Blood Pressure Lowering Properties Research Articles

Reduction of leptin levels by four cardiac hormones: Implications for hypertension in obesity

Circulating levels of leptin are increased in obesity and have been proposed to contribute to the development of hypertension in obese individuals. Four cardiac hormones, specifically, vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide and atrial natriuretic peptide (ANP), have blood pressure-lowering properties and correlate with the presence of hypertension in obesity. The objective of this study was to determine whether one or more of these cardiac hormones was able to decrease the levels of leptin in the hypothalamus, an area of the brain that has been demonstrated to synthesize more than 40% of leptin in the circulation. The effects of these four cardiac hormones on leptin were examined using dose-response curves in the rat hypothalamus, which synthesizes leptin. Vessel dilator, LANP, kaliuretic peptide and ANP maximally decreased the levels of leptin in hypothalamic cells by 79, 76, 80 and 62%, respectively (P<0.0001 for each). The cardiac hormones decreased leptin levels over a concentration range of 100 pM to 10 μM, with the most significant reductions in leptin levels occurring when the concentrations of the hormones were at micromolar levels. The results of the study suggest that the four cardiac hormones lead to significant reductions in hypothalamic leptin levels, which may be an important mechanism for alleviating leptin-induced hypertension in obesity.

Aged garlic extract reduces blood pressure in hypertensives: a dose–response trial

Background/objectives:Hypertension affects about 30% of adults worldwide. Garlic has blood pressure-lowering properties and the mechanism of action is biologically plausible. Our trial assessed the effect, dose–response, tolerability and acceptability of different doses of aged garlic extract as an adjunct treatment to existing antihypertensive medication in patients with uncontrolled hypertension.Subjects/methods:A total of 79 general practice patients with uncontrolled systolic hypertension participated in a double-blind randomised placebo-controlled dose–response trial of 12 weeks. Participants were allocated to one of three garlic groups with either of one, two or four capsules daily of aged garlic extract (240/480/960 mg containing 0.6/1.2/2.4 mg of S-allylcysteine) or placebo. Blood pressure was assessed at 4, 8 and 12 weeks and compared with baseline using a mixed-model approach. Tolerability was monitored throughout the trial and acceptability was assessed at 12 weeks by questionnaire.Results:Mean systolic blood pressure was significantly reduced by 11.8±5.4 mm Hg in the garlic-2-capsule group over 12 weeks compared with placebo (P=0.006), and reached borderline significant reduction in the garlic-4-capsule group at 8 weeks (−7.4±4.1 mm Hg, P=0.07). Changes in systolic blood pressure in the garlic-1-capsule group and diastolic blood pressure were not significantly different to placebo. Tolerability, compliance and acceptability were high in all garlic groups (93%) and highest in the groups taking one or two capsules daily.Conclusions:Our trial suggests aged garlic extract to be an effective and tolerable treatment in uncontrolled hypertension, and may be considered as a safe adjunct treatment to conventional antihypertensive therapy.

Characterization of Telmisartan‐Derived PPARγ Agonists: Importance of Moiety Shift from Position 6 to 5 on Potency, Efficacy and Cofactor Recruitment

Selective modulation of the peroxisome proliferator-activated receptor gamma (PPARγ) by direct binding of small molecules demonstrates a promising tool for treatment of insulin resistance and type 2 diabetes mellitus. Besides its blood pressure-lowering properties, the AT1-receptor blocker telmisartan has been shown to be a partial agonist of PPARγ with beneficial metabolic effects in vitro and in mice. In our previous work, comprehensive structure-activity relationship (SAR) studies discussed the different parts of the telmisartan structure and various moieties. Based on these findings, we designed and synthesized new PPARγ ligands with a benzimidazole (agonists 4-5 and 4-6), benzothiophene (agonists 5-5 and 5-6) or benzofuran (agonists 6-5 and 6-6) moiety either at position 5 or 6 of the benzimidazole core structure. Lipophilicity and EC50 values were improved for all new compounds compared with telmisartan. Regarding PPARγ activation, the compounds were characterized by a differentiation assay using 3T3-L1 cells and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPARgDEF, pGal5-TK-pGL3 and pRL-CMV. A decrease in both potency and efficacy was observed after the shift of either the benzothiophene or the benzofuran moiety from position 6 to position 5. Selective recruitment of the coactivators TRAP220, SRC-1 and PGC-1α, and release of corepressor NCoR1 determined by time-resolved fluorescence resonance energy transfer (TR-FRET) was detected depending on residues in position 5 or 6.

