Evaluation of Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild-to-Moderate Hypertension.

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, three-period, single sequence study, patients with mild-to-moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470.

The effect of saponins from Ampelozizyphus amazonicus Ducke on the renal Na+ pumps' activities and urinary excretion of natriuretic peptides.

BACKGROUND: In a previous study, we showed that a saponin mixture isolated from the roots of Ampelozizyphus amazonicus Ducke (SAPAaD) reduces urine excretion in rats that were given an oral loading of 0.9 % NaCl (4 ml/100 g body weight). In the present study, we investigated whether atrial natriuretic peptides (ANP) and renal ATPases play a role in the SAPAaD- induced antidiuresis in rats. METHODS: To evaluate the effect of SAPAaD on furosemide-induced diuresis, Wistar rats (250-300 g) were given an oral loading of physiological solution (0.9 % NaCl, 4 ml/100 g body weight) to impose a uniform water and salt state. The solution containing furosemide (Furo, 13 mg/kg) was given 30 min after rats were orally treated with 50 mg/kg SAPAaD (SAPAaD + Furo) or 0.5 ml of 0.9 % NaCl (NaCl + Furo). In the SAPAaD + NaCl group, rats were pretreated with SAPAaD and 30 min later they received the oral loading of physiological solution. Animals were individually housed in metabolic cages, and urine volume was measured every 30 min throughout the experiment (3 h). To investigate the role of ANP and renal Na(+) pumps on antidiuretic effects promoted by SAPAaD, rats were given the physiological solution (as above) containing SAPAaD (50 mg/kg). After 90 min, samples of urine and blood from the last 30 min were collected. Kidneys and atria were also removed after previous anesthesia. ANP was measured by radioimmunoassay (RIA) and renal cortical activities of Na(+)- and (Na(+),K(+))-ATPases were calculated from the difference between the [32P] Pi released in the absence and presence of 1 mM furosemide/2 mM ouabain and in the absence and presence of 1 mM ouabain, respectively. RESULTS: It was observed that SAPAaD inhibited furosemide-induced diuresis (at 90 min: from 10.0 ± 1.0 mL, NaCl + Furo group, n = 5, to 5.9 ± 1.0 mL, SAPAaD + Furo group n = 5, p < 0.05), increased both Na(+)-ATPase (from 25.0 ± 5.9 nmol Pi.mg(-1).min(-1), control, to 52.7 ± 8.9 nmol Pi.mg(-1).min(-1), p < 0.05) and (Na(+),K(+))-ATPase (from 47.8 ± 13.3 nmol Pi.mg(-1).min(-1), control, to 79.8 ± 6.9 nmol Pi .mg(-1).min(-1), p < 0.05) activities in the renal cortex. SAPAaD also lowered urine ANP (from 792 ± 132 pg/mL, control, to 299 ± 88 pg/mL, p < 0.01) and had no effect on plasma or atrial ANP. CONCLUSION: We concluded that the SAPAaD antidiuretic effect may be due to an increase in the renal activities of Na(+)- and (Na(+),K(+))-ATPases and/or a decrease in the renal ANP.

Effect of high and low sodium intake on urinary aquaporin-2 excretion in healthy humans.

The degree of water transport via aquaporin-2 (AQP2) water channels in renal collecting duct principal cells is reflected by the level of the urinary excretion of AQP2 (u-AQP2). In rats, the AQP2 expression varies with sodium intake. In humans, the effect of sodium intake on u-AQP2 and the underlying mechanisms have not previously been studied. We measured the effect of 4 days of high sodium (HS) intake (300 mmol sodium/day; 17.5 g salt/day) and 4 days of low sodium (LS) intake (30 mmol sodium/day; 1.8 g salt/day) on u-AQP2, fractional sodium excretion (FE(Na)), free water clearance (C(H2O)), urinary excretion of PGE(2) (u-PGE(2)) and cAMP (u-cAMP), and plasma concentrations of vasopressin (AVP), renin (PRC), ANG II, aldosterone (Aldo), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) in a randomized, crossover study of 21 healthy subjects, during 24-h urine collection and after hypertonic saline infusion. The 24-h urinary sodium excretion was significantly higher during HS intake (213 vs. 41 mmol/24 h). ANP and BNP were significantly lower and PRC, ANG II, and Aldo were significantly higher during LS intake. AVP, u-cAMP, and u-PGE(2) were similar during HS and LS intake, but u-AQP2 was significantly higher during HS intake. The increases in AVP and u-AQP2 in response to hypertonic saline infusion were similar during HS and LS intake. In conclusion, u-AQP2 was increased during HS intake, indicating that water transport via AQP2 was increased. The effect was mediated by an unknown AVP-independent mechanism.

