Lactotripeptides do not lower ambulatory blood pressure in untreated whites: results from 2 controlled multicenter crossover studies.

BACKGROUND: Dietary factors directly influence blood pressure (BP). The lactotripeptides (LTPs) IPP (isoleucine-proline-proline) and VPP (valine-proline-proline), formed by hydrolyzing dairy proteins, and potassium, a mineral mainly found in fruit, vegetables, and dairy products, are extensively studied for their BP-lowering effect. The efficacy of LTPs seems modest in whites compared with that in Asians. OBJECTIVE: The objective was to study the effects of enzymatically produced LTPs alone or in combination with potassium on ambulatory BP in whites. DESIGN: Two multicenter, placebo-controlled, randomized, crossover studies were conducted; each consisted of two 4-wk intervention periods separated by a 4-wk washout period. In study 1, 69 subjects received 200 g/d of a dairy drink with 5.8 mg IPP and 4.4 mg VPP or placebo. In study 2, 93 subjects received 100 g/d of a dairy drink with 2.7 mg IPP, 1.9 mg VPP, and 350 mg added K or placebo. The subjects were randomly assigned according to their daytime ambulatory BP. RESULTS: Mean 24-h systolic and diastolic BP (baseline values-study 1: 137.1/81.6 mm Hg; study 2: 139.2/80.9 mm Hg) remained similar with no significant differences between treatments in either study (P > 0.10). Office BP decreased over the course of both studies (systolic BP > 5 mm Hg), but differences between interventions were not significant (P > 0.10). In both studies, nighttime BP dipped during all treatments (> or =15%) but was statistically more significant with placebo (P < 0.05). Sodium excretion increased significantly after consumption of LTPs and potassium compared with after placebo intervention (P = 0.01), but not after consumption of LTPs alone. CONCLUSION: The data do not support a BP-lowering effect of LTPs in whites.

Enzymatically hydrolyzed lactotripeptides do not lower blood pressure in mildly hypertensive subjects.

BACKGROUND: Several placebo-controlled clinical studies suggest that products containing isoleucyl-prolyl-proline and valyl-prolyl-proline are able to lower blood pressure without adverse effects. The most efficient way of producing high concentrations of these lactotripeptides (LTPs) is enzymatic hydrolysis of dairy protein (casein) with the use of a mixture of several enzymes derived from the nongenetically modified organism Aspergillus oryzae, including proteases and peptidases. To date, no large studies of the blood pressure-lowering properties of enzymatically produced LTP (ELTP) powder in European populations have been published. OBJECTIVE: This study was performed to evaluate the hypothesis that consumption of ELTP in a yogurt beverage for 8 wk significantly lowers blood pressure. DESIGN: In this multicenter, double-blind, parallel, placebo-controlled trial, office blood pressure was evaluated in 275 Dutch hypertensive subjects. Blood pressures and body weight were measured on several days at baseline and at weeks 4 and 8 of the intervention between 2.5 and 3 h after intake of the test product. Twenty-four-h urine samples were collected at baseline and at the end of the intervention for urinalysis of sodium, potassium, creatinine, and microalbumin excretion. RESULTS: The results showed that 10.2 mg ELTP/d does not lead to a reduction in systolic blood pressure (P = 0.66) or diastolic blood pressure (P = 0.72) compared with placebo. CONCLUSION: This study showed no effect of an ELTP-enriched yogurt beverage on blood pressure in hypertensive subjects in a fairly large study.

Vascular and renal actions of brain natriuretic peptide in man: physiology and pharmacology.

During the last decade brain natriuretic peptide (BNP) has received increasing attention as a potential marker of cardiovascular disease. BNP may act as a compensating mechanism in cardiovascular diseases in order to reduce preload. However, the increase in endogenous BNP is often not sufficient to compensate for volume overload in diseases like established hypertension and heart failure. The reported hemodynamic and renal effects of BNP in man differ largely between studies, because of differences in design and doses of BNP employed. In the pharmacological range, BNP has clear blood pressure and afterload lowering effects, and in the kidney blood flow and filtration is increased with concomitant natriuresis and diuresis. While in the physiological range BNP does not affect blood pressure and reduces preload only, and induces natriuresis/diuresis without changes in renal blood flow and filtration. There is increasing evidence from vascular studies that BNP preferentially acts on the venous system resulting in preload reduction, in contrast to atrial natriuretic peptide which acts preferentially on the arterial system to reduce afterload. This review summarizes our current understanding of BNP, and discuss its regulation and mechanisms of action on the vasculature and the kidneys.

Hemodynamic and renal effects of low-dose brain natriuretic peptide infusion in humans: a randomized, placebo-controlled crossover study.

