +/- 2.7 and during exercise 39.8 +/- 11.6 mmHg (P < 0.0001). During the placebo period, hypoxia induced a significant decrease in SaO(2), PaO(2) and PCO(2) and increase in pH. PASP at rest increased significantly: 32.1 +/- 3.5 mmHg (P < 0.001 vs. normoxia). Bosentan significantly blunted the hypoxia-induced increase in PASP: bosentan: 27.0 +/- 3.3 mmHg, P = 0.002 vs. placebo at rest, but not during exercise: bosentan 39.8 +/- 11.6 vs. placebo 43.0 +/- 8.5 mmHg, ns. Bosentan had no effect on the hypoxia-induced changes in blood gases, or on cardiac output and systolic arterial blood pressure, which were not modified by hypoxia. CONCLUSION: A single oral dose of bosentan blunted an acute hypoxia-induced increase in PASP in healthy subjects, without altering cardiac output or systemic blood pressure.

N-terminal pro-B-type natriuretic peptide: an independent marker for coronary artery disease in asymptomatic diabetic patients.

AIMS: To determine whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, a marker for cardiac failure and potentially for the severity of coronary artery disease (CAD), predicts silent myocardial ischaemia (SMI) and silent CAD in asymptomatic high-risk diabetic patients. METHODS: Five hundred and seventeen asymptomatic diabetic patients with > or = 1 additional cardiovascular risk factor but without heart failure were prospectively screened between 1998 and 2008 for SMI, defined as an abnormal stress myocardial scintigraphy, and subsequently for significant (> 70%) angiographic CAD. The 323 patients with interpretable echocardiography and for whom NT-proBNP was measured were included in this analysis. RESULTS: SMI was found in 108 (33.4%) patients, 39 of whom had CAD. NT-proBNP was higher in the patients with CAD than in the patients without CAD [45.0 (1-3199) vs. 20.0 (1-1640) pg/ml; P < 0.0001 median (range)], even after adjustment for confounding factors: age, gender, body mass index, glycated haemoglobin (HbA(1c)), retinopathy, nephropathy, hypertension, echocardiographic parameters (P < 0.05). NT-proBNP in the third tertile (> or = 38 pg/ml) predicted CAD with a sensitivity of 59% and a specificity of 67%. In a multiple logistic regression analysis including NT-proBNP > or = 38 pg/ml, age, body mass index, gender, HbA(1c), hypertension, retinopathy, nephropathy, peripheral occlusive arterial disease, left ventricular systolic dysfunction, dilatation and hypertrophy and Type 1 transmitral flow, NT-proBNP > or = 38 pg/ml was the only significant independent predictor of silent CAD [odds ratio (OR) 3.1 (95% confidence interval 1.3-7.6), P = 0.015]. CONCLUSIONS: NT-proBNP measurement helps to better define asymptomatic diabetic patients with an increased likelihood for CAD, independently of cardiac function and structure.

Postprandial endothelial dysfunction: role of glucose, lipids and insulin.

Endothelium plays a key role in the regulation of vascular tone and development of atherosclerosis. Endothelial function is impaired early in patients with risk factors and endothelial dysfunction is a strong and independent predictor of cardiovascular events. Because in normal subjects blood concentrations of glucose, lipids and insulin are increased after each meals, and postprandial changes last a long time after the meals, these changes might be of importance in the process of atherosclerosis initiation and development. Experimental and human studies have shown that a transient increase of blood concentrations of glucose, triglycerides and fatty acids, and insulin are able to depress endothelium-dependent vasodilation in healthy subjects and that hyperglycemia, hypertriglyceridemia and hyperinsulinemia are generator of reactive oxygen species at the origin of a cascade of pathophysiological events resulting in the activation of nuclear factor-kappaB. Nuclear factor-kappaB is an ubiquitous transcription factor controlling the expression of numerous genes and is involved in immunity, inflammation, regulation of cell proliferation and growth and apoptosis. These mechanisms may be involved in the development of atherosclerosis in normal subjects when food intake is chronically modified towards glucids and lipids with cumulative effects both on depression of endothelium dependent dilation and oxidative stress.