Dietary salt exacerbates isoproterenol-induced cardiomyopathy in rats.

Spontaneously hypertensive heart failure rats (SHHFs) take longer to develop compensated heart failure (HF) and congestive decompensation than common surgical models of HF. Isoproterenol (ISO) infusion can accelerate cardiomyopathy in young SHHFs, while dietary salt loading in hypertensive rats induces cardiac fibrosis, hypertrophy, and--in a minority-congestive HF. By combining ISO with dietary salt loading in young SHHFs, the authors sought a nonsurgical model that is more time--and resource-efficient than any of these factors alone. The authors hypothesized that salt loading would enhance ISO-accelerated cardiomyopathy, promoting fibrosis, hypertrophy, and biochemical characteristics of HF. SHHFs (lean male, 90d) were infused for 4 wk with ISO (2.5 mg/kg/day) or saline. After 2 wk of infusion, a 6-wk high-salt diet (4%, 6%, or 8% NaCl) was initiated. Eight percent salt increased heart weight, HF markers (plasma B-type natriuretic peptide, IL-6), lung lymphocytes, and indicators of lung injury and edema (albumin and protein) relative to control diet, while increasing urine pro-atrial natriuretic peptide relative to ISO-only. High salt also exacerbated ISO-cardiomyopathy and fibrosis. Thus, combining ISO infusion with dietary salt loading in SHHFs holds promise for a new rat HF model that may help researchers to elucidate HF mechanisms and unearth effective treatments.

Glucocorticoids improve renal responsiveness to atrial natriuretic peptide by up-regulating natriuretic peptide receptor-A expression in the renal inner medullary collecting duct in decompensated heart failure.

In heart failure, the renal responsiveness to exogenous and endogenous atrial natriuretic peptide (ANP) is blunted. The mechanisms of renal hyporesponsiveness to ANP are complex, but one potential mechanism is decreased expression of natriuretic peptide receptor-A (NPR-A) in inner medullary collecting duct (IMCD) cells. Newly emerging evidence shows that glucocorticoids could produce potent diuresis and natriuresis in patients with heart failure, but the precise mechanism is unclear. In the present study, we found dexamethasone (Dex) dramatically increased the expression of NPR-A in IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time- and dose-dependent manner, which emerged after 12 h and peaked after 48 h. The cultured IMCD cells were then stimulated with exogenous rat ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cGMP (the second messenger for the ANP) generation in IMCD cells, which presented in a time- and dose-dependent manner as well. In rats with decompensated heart failure, Dex dramatically increased NPR-A expression in inner renal medulla, which was accompanied by a remarkable increase in renal cGMP generation, urine flow rate, and renal sodium excretion. It is noteworthy that Dex dramatically lowered plasma ANP, cGMP levels, and left ventricular end diastolic pressure. These favorable effects induced by Dex were glucocorticoid receptor (GR)-mediated and abolished by the GR antagonist 17ß-hydroxy-11ß-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486). Collectively, glucocorticoids could improve renal responsiveness to ANP by up-regulating NPR-A expression in the IMCD and induce a potent diuretic action in rats with decompensated heart failure.

Diuretic effects of medetomidine compared with xylazine in healthy dogs.