Brain natriuretic peptide (BNP) is a cardiac hormone with natriuretic activity. The aim of this study was to investigate the cardiovascular effects of pathophysiological levels of BNP on central hemodynamics, cardiac function, renal hemodynamics and function, and microvascular hemodynamics in healthy subjects. In this double-blind, placebo-controlled crossover study, we intravenously infused BNP (4 pmol. kg-1. min-1) or placebo for 1 h on two separate days in 12 healthy subjects (mean age, 60 +/- 5 yr). Nailfold and conjunctival capillary density, finger-skin (thermoregulatory) microvascular blood flow, and cardiac output were studied before and after infusion using intravital videomicroscopy, laser-Doppler fluxmetry, and echocardiography, respectively. Furthermore, during infusion, we measured the effective renal plasma flow and glomerular filtration rate using p-aminohippurate and inulin clearances. Blood pressure and heart rate were monitored for all measurements. Compared with placebo, BNP significantly decreased stroke volume with a tendency to decrease cardiac output. With subjects in the sitting position, mean arterial pressure decreased and heart rate increased after BNP infusion, whereas with subjects in the supine position, these variables remained unchanged. BNP increased natriuresis, diuresis, glomerular filtration rate, filtration fraction, and filtered load of Na+ compared with placebo, whereas effective renal plasma flow did not change. BNP did not affect the microvascular capillary density of conjunctiva and skin, microvascular blood flow, total skin oxygen capacity, and postocclusive recruitment. These results suggest that BNP has predominantly central and renal hemodynamic effects; however, it does not influence peripheral microcirculation in skin and conjunctiva.

Does brain natriuretic peptide have a direct renal effect in human hypertensives?

Systemic infusion of brain natriuretic peptide (BNP) stimulates natriuresis and diuresis but has variable effects on the renal vasculature. In this study, we investigated whether BNP has any direct effects on the kidney in hypertensive patients. Three stepwise increasing doses of BNP (60, 120, and 180 pmol/min) or placebo were infused into the renal artery of 26 hypertensive patients. Renal blood flow was determined with the 133Xenon washout technique. Before and after infusion of BNP, arterial and venous blood samples were taken for cGMP, renin, and creatinine concentration. Intra-arterial blood pressure and heart rate were monitored continuously. Intrarenal BNP infusion did not induce significant changes in renal blood flow despite increases in circulating levels of cGMP. The latter, however, was not associated with changes in the cGMP gradient across the kidney. In addition, we did not find any BNP-related changes in the secretion of active renin and in creatinine extraction. At the highest dose, heart rate increased after BNP infusion without a change in mean intra-arterial blood pressure. In conclusion, this study suggests that at least in hypertensive subjects, BNP has no direct intrarenal hemodynamic effects and that the rise in circulating cGMP without changes in net renal extraction of this second messenger is related to a primary extrarenal target of BNP.

Nitric oxide and potassium channels are involved in brain natriuretic peptide induced vasodilatation in man.

OBJECTIVE: Brain natriuretic peptide (BNP) causes vasodilatation but the mechanisms by which this is accomplished are not fully known. The aim of the present study was to determine whether, besides K+Ca2+-channels, nitric oxide (NO) is involved in BNP-induced vasodilatation. METHODS: We studied 10 healthy males twice, in random order, at an interval of 2 weeks. Experiments always started with infusion of BNP (8-16-32-64 pmol/dl per min) into the brachial artery. On the first day this infusion was followed by a second BNP infusion combined with the K+Ca2+-channel-blocker, tetraethylammonium (TEA, 0.1 mg/dl per min), and on the other day by BNP infusion combined with the NO-synthase inhibitor, l-NG-monomethyl arginine (l-NMMA, 0.8 mumol/dl per min). The latter was then followed by a combined infusion of BNP, l-NMMA and TEA. All infusions were separated by a 1 h washout period. Forearm blood flow (FBF) was determined by venous occlusion plethysmography. RESULTS: Mean arterial pressure and heart rate did not change during any of the experiments. BNP alone induced a dose-dependent dilatation, which was similar on both days. TEA, l-NMMA, and their combination all reduced the BNP-induced dilatation (P < 0.05). The combined infusion had a significantly greater effect than TEA alone (P = 0.005). BNP infusions were associated with a significant increase in plasma cyclic guanosine monophosphate (cGMP) and C-type natriuretic peptide (CNP) (P < 0.05). CONCLUSIONS: BNP induces arterial vasodilatation not only by opening K+Ca2+-channels, but also via stimulation of NO production. In addition, BNP stimulates net CNP increase.