Expression of biologically active atrial natriuretic factor following intrahepatic injection of a replication-defective adenoviral vector in dogs.

Atrial natriuretic factor (ANF) is a potent natriuretic, diuretic, and vasoactive hormone produced and released by atrial cardiomyocytes. We investigated whether adenovirus-mediated ANF gene delivery to dogs leads to a sustained increase in circulating ANF levels resulting in long-lasting biological effects. An adenoviral vector containing the canine ANF cDNA under the control of the Rous sarcoma virus 3' long terminal repeat (AdRSV-ANF) was injected via the intrahepatic route to nonvaccinated 2-month-old dogs. In the first group of four dogs injected with AdRSV-ANF (10(10.2) TCID50), a short-lived increase in plasma ANF concentrations not associated with biological effects occurred 8-10 days after the injection, as compared with four control dogs injected with an adenovirus encoding a luciferase reporter gene (AdRSV-luc). In a second series of experiments, six dogs received AdRSV-ANF at a dose of 10(10) TCID50 and a replication-defective type 5 adenovirus harboring a modified VAI gene (Ad-VAr) at the same dose. Sustained increases in plasma ANF concentrations and urinary cGMP excretion starting on day 2 and persisting until day 20 were seen, as well as concomitant elevations in natriuresis and diuresis, a transient increase in cardiac output, and a delay in body weight gain, as compared with control dogs injected with AdRSV-luc/Ad-VAr. These results show that adenovirus-mediated ANF gene expression can lead to systemic biological effects in dogs, a finding of potential relevance for the treatment of cardiovascular diseases and sodium-retaining disorders.

New dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme: rational design, bioavailability, and pharmacological responses in experimental hypertension.

In the treatment of cardiovascular diseases, it could be of therapeutic interest to associate the hypotensive effects resulting from the inhibition of angiotensin II formation, ensured by endothelial angiotensin-converting enzyme (ACE), with the diuretic and natriuretic responses due to the protection of the endogenous atrial natriuretic peptide (ANP) from inactivation by epithelial neutral endopeptidase (NEP). However, an investigation of this hypothesis requires an orally active compound able to jointly inhibit ACE and NEP. Dual inhibitors have therefore been designed by a rational approach, based on the characteristics of the active sites of both enzymes, which belong to the same family of zinc metallopeptidases, and on the structures of their most potent and selective inhibitors. As both NEP and ACE contain a large S'1-S'2 domain able to accommodate aromatic residues, the cyclic ACE inhibitor 3-(mercaptomethyl)-3,4,5,6-tetrahydro-2-oxo-1H-1-benzazocine-1-ace tic acid was selected as a template. Various aliphatic constraints were introduced on the benzyl moiety of the potent NEP inhibitor N-[2-(mercaptomethyl)-3-phenylpropanoyl]-L-tyrosine (IC50 NEP = 2 nM, IC50 ACE = 25 nM) to improve the fit between the computed most stable conformers of these molecules and the ACE template. New dual inhibitors, of general formula, N-[2(R,S)-(mercaptomethyl)-3(R,S)-phenylbutanoyl]-L-amino acid with IC50 values in the nanomolar range for both enzymes were generated by this approach. The separation of the four stereoisomers using chiral amines and the stereoselective synthesis of the 2-(mercaptomethyl)-3-phenylbutanoyl moiety showed that inhibitors with the 2S,3R configuration are the most potent on both NEP and ACE. The "in vivo" potency of various prodrugs of these inhibitors to inhibit ACE activity in lung and NEP activity in kidney was measured after oral administration in mice. From this pharmacokinetical study the most potent dual inhibitor RB 105 (N-[(2S,3R)-2-(mercaptomethyl)-3-phenylbutanoyl-L-alanine (compound 44c) (KI NEP 1.7 nM, KI ACE 4.5 nM) and its most efficient in vivo prodrug mixanpril, [N-[(2S,3R)-2-[(benzoylthio)methyl]-3-phenylbutanoyl]-L-alan ine (compound 18) (ED50 NEP approximately 1 mg/kg, ED50 ACE approximately 7 mg/kg) were selected. Competition experiments with a tritiated inhibitor of ACE or NEP bound to mouse lung and kidney membranes respectively showed that mixanpril has a long duration of action (> 8 h). As expected, after i.v. administration in the spontaneously hypertensive rat (SHR), RB 105 decreased blood pressure and increased diuresis and natriuresis.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of angiotensin-converting enzyme and neutral endopeptidase inhibitors: influence of bradykinin.