This study aimed to investigate and compare the effects of medetomidine and xylazine on diuretic and hormonal variables in healthy dogs. Five dogs, used in each of 11 groups, were injected intramuscularly with physiological saline solution (control), 5, 10, 20, 40, and 80 microg/kg of medetomidine, and 0.25, 0.5, 1, 2, and 4 mg/kg of xylazine. Urine and blood samples were taken 11 times over 24 h. Both medetomidine and xylazine increased urine production in a dose-dependent manner up to 4 h after injection, but the increase was much less with medetomidine than with xylazine at the tested doses. Urine specific gravity, pH, osmolality, and concentrations of creatinine, sodium, potassium, chloride, and arginine vasopressin (AVP) were decreased in a dose-dependent manner with both medetomidine and xylazine. Plasma osmolality and concentrations of sodium, potassium, and chloride were increased significantly with both drugs. Total amounts of urine AVP excreted and plasma AVP concentrations were significantly decreased by higher doses of medetomidine but were not significantly decreased by xylazine. Higher doses of both drugs significantly increased the plasma concentration of atrial natriuretic peptide (ANP), but the effect was greater with medetomidine than with xylazine. The results revealed that both drugs induce a profound diuresis, but medetomidine's effect is less dose-dependent than xylazine's effect. Although changes in plasma concentrations of AVP and ANP may partially influence the diuresis induced by medetomidine, other factors may be involved in the mechanism of the diuretic response to both drugs. Thus, both agents can be used clinically for transient but effective diuresis accompanied by sedation.

Antagonistic effects of atipamezole and yohimbine on xylazine-induced diuresis in healthy dogs.

The aim of this study was to investigate and compare the antagonistic effects of atipamezole and yohimbine on xylazine-induced diuresis in healthy dogs. Five healthy male beagles were assigned to each of the 8 treatment groups in a randomized design at 1-week intervals in the same dog. One group was not medicated. The dogs in the other groups received 2 mg/kg xylazine intramuscularly (IM) and a treatment of saline (control), 50, 100 or 300 microg/kg of each atipamezole or yohimbine IM 0.5 hr later. Urine and blood samples were collected 11 times over the course of 24 hr. Urine volume, pH, specific gravity and creatinine values; osmolality, electrolyte and arginine vasopressin (AVP) values in both urine and plasma; and plasma atrial natriuretic peptide (ANP) concentration were measured. Both atipamezole and yohimbine antagonized xylazine-induced diuresis. The reversal effect of yohimbine was more potent, but not dose-dependent at the tested doses, in contrast with atipamezole. Both atipamezole and yohimbine exhibited similar potency in reversing the decreases in urine specific gravity, osmolality, creatinine, sodium and chloride concentrations and the increase in the plasma potassium concentration induced by xylazine. Both also inhibited xylazine-induced diuresis without significantly altering the hormonal profile in the dogs. A higher dose of atipamezole tended to increase the plasma ANP concentration. This may not be due only to actions mediated by alpha(2)-adrenoceptors. Both drugs can be used as antagonistic agents against xylazine-induced diuresis in healthy dogs.

[Puberty, pregnancy, gender and hormonal status--putative risk factors for diabetic nephropathy]. / Pubertatea, sarcina, sexul si statusul hormonal--posibili factori de risc pentru nefropatia diabetica.

Contemplation of non-genetic risk factors that are influencing the onset and development of diabetic nephropathy (diabetic kidney disease--DKD) is very important. This article is integrative, assessing the existent data about several possible risk factors for DKD. Because the age of onset and postpubertal duration of diabetes seems to be strongly correlated with DKD, it is feasible for puberty to be another independent risk factor. Data analysis regarding puberty and possible explanatory mechanisms to link it with DKD, as the connection with DKD of other situations, with special hormonal status (like pregnancy), is also part of this article. Summing up the data about hormonal status, we can conclude that ANF levels are a risk factor for diabetic nephropathy because they are implicated in diminution of urinary Na elimination and hypertension and subsequent urinary albumin excretion (UAE) in case of inadequate glycaemic control. The evidences regarding GH are indicating that it is a risk factor for DKD and that he is probably implicated in glomerular hypertrophy onset at puberty. The urinary elimination levels of GH are very strong correlated with UAE being putative early marker for DKD. Also the GH deficiency seems to be a protective mechanism for DKD apparition. GH is strongly correlated with IGF-1 that has very high urinary levels in microalbuminuric patients. These levels are very well related to UAE, kidney volume--important markers for glomerular hypertrophy. The evidences accumulated until now regarding the role of masculine gender, testosterone and estrogens in DKD are inarticulate.