MANP: A Novel Designer Natriuretic Peptide for Cardiometabolic Disease

Introduction: Atrial natriuretic peptide (ANP) is a cardiac hormone that plays an important role in blood pressure regulation via the guanylyl cyclase receptor A (GC-A) and cGMP. ANP also induces lipolysis in vitro and in vivo and we have reported that an ANP genetic variant (rs5068), which is associated with higher circulating levels of ANP is also associated with lower prevalence of metabolic syndrome in a US general population. MANP is a newly Mayo engineered designer natriuretic peptide (NP) consisting of the native ANP with 12-amino-acid C-terminus extension. Studies in canines established that MANP has greater blood pressure (BP) lowering, natriuretic, and aldosterone-suppressing properties than ANP. To date, the metabolic actions of MANP remain unexplored. Hypothesis: MANP possesses not only cardiovascular but also metabolic properties. Methods: For in vitro studies, human embryonic kidney (HEK) 293 cells transfected with either GC-A or guanylyl cyclase receptor B (GC-B), and human subcutaneous and visceral preadipocytes were assessed for cGMP production by MANP. Cells were treated with 10 M, 10 8 M, or 10 M MANP for 10 min. In vivo, we defined the BP lowering and metabolic actions of acute MANP (30 pmol/kg/min, iv) or vehicle in normal Sprague-Dawley rats. After equilibration (45 minutes) MANP was administered iv for 75 min. Results: In vitro, MANP induced cGMP production in GC-A but not GC-B expressing HEK cells. MANP significantly increased cGMP in human subcutaneous and visceral preadipocytes. In vivo, infusion of MANP significantly increased plasma MANP levels compared to vehicle (222 vs 10 pg/ml, p50.019). MANP infusion decreased BP when compared to baseline (91 vs 100 mmHg, p50.016), vehicle had no significant effect (92 vs 95 mmHg, p5 0.19). Plasma levels of nonesterified fatty acids (NEFA), a marker for lipolysis, tended to be higher after infusion of MANP than after vehicle (598 vs 462 mg/dl, p5 0.06). Conclusions: The designer NP MANP demonstrates specificity for GC-A and activates cGMP in human subcutaneous and visceral preadipocytes. In vivo, MANP possesses blood pressure lowering actions and causes an increase in NEFA plasma levels suggesting a lipolytic effect. Further studies are warranted to better define the cardiorenal and metabolic actions of MANP and its possible therapeutic roles in cardiometabolic disease which is a risk factor for future heart failure.

Reply to Lundberg, Larsen, and Weitzberg

to the editor: The letter of Lundberg et al. ([12][1]) does not relate directly to any of the articles we published in this journal ([1][2], [2][3], [6][4]). Rather, the correspondents make a general point on the potential risks to athletes who might choose to supplement their diet with nitrate or (

In Vitro and In Vivo Actions of a Novel ANP Genetic Variant: Unique Actions on Human Endothelial Cells

In Vitro and In Vivo Actions of a Novel ANP Genetic Variant: Unique Actions on Human Endothelial Cells

Hypotensive effect of Achillea wilhelmsii aqueous-ethanolic extract in rabbit

Objective: For many years in herbal medicine the antihypertens ive and lowering blood lipid properties of Achillea wilhelmsii (A. wilhelmsii) have been suggested . In the present study the impacts of the plant extract on rabbit’s blood pres sure and heart rate have been investigated. Materials and Methods: Twelve NWZ rabbits weighed 2-3 kg were randomly divided into two groups of 6 rabbits. The test group received A. wilhelmsii extract (20, 40 and 80 mg/kg) and the control group received normal saline by jugular vei n cannula. Blood pressure and heart rate were measured via carotid cannula using pressure transdu cer connected to a power lab system. Results: The blood pressure was significantly decreased (16. 7± 1.4 mmHg) in 80 mg/kg dose of the extract (p<0.05). However, there were not any s ignificant effects on heart rate in the other doses of the extract or normal saline. Conclusion: the aqueous-ethanolic extract has blood pressure lo wering property which may due to cardiac depressant and/or vasorelaxant effects.