These experiments compare the effects of a neutral endopeptidase inhibitor, retrothiorphan, 1-[(1-mercaptomethyl-2-phenyl)ethyl]amino-1-oxopropanoic acid, a converting enzyme inhibitor, enalaprilat, and the combination of the two inhibitors on changes in blood pressure and renal function induced by exogenous and endogenous bradykinin in deoxycorticosterone acetate (DOCA)-salt rats. Enalaprilat potentiated the exogenous bradykinin-induced hypotensive responses while retrothiorphan potentiated the effects on urinary cyclic-GMP (cGMP) and bradykinin. The combination potentiated the exogenous bradykinin-induced hypotensive effects and the bradykinin-induced urinary excretion of cGMP, bradykinin and prostaglandin. The bradykinin B2 receptor antagonist, Hoe 140, had no effect on the enalaprilat- and retrothiorphan-induced changes in blood pressure and renal function. In conclusion, while angiotensin-converting enzyme and neutral endopeptidase are involved in the vascular and renal catabolism of exogenous bradykinin, the effects of the peptidase inhibitors do not appear to depend on the protection of endogenous bradykinin under acute conditions in DOCA-salt rats.

Acute hemodynamic effects of combined inhibition of neutral endopeptidase and angiotensin converting enzyme in spontaneously hypertensive rats.

Neutral endopeptidase inhibitors (NEPI) potentiate the hypotensive effect of converting enzyme inhibitors (CEI) in conscious spontaneously hypertensive rats (SHR) but the mechanism of this potentiation remains unknown. The present study assesses the hemodynamic effects of a CEI (enalaprilat 1 mg/kg; n = 9), a NEPI (retrothiorphan 25 mg/kg + 25 mg/kg/h; n = 9) and the combination (CEI+NEPI; n = 9) versus a control group (n = 9) in anesthetized spontaneously hypertensive rats. CEI alone induced a significant hypotensive effect due to a decrease (-35.1%) in total peripheral resistance (TPR), with no significant increase in cardiac output (CO). NEPI alone had a slight hypotensive effect due to a small decrease in CO. CEI+NEPI decreased the mean arterial pressure to the same extent (-26.7%) as the CEI-induced hypotensive effect, decreased TPR (-44.4%) and induced an increase in CO (+38.2%) with an increase in heart rate. In summary, NEPI combined with CEI induces large decreases in blood pressure and in TPR which do not significantly differ from the CEI-induced effects. It also induces increases in heart rate and in cardiac output in anesthetized SHR.

[Regression of coronary atherosclerosis evaluated by angiography. A review of principal trials and critical study]. / La régression de l'athérosclérose coronaire évaluée par l'angiographie. Revues des principaux essais et étude critique.

The concepts of acceleration of atherosclerosis with fat rich diets and the regression or at least stabilisation of atherosclerosis by suppressing the cholesterol, introducing exercise programmes or administering calcium antagonists or aspirin, have been validated in the animal model. In the clinical situation, repeat coronary angiography has demonstrated that hyperlipidemia and the interval between two investigations are the main factors influencing the progression of atherosclerosis. However, the factors underlying the appearance and progression of atheromatous plaques remain unknown. Interventional trials based on the principle of introducing treatment after reference angiography have been undertaken. The results were assessed after variable time intervals. The general conclusion is that there is a direct relationship between the lowering of plasma cholesterol, the intensity of exercise and the slowing of progression of atherosclerosis as far as can be evaluated by repeat angiography. The data concerning the effect of calcium antagonists is confusing. The main criticism of these trials is the instrument of measurement and the practical significance or even the reality of the observed changes. In the present state of our knowledge, trials of the regression of atherosclerosis can not replace longitudinal studies of the long-term effects of drugs on cardiovascular and general morbidity and mortality.