Antagonistic effects of atipamezole and yohimbine on medetomidine-induced diuresis in healthy dogs.

This study aimed to investigate and compare the antagonistic effects of atipamezole and yohimbine on medetomidine-induced diuresis in healthy dogs. Five dogs were used repeatedly in each of 8 groups. One group was not medicated. Dogs in the other groups received 20 microg/kg of medetomidine intramuscularly and, 0.5 h later, saline (as the control injection), 50, 100, or 300 microg/kg of atipamezole, or 50, 100, or 300 microg/kg of yohimbine intramuscularly. Urine and blood samples were taken 11 times over 24 h for measurement of the following: urine volume, specific gravity, and creatinine concentration; urine and plasma osmolality; urine and plasma concentrations of electrolytes and arginine vasopressin (AVP); and the plasma concentration of atrial natriuretic peptide (ANP). Both atipamezole and yohimbine antagonized the diuretic effect of medetomidine, inhibiting medetomidine-induced decreases in urine specific gravity, osmolality, and concentrations of creatinine, sodium, potassium, chloride, and AVP and reversing both the medetomidine-induced increase in plasma concentrations of sodium, potassium, and chloride and the medetomidine-induced decrease in the plasma AVP concentration. Atipamezole significantly stimulated ANP release. The antidiuretic action of yohimbine was more potent than that of atipamezole but was not dose-dependent, in contrast to the action of atipamezole. The effects of these drugs may not be due only to actions mediated by alpha(2)-adrenoceptors.

Renal hyporesponsiveness to brain natriuretic peptide: both generation and renal activity of cGMP are decreased in patients with pulmonary hypertension.

We examined the mechanisms of renal resistance to atrial and brain natriuretic peptides (ANP and BNP) in pulmonary hypertension (PH). Compared to eight controls, nine PH patients showed a reduced ability to excrete an acute sodium load despite increased circulating ANP, BNP and cyclic guanosine monophosphate (cGMP), their second messenger. Patients' reduced urinary cGMP/BNP and natriuresis/urinary cGMP ratios demonstrated impaired generation of and reduced renal response to cGMP, respectively. Therefore, PH patients hyporesponsiveness to cardiac natriuretic peptides is likely located both upstream and downstream cGMP generation. Natriuretic peptide signalling pathway disruptions might be accessible to therapy.

Phosphodiesterase 5 inhibitor ameliorates renal resistance to atrial natriuretic peptide associated with obesity and hyperleptinemia.

BACKGROUND: Abnormal neurohormonal regulation of renal sodium handling plays an important role in obesity-associated hypertension. We investigated the effect of experimental obesity on renal response to atrial natriuretic peptide (ANP). METHODS: The effect of ANP was studied in three groups of rats: (1) lean controls, (2) animals made obese by a highly palatable diet, (3) rats treated with adipose tissue hormone, leptin, for 7 days to reproduce hyperleptinemia observed in obesity. RESULTS: ANP administered at a dose of 50 pmol/kg min(-1) induced about a 3-fold lower increase in Na+ and cGMP excretion in obese and leptin-treated rats than in the control group. ANP decreased Na+,K+-ATPase activity in the renal medulla only in the control group. Natriuretic effect of exogenous cGMP was also impaired in obese and leptin-treated rats. In contrast, hydrolysis-resistant cGMP derivative, 8-bromo-cGMP exerted comparable natriuretic effects in all groups. Neutral endopeptidase inhibitor, phosphoramidon, and ANP clearance receptor antagonist, C-ANP, increased urinary ANP excretion in all groups to a similar level, but their natriuretic effect was impaired in obese and leptin-treated groups. A specific inhibitor of cGMP-degrading phosphodiesterase, zaprinast, had comparable natriuretic and Na+,K+-ATPase-lowering effects in all groups and restored normal sensitivity to ANP. CONCLUSIONS: (1) Dietary-induced obesity is accompanied by impaired natriuretic effect of ANP, (2) ANP resistance in obesity may be accounted for by increased leptin level, (3) accelerated degradation of cGMP may contribute to ANP resistance associated with obesity and hyperleptinemia, suggesting that inhibiting cGMP-specific phosphodiesterases may be useful in the treatment of obesity-associated hypertension.