Benefits of Prestroke Use of Angiotensin Type 1 Receptor Blockers on Ischemic Stroke Severity

There is a general agreement that the stroke prevention benefit of antihypertensive agents is mainly based on their blood pressure lowering properties. The aim of this retrospective study was to assess the benefits of angiotensin type 1 receptor blockers (ARBs) used before the onset of ischemic stroke. Data were obtained between April 2007 and March 2009 using the discharge statistics of the neurologic service at Juntendo hospital. We retrieved the demographic and clinical characteristics of stroke patients and functional status upon discharge assessed by the modified Rankin Scale (mRS) and Barthel index (BI). We enrolled 151 patients. Patients treated with ARBs were less often treated with a calcium channel blocker (CaB)/angiotensin-converting enzyme inhibitor (ACEI). They often had diabetes and showed better outcomes than the non-ARB group. Logistic regression analysis indicated that in patients with a mRS score of 0 to 2, older age (P < .007) was associated with severe outcomes, while the factor of pretreatment with ARB (P < .014) was associated with better outcomes. For patients with BI scores of more than 75, older age (P < .015) and large artery atherosclerosis (P < .035) were associated with severe outcomes. Logistic regression analysis identified the factor of pretreatment with ARB (P < .020) to be associated with better outcomes. ARB is widely used in patients with hypertension and cardiovascular disease, and our results further support this indication.

A Novel Atrial Natriuretic Peptide Based Therapeutic in Experimental Angiotensin II Mediated Acute Hypertension

M-atrial natriuretic peptide (ANP; M-ANP) is a novel next generation 40 amino acid peptide based on ANP, which is highly resistant to enzymatic degradation and has greater and more sustained beneficial actions compared with ANP. The current study was designed to advance our understanding of the therapeutic potential of M-ANP in a canine model of acute angiotensin II-induced hypertension with elevated cardiac filling pressures and aldosterone activation. We compare M-ANP with vehicle and equimolar human B-type natriuretic peptide, which possesses the most potent in vivo actions of the native natriuretic peptides. M-ANP significantly lowered mean arterial pressure and systemic vascular resistance. Importantly, despite a reduction in blood pressure, renal function was enhanced with significant increases in renal blood flow, glomerular filtration rate, diuresis, and natriuresis after M-ANP infusion. Although angiotensin II induced an acute increase in pulmonary capillary wedge pressure, M-ANP significantly lowered pulmonary capillary wedge pressure, pulmonary artery pressure, and right atrial pressure. Further, M-ANP significantly suppressed angiotensin II-induced activation of aldosterone. These cardiovascular and renal enhancing actions of M-ANP were accompanied by significant increases in plasma and urinary cGMP, the second messenger molecule of the natriuretic peptide system. When compared with human B-type natriuretic peptide, M-ANP had comparable cardiovascular actions but resulted in a greater natriuretic effect. These results suggest that M-ANP, which is more potent than ANP in normal canines, has potent blood pressure lowering and renal enhancing properties and may, therefore, serve as an ANP based therapeutic for acute hypertension.

Anticancer activity of a sub-fraction of dichloromethane extract of Strobilanthes crispus on human breast and prostate cancer cells in vitro

BackgroundThe leaves of Strobilanthes crispus (S. crispus) which is native to the regions of Madagascar to the Malay Archipelago, are used in folk medicine for their antidiabetic, diuretic, anticancer and blood pressure lowering properties. Crude extracts of this plant have been found to be cytotoxic to human cancer cell lines and protective against chemically-induced hepatocarcinogenesis in rats. In this study, the cytotoxicity of various sub-fractions of dichloromethane extract isolated from the leaves of S. crispus was determined and the anticancer activity of one of the bioactive sub-fractions, SC/D-F9, was further analysed in breast and prostate cancer cell lines.MethodsThe dichloromethane extract of S. crispus was chromatographed