[Role of antithrombotic agents after myocardial infarction]. / La place des antithrombotiques après un infarctus du myocarde.

Thrombosis is the causal mechanism of myocardial infarction: severe atherosclerotic narrowing, ulceration of the atherosclerotic plaque and disequilibrium between pro and antithrombotic factors, predispose to this complication. Recurrent myocardial infarction is a common complication in the year following an initial event: the risk is higher when the diseased artery has been recanalized in the acute phase. Reocclusion of the recanalized artery without signs of infarction is also a common occurrence. It was therefore logical to have striven over the years to prevent reinfarction and/or rethrombosis after reperfusion. Mechanical methods have not been crowned with resounding success and antithrombotic drugs are the only products associated with real benefits in this prevention. In this article, the authors review the efficacy of aspirin and vitamin K antagonists in the prevention of recurrent myocardial infarction; the data in favour of an efficacy of aspirin in preventing early reinfarction is also analysed; finally, results suggesting a benefit of platelet antiaggregant therapy (Flurbiprofen or aspirin) on the risk of reocclusion after therapeutic recanalisation are also assessed.

[Functional compartmentation of the endocrine action of cardiac natriuretic peptides]. / Compartimentation fonctionnelle de l'action endocrine des peptides natriurétiques cardiaques.

The endocrine function of the heart is to secrete Atrial and Brain natriuretic -peptides (ANP and BNP). These peptides are biologically active via particulate guanylate cyclases which generate cyclic GMP, the second intracellular messenger. A polysaccharide antagonist, HS-142-1 has been recently described by a Japanese Group. Cyclic GMP is partly secreted from the target cells into the extra cellular medium in which its accumulation is proportional to the concentration of the natriuretic peptide. Neutral Endopeptidase (NEP) is a zinc ectoenzyme involved in the catabolism of natriuretic peptides. NEP is absent in plasma but present on the surface of endothelial and smooth muscle cells. NEP is mainly expressed at the apical pole of the epithelial cells of the proximal tubule in the nephron. Chronic increase in volume and pressure within the cardiac cavities is associated with the oversecretion of natriuretic peptides. This chronic phenomenon involves the recruitment of all the cardiac myocytes to express natriuretic peptide genes. The clinical application of this hyperplasic phenomenon is congestive heart failure, in which the plasma levels of natriuretic peptides correlate with the level of the -hemodynamic stress. Therefore the plasma levels of natriuretic peptides are good pronostic markers in both experimental and human heart failure. The degree of congestive heart failure as well as the plasma levels of ANP and BNP are also -correlated with the plasma and urinary levels of cyclic GMP. The plasma level of -cyclic GMP is correlated with the endothelial concentration of cyclic GMP but not with the cyclic GMP concentration in smooth muscle cells. From these experimental data, we can conclude that plasma cyclic GMP originates from endothelial cells and is related to particulate guanylate cyclase activity. In contrast natriuretic peptides do not modulate vascular wall cyclic GMP content. The natriuretic action of ANP is probably due to the interaction of the filtered peptide with the particulate guanylate cyclase at the apical pole of the epithelial cells. The apparition of peptiduria associated with natriuresis during NEP inhibition provides evidence of the action of the peptide in the urinary compartment. It is also by a urinary pathway via the macula densa that ANP, and its potentiation by NEP inhibition, decreases renin secretion. The fact that plasma levels of ANP and plasma and urine levels of cyclic GMP correlate with the degree of salt retention in congestive heart failure, provides evidence for chronic desensitization of the system. An up-regulation of Na(+), K(+), 2Cl(-) expression associated with experimental congestive heart failure has recently been shown. Similarly, a modulation of the different sodium transporter systems along the nephron could be one of the counter-regulations leading to desensitization to natriuretic peptides. In conclusion, natriuretic peptides are true endocrine peptides, secreted by the heart, transported in the plasma, filtered by the glomeruli and active at the nephron level. The molecular effector of ANP and cyclic GMP in the epithelial cells is probably the G-kinase II, isoform phosphorylating the cystic fibrosis transmembrane conductance regulator (CFTR). The exact mechanism of desensitization remains to be elucidated.

[Converting enzyme inhibitors and coronary failure]. / Inhibiteurs de l'enzyme de conversion et insuffisance coronaire.

Nearly 15 years ago, it has been shown that myocardial infarction is accompanied by left ventricular dilatation. In the following years more details were obtained on morphological changes consecutive to myocardial infarction, now grouped together under the term left ventricular remodelling. These changes enable the patients to survive despite reduction of the contractile ventricular mass, but they expose the ventricles to constraints resulting in excessive work load. It has been shown that these changes can be reduced by early myocardial reperfusion and by administration of angiotensin-converting enzyme (ACE) inhibitors. These findings were established first in animals, then in man. Administering ACE inhibitors to patients with symptomatic heart failure consecutive to advanced ischaemic cardiopathy prolongs the patients' survival. When ACE inhibitors are given to patients with severe asymptomatic left ventricular dysfunction which started soon or long after a myocardial infarction, they reduce the frequency of ischaemic events, passage to symptomatic heart failure and, at least in one study, mortality. ACE inhibitors have also been shown to reduce the size of myocardial necrosis when administered in the acute phase of experimental myocardial infarction. Preliminary data have demonstrated that ACE inhibitors given in the acute phase of myocardial infarction reduce the left ventricular dilatation which follows infarction. However, a study of ACE inhibitors administered to a large number of patients in the acute phase of myocardial infarction had to be interrupted because of the over-mortality in the treated group. These facts are reviewed in this article, and attempts have been made at deducing from them the current indications of ACE inhibitors in patients with coronary heart disease.

[Which medical treatment after myocardial infarction?]. / Quel traitement médical après un infarctus du myocarde?

Patients leaving the hospital after a myocardial infarction are given a prescription containing several drugs. The purpose of this paper is to determine which of these drugs have a proven value and for which types of patients. Antithrombotic agents (be it acetyl-salicylic acid or antivitamin K drugs) have been shown to be efficient after a myocardial infarction. Beta-blockers are certainly useful, notably in cases with severe necrosis. Conversely, the usefulness of calcium antagonists for secondary prevention has not been demonstrated and indeed, it seems probable that the drugs of this class might be harmful in patients who had severe infarction. There is little divergence concerning the necessity to control the risk factors for coronary atherosclerosis after a myocardial infarction. The evidence is strong concerning giving up smoking; it is intuitive as regards controlling arterial hypertension and more controversial as regards the need for lowering blood cholesterol levels. The systematic prescription of antiarrhythmic agents after myocardial is certainly noxious. Finally, prospects are now opened by the prevention of left ventricular remodelling under treatment with angiotensin-converting enzyme inhibitors.

Transthoracic echocardiographic abnormalities in asymptomatic diabetic patients: association with microalbuminuria and silent coronary artery disease.

AIMS: This study aimed to assess, on routine echocardiography, cardiac left ventricular (LV) disorders, their determinants and their role in the screening process of silent myocardial ischaemia (SMI) in asymptomatic diabetic patients. METHODS: A total of 586 asymptomatic diabetic patients with one or more additional cardiovascular risk factors, but no history of heart failure or myocardial infarction, prospectively underwent rest echocardiography and myocardial scintigraphy. Those with SMI (abnormal scintigraphy) were subsequently screened for angiographic coronary artery disease (CAD). RESULTS: LV hypertrophy, LV dilatation, systolic dysfunction and hypokinesia were found in 33.6, 8.6, 3.2 and 6.1%, respectively, of the study population. SMI was found in 156 (26.6%) patients, 55 of whom had silent CAD. On multivariate analysis, age (OR: 1.03 [1.00-1.05], P=0.02), microalbuminuria (OR: 2.2 [1.4-3.2], P<0.0001) and silent CAD (OR: 2.4 [1.3-4.6], P=0.007) were predictive of LV hypertrophy. Creatinine clearance (OR: 0.97 [0.96-0.99], P=0.002) and silent CAD (OR: 3.7 [1.3-10.0]) were associated with LV dilatation. LV systolic dysfunction was associated with microalbuminuria (OR: 3.8 [1.3-11.4], P=0.02) and silent CAD (OR: 3.8 [1.1-12.6], P=0.03). Hypokinesia was associated with retinopathy (OR: 2.4 [1.1-5.4], P=0.04), microalbuminuria (OR: 2.3 [1.1-5.0], P=0.04) and LV dilatation (OR: 3.0 [1.1-8.1], P=0.03). In patients with SMI, the positive predictive value of LV hypertrophy associated with another echocardiographic abnormality (n=19) for CAD was 63.2%. CONCLUSION: LV hypertrophy was found in one-third of asymptomatic diabetic patients, while LV dilatation, systolic dysfunction or hypokinesia was seen in<10%. The main predictors of LV abnormalities were microalbuminuria and silent CAD. The presence of LV hypertrophy with another abnormality should raise the possibility of the presence of silent CAD.

Hypotensive and natriuretic effects of RB 105, a new dual inhibitor of angiotensin converting enzyme and neutral endopeptidase in hypertensive rats.

Neutral endopeptidase (NEP) is involved in the metabolism of atrial natriuretic peptide (ANP), whereas angiotensin-converting enzyme (ACE) is involved in the metabolism of angiotensin I; both enzymes participate in bradykinin metabolism. RB 105 is a new dual inhibitor which inhibits both peptidases, NEP (Ki = 1.7 nM) and ACE (Ki = 4.2 nM). In conscious spontaneously hypertensive rats (SHR), RB 105 i.v. dose-dependently decreased blood pressure and dose-independently caused natriuresis with dose-dependent increases in urinary cGMP and plasma renin concentration, and decrease in plasma ACE activity. RB 105 increased urinary excretion of both immunoreactive ANP and bradykinin. RB 105 completely blocked the hypertensive response of exogenous angiotensin I. Furthermore, RB 105 potentiated the hypotensive and natriuretic response to ANP and potentiated the hypotensive responses of bradykinin in SHR. Intravenous RB 105 decreased blood pressure similarly in DOCA-salt, renovascular (1C-2K) and spontaneously hypertensive rats and induced a similar natriuretic response in these three different renin-dependent and -independent models of hypertension. RB 105 also had hypotensive and natriuretic effects in normotensive rats. RB 105 also induced an increase in urinary excretion of cGMP and bradykinin and in plasma renin concentration in hypertensive and normotensive rats. In conclusion, RB 105 is a new dual inhibitor of ACE and NEP able to target both blood pressure and renal sodium handling in different experimental renin-dependent and -independent models of hypertension.

Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase by the orally active inhibitor mixanpril: a potential therapeutic approach in hypertension.

In the treatment of cardiovascular disease, it could be of therapeutic interest to associate the hypotensive effects due to the inhibition of angiotensin II formation with the diuretic and natriuretic responses induced by the protection of the endogenous atrial natriuretic peptide (ANP). Investigation of this hypothesis requires an orally active compound able to simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), which is involved in renal ANP metabolism. Such compounds have been rationally designed by taking into account the structural characteristics of the active site of both peptidases. Among them, RB 105, N-[(2S,3R)-2-mercaptomethyl-1-oxo-3-phenylbutyl]-(S)-alanine, inhibited NEP and ACE with Ki values of 1.7 +/- 0.3 nM and 4.2 +/- 0.5 nM, respectively. Intravenous infusion of RB 105 in conscious spontaneously hypertensive rats prevented the pressor response to exogenous angiotensin I and potentiated the natriuretic response to ANP. Infusion of RB 105, at 2.5, 5, 10, 25, and 50 mg/kg per hr decreased blood pressure dose-dependently in conscious catheterized spontaneously hypertensive rats and increased diuresis and natriuresis. Infusion of RB 105 as a bolus of 25 mg/kg followed by 25 mg/kg per hr similarly decreased blood pressure and increased natriuresis in three different models of hypertension (renovascular, deoxycorticosterone acetate-salt, and spontaneously hypertensive rats). Mixanpril, a lipophilic prodrug of RB 105 (ED50 values when given orally to mice, 0.7 mg/kg for NEP; 7 mg/kg for ACE), elicited dose-dependent hypotensive effects of long duration in spontaneously hypertensive rats after oral administration [-37 mmHg for 50 mg/kg twice a day (1 mmHg = 133 Pa) and is therefore the first dual NEP/ACE inhibitor potentially useful for clinical investigations.

Effects of the selective neutral endopeptidase inhibitor, retrothiorphan, on renal function and blood pressure in conscious normotensive Wistar and hypertensive DOCA-salt rats.

Atrial natriuretic peptide (ANP) is degraded by neutral endopeptidase (NEP) mainly in the proximal tubule of the kidneys. We studied the effects of retrothiorphan, a potent and highly specific NEP inhibitor on renal function and blood pressure (BP). A 25-mg/kg bolus injection (group bolus), or bolus injection plus infusion 25 mg/kg + 25 mg/kg/h (group infusion), was given to conscious normotensive Wistar and hypertensive DOCA-salt rats. Bolus and infusion produced increases in diuresis (110 +/- 15 vs. 103 +/- 15 vs. 42 +/- 9 microliters/min) and natriuresis (10.6 +/- 3.0 vs. 7.0 +/- 1.0 vs. 5.4 +/- 1.0 mumol/min) in normotensive rats, with a maximum change at 30 min. Change in kaliuresis was not significant. These renal effects were associated with nonsignificant increases in urinary cyclic GMP and ANP. Arterial pressure and heart rate (HR) were not affected. Bolus or infusion of retrothiorphan also induced increases in diuresis (92 +/- 16 vs. 124 +/- 13 vs. 38 +/- 6 microliters/min) and natriuresis (10.3 +/- 2.0 vs. 12.5 +/- 1.0 vs. 5.0 +/- 1.0 mumol/min) in DOCA-salt hypertensive rats, with a maximum change at 30 min. The changes in diuresis and natriuresis induced by retrothiorphan were correlated with a significant increase in urinary cyclic GMP excretion (r = 0.89, p < 0.001 and r = 0.91, p < 0.001). Urinary ANP did not change in controls but significantly increased in the treated rats; urinary immunoreactive bradykinin (BK) also tended to increase. Plasma ANP and hematocrit did not change after retrothiorphan, but plasma cyclic GMP increased significantly after infusion. Only infusion caused a decrease in arterial pressure in DOCA-salt rats (-20 mm Hg at 120 min). Renal clearance studies in DOCA-salt rats showed that retrothiorphan has a transient effect on renal hemodynamics, with increases in glomerular filtration and renal blood flow (RBF) and a decrease in renal vascular resistance (RVR). Its renal action was also tubular, with an increase in fractional sodium excretion. We also compared the effects of retrothiorphan in normotensive Brown-Norway kininogen-deficient rats (BN-Kat) and DOCA-salt hypertensive kininogen-deficient rats. The NEP inhibitor induced increases in diuresis and natriuresis in both groups, with increased urinary cyclic GMP. Urinary immunoreactive BK did not change significantly in normotensive or DOCA-salt hypertensive kininogen-deficient rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased erythropoietin synthesis in patients with COLD or left heart failure is related to alterations in renal haemodynamics.