Urodilatin excretion and its correlation with sodium excretion in healthy full-term newborn infants.

BACKGROUND: Urodilatin (URO) is a member of the natriuretic family, cleaved by the kidney, which acts as a paracrine hormone in the regulation of natriuresis and diuresis. In newborn infants the excretion of urodilatin and its biological effects have not been explored. METHODS: We measured urinary URO excretion, by direct RIA (radioimmunoassay), as well as its correlation to neonatal body weight loss, and sodium homeostasis in 30 full-term newborn infants on the 4th day of life. RESULTS: The URO excretion, estimated as URO:creatinine ratio, was significantly correlated to sodium excretion. CONCLUSION: These data show that in full-term newborn infants the mechanisms that control synthesis, excretion and signal transduction of URO are developed and that URO contributes to natriuresis regulation.

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans.

OBJECTIVE: Our objective was to define the pharmacodynamic profile of the new dual neutral endopeptidase (NEP)/angiotensin-converting enzyme (ACE) inhibitor AVE7688. METHODS: We compared the effects of single oral doses of AVE7688 (5 and 25 mg) with those of 10 mg ramipril (R10), a selective ACE inhibitor, in a placebo-controlled crossover study in sodium-depleted normotensive subjects. We also compared the effects of 25 mg AVE7688 with those of a renin-angiotensin system (RAS) blockade induced by a high dose of an angiotensin II receptor antagonist (300 mg irbesartan) and a dual blockade of the RAS (150 mg irbesartan plus 10 mg ramipril) in sodium-replete normotensive subjects by use of the same study design. The in vivo inhibition of ACE and NEP was monitored by measuring the urinary excretion of N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) and atrial natriuretic peptide (ANP), respectively. The intensity of RAS blockade was assessed by the increase in plasma active renin concentration. RESULTS: The 24-hour urine AcSDKP cumulative excretion increased significantly more after 25 mg AVE7688 (919 nmol [95% confidence interval (CI), 803-1052 nmol], P < .05) than after 5 mg AVE7688 (706 nmol [95% CI, 612-813 nmol]) or 10 mg ramipril (511 nmol [95% CI, 440-593 nmol]). The 25-mg dose of AVE7866 significantly and transiently (4 to 8 hours after drug intake) increased urinary ANP (2.02 +/- 1.05 ng/h, P < .05), whereas 5 mg AVE7688 (1.14 +/- 0.77 ng/h) and 10 mg ramipril (0.93 +/- 0.65 ng/h) had no effect compared with placebo (0.80 +/- 0.37 ng/h). In the low-salt panel the rise in plasma active renin concentration achieved 24 hours after dosing by 25 mg AVE7688 (247 pg/mL [95% CI, 157-389 pg/mL], P < .05) was significantly higher than that achieved by 5 mg AVE7688 (129 pg/mL [95% CI, 75-221 pg/mL]) or 10 mg ramipril (113 pg/mL [95% CI, 67-193 pg/mL]), which did not differ. In the high-salt panel group the effects of 25 mg AVE7688 on renin release did not significantly differ from those after administration of the combination of 150 mg irbesartan plus 10 mg ramipril or 300 mg irbesartan alone. All of these active drugs similarly decreased blood pressure compared with placebo. CONCLUSION: AVE7688 at a dose of 25 mg has a favorable pharmacodynamic profile compared with other RAS blockers. These results support further clinical studies of its long-term effects in essential or resistant hypertension, chronic proteinuric nephropathy, and chronic heart failure.

Equimolar doses of atrial and brain natriuretic peptides and urodilatin have differential renal actions in overt experimental heart failure.

A hallmark of overt congestive heart failure (CHF) is attenuated cGMP production by endogenous atrial natriuretic peptide (ANP) with renal resistance to ANP. ANP and brain natriuretic peptides (BNP) are of myocardial origin, whereas urodilatin (Uro) is thought to be derived from kidney. All three peptides are agonists to the natriuretic peptide-A receptor. Our objective was to compare the cardiorenal and humoral actions of ANP, BNP, and Uro in experimental overt CHF. We determined cardiorenal and humoral actions of 90 min of intravenous equimolar infusion of ANP, BNP, and Uro (2 and 10 pmol.kg-1.min-1) in three separate groups of anesthetized dogs with rapid ventricular pacing-induced overt CHF (240 beats/min for 10 days). BNP resulted in increases in urinary sodium excretion (U(Na)V) (2.2+/-0.7 to 164+/-76 microeq/min, P<0.05) and glomerular filtration rate (GFR) (27+/-4 to 52+/-11 ml/min, P<0.05) that were greater than those with Uro (P<0.05), whereas ANP did not result in increases in U(Na)V or GFR. Increases in plasma cGMP (25+/-2 to 38+/-2 pmol/ml, P<0.05) and urinary cGMP excretion with BNP (1,618+/-151 to 6,124+/-995 pmol/min, P<0.05) were similar to those with Uro; however, there was no change with ANP. Cardiac filling pressures were reduced in all three groups. These studies also support the conclusion that in experimental overt CHF, renal resistance to natriuretic peptides in increasing rank order is BNP

Effect of prolonged physical exercise on urinary proANP1-30 and proANP31-67.

Dynamic exercise strongly affects atrial natriuretic peptides (ANP), in particular the mature bioactive alphaANP and the proANP fragments, namely proANP1-98, proANP1-30 and proANP31-67. The proANPs influence kidney functions and their plasma levels increase after physical exercise. We measured urinary proANP1-30 and proANP31-67 levels before and at the end of physical exercise in 28 well-trained male cyclists. For the first time, the proANP1-30 and proANP31-67 urinary levels in athletes before and at the end of a prolonged agonistic bicycle race were measured. Urinary creatinine and total proteins were also measured. The urinary proANP31-67, creatinine and total protein levels were significantly higher at the end of exercise than before. In contrast, proANP1-30/protein and proANP31-67/protein ratios decreased after exercise. Even proANP1-30/creatinine and proANP31-67/creatinine ratios were lower after exercise. A significant correlation between proANP1-30 and proANP31-67 urinary levels at the end of exercise was found. The proANP31-67/creatinine ratio before and after exercise also showed a significant correlation. The variation of urinary proANP fragments confirmed their possible role in physical exercise. In particular, it could be interpreted as a response of the body or kidney to renal impairment occurring during exercise.

Diagnosis of heart failure using urinary natriuretic peptides.

In the present study, we assessed the use of urinary natriuretic peptides [N-terminal proatrial natriuretic peptide (N-ANP) and N-terminal pro-brain natriuretic peptide (N-BNP) and C-type natriuretic peptide (CNP)] in the diagnosis of heart failure. Thirty-four consecutive hospitalized heart failure patients (median age, 75.5 years; 14 female) were compared with 82 age- and gender-matched echocardiographically normal controls. All subjects provided plasma and urine specimens. Plasma was assayed for N-BNP, and urine was assayed for N-ANP, N-BNP and CNP. The diagnostic efficiency of peptides was assessed using receiver operating characteristic (ROC) curve analysis. All three urinary natriuretic peptides were significantly elevated in heart failure patients ( P <0.001). Urine N-BNP was correlated with plasma N-BNP ( r (s)=0.53, P <0.0005). Areas under the ROC curves for urinary N-ANP, N-BNP and CNP were 0.86, 0.93 and 0.70 and for plasma N-BNP was 0.96. Correcting urinary peptide levels using urine creatinine produced ROC areas of 0.89, 0.93 and 0.76 respectively. A urine N-BNP level cut-off point of 11.6 fmol/ml had a sensitivity and specificity for heart failure detection of 97% and 78% respectively, with positive and negative predictive values of 64.7 and 98%. In conclusion, although all three natriuretic peptides were elevated in urine in heart failure, urinary N-BNP had diagnostic accuracy comparable with plasma N-BNP. Use of urinary N-BNP for heart failure diagnosis may be suitable for high-throughput screening, especially in subjects reluctant to provide blood samples.

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects.