The mechanisms controlling erythropoietin (EPO) synthesis by the kidney in patients with chronic obstructive lung disease (COLD) or congestive left heart failure (CLHF) remain incompletely understood. Renal dysfunction occurs as a consequence of decreased renal blood flow (RBF) in these diseases. Because alterations in renal haemodynamics may affect EPO synthesis and red blood cell production, we investigated the potential relationships between renal function and plasma EPO synthesis in patients with COLD or CLHF. Thirty-two patients with COLD and 13 with CLHF underwent determination of renal physiology parameters, plasma EPO levels and haemoglobin levels. Plasma EPO concentrations were increased in patients with COLD or CLHF as compared to normal subjects, and were inversely correlated to haemoglobin concentrations. In patients with COLD or CLHF, plasma EPO was negatively correlated with both RBF and renal oxygen delivery (ROD) and positively correlated with filtration fraction. Plasma EPO was not correlated with glomerular filtration rate, fractional excretion of sodium, PO2 or PCO2. Among the patients with COLD, those with polycythemia (haemoglobin > 150 g L-1) had lower plasma EPO and higher RBF and ROD values than those with normocythemia (haemoglobin < or = 150 g L-1). Taken together, our data suggest that in patients with COLD or CLHF the critical determinant for EPO production is impairment of renal haemodynamics.

Effects of ANF infusion on the renal responses to lower-body negative pressure in humans.

To investigate the role of atrial natriuretic factor (ANF) in renal responses to a decrease in central blood volume, we examined the effects of ANF infusion on renal function and hormones during prolonged lower-body negative pressure (LBNP). Ten healthy volunteers participated in two experimental sequences, each comprising a 120-min baseline period followed by the application of -20 mm Hg LBNP for 90 min. During one of the two sequences, ANF was infused throughout LBNP application at the constant rate of 2.5 ng/kg/min. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by using inulin and p-aminohippuric acid clearance techniques. LBNP induced a significant decrease in ERPF (534 +/- 28 to 457 +/- 26 ml/min; p < 0.05), GFR (120 +/- 2.5 to 112 +/- 2.5 ml/min; p < or = 0.01), in urine excretion (12 +/- 0.9 to 5.6 +/- 0.5 ml/min; p < 0.001), in sodium excretion (0.36 +/- 0.03 to 0.30 +/- 0.02 mmol/min; p < 0.05), and in plasma ANF (19 +/- 3 to 11 +/- 2 pg/ml; p = 0.001) concomitant with an increase in plasma renin activity (PRA; 0.48 +/- 0.09 to 0.87 +/- 0.16 ng/ml/h; p = 0.01) and of forearm vascular resistance (FVR; p < 0.05). The combination of ANF infusion with LBNP led to a slight increase in plasma ANF from baseline (from 20 +/- 2 to 28 +/- 3 pg/ml; p < 0.05). Compared with values obtained during LBNP with saline vehicle infusion, values obtained during LBNP with ANF infusion were similar for ERPF (463 +/- 23 vs. 457 +/- 26 ml/min), for GFR (111 +/- 2 vs. 112 +/- 2 ml/min), and for urine excretion (7 +/- 0.6 vs. 5.6 +/- 0.5 ml/min; p = 0.07), but greater for fractional excretion of sodium (2.38 +/- 0.25% vs. 1.91 +/- 0.11%; p < 0.05) and FVR (p < 0.05), and smaller for PRA (0.49 +/- 0.1 vs. 0.87 +/- 0.16 ng/ml/h; p < 0.01). These data show that ANF infusion attenuates the antinatriuretic effect of low-level LBNP and its PRA-increasing effects without altering renal hemodynamic responses to LBNP, although there is a decrease in the LBNP-induced forearm vasoconstriction. These results were obtained with plasma ANF levels slightly higher than those in baseline. They support the hypothesis that a decrease in ANF secretion might contribute to the antinatriuretic effect of LBNP.