AIMS: To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects. METHODS: The effects of oral omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days. RESULTS: In the multiple-dose study, peak plasma concentrations (Cmax = 10-895 ng ml(-1); tmax = 0.5-2 h) of omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14-19 h), attaining steady state in 3-4 days. In the single-dose study, Cmax (1-1009 ng ml(-1)) and AUC(0,t) (0.4-1891 ng ml(-1) h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, Cmax but not AUC(0,t) was linear at the lower doses on day 10. The lowest dose of omapatrilat (2.5 mg) almost completely inhibited (> 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 +/- 4.1 (+/- SD) ng 24 h(-1) in the placebo group to 60.0 +/- 18.2 ng 24 h(-1) in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single- and multiple-dose studies. CONCLUSIONS: Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once-daily dosing.

Physiologic consequences of vasopeptidase inhibition in humans: effect of sodium intake.

The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodium-depleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.

Renal hemodynamic and natriuretic effects of concomitant Angiotensin-converting enzyme and neutral endopeptidase inhibition in men.

This double-blind placebo-controlled study was designed to investigate the acute and sustained hormonal, renal hemodynamic, and tubular effects of concomitant ACE and neutral endopeptidase (NEP) inhibition by omapatrilat, a vasopeptidase inhibitor, in men. Thirty-two normotensive subjects were randomized to receive a placebo, omapatrilat (40 or 80 mg), or the fosinopril/hydrochlorothiazide (FOS/HCTZ; 20 and 12.5 mg, respectively) fixed combination for 1 week. Blood pressure, renal hemodynamics, urinary electrolytes and atrial natriuretic peptide excretion, and several components of the renin-angiotensin system were measured for 6 hours on days 1 and 7 of drug administration. When compared with the placebo and the FOS/HCTZ combination, omapatrilat induced a significant decrease in plasma angiotensin II levels (P<0.001 versus placebo; P<0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (P<0.01). These hormonal effects were associated with a significant fall in blood pressure (P<0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (P<0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (P<0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (P<0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (P=NS versus FOS/HCTZ). In conclusion, the results of the present study in normal subjects demonstrate that omapatrilat has favorable renal hemodynamic effects. Omapatrilat combines potent ACE inhibition with a sustained natriuresis, which explains its well-documented potent antihypertensive efficacy.

Relação das pressões atriais com o peptídio natriurético atrial e seus efeitos na diurese e natriurese durante operação cardíaca com circulação extracorpórea / Variations of the atrial natriuretic peptide (ANP) introduced by estracorporeal circulation (ECC) during cardiac surgery

OBJETIVO: Estudar as variações do peptídio natriurético atrial (PNA) introduzidas pela circulação extracorpórea (CEC) durante operação cardíaca e testar a hipótese de que existe correlação entre os níveis plasmáticos de PNA, pressão atrial direita (PAD) pressão atrial esquerda (PAE), diurese e natriurese. MÉTODO: Estudo de coorte de 15 pacientes submetidos a revascularização do miocárdio com CEC. Os intervalos de tempo de observação foram: t0 = 10 minutos antes da CEC (valor controle); t1 = 10 minutos depois de fluxo total em CEC; t2 30 minutos em fluxo total em CEC; t3 = fase final da CEC em temperatura nasofaringeana de 36º C; e t4 = 30 minutos após o término da CEC. RESULTADOS: Os valores do PNA, PAE e PAD variaram significativamente (p<0,001). O PNA diminuiu de t0 para t1 (NS) e após elevou-se progressivamente até t4 (p<0,001). A PAE e a PAD reduziram (p<0,001) entre t0 e t1, elevando-se progressivamente até t4 (p<0,001). O Na+ urinário aumentou entre t0 e t3 (p<0,001), com queda em t4. A diurese aumentou progressivamente em todos os tempos considerados (p<0,001). Foi encontrada correlação significativa entre PNA e o volume de diurese no t0, coeficiente de correlação de 0,535 (p=0,040), e no tempo igual a t2 entre PNA e PAD, coeficiente de correlação de 0,590 (p=0,021). CONCLUSÃO: As concentrações do PNA apresentam variações durante a operação de revascularização com CEC, o que favorece o conceito de estar relacionadas com as pressões atriais, e ao término da CEC, têm uma importante função na excreção de sódio e no volume da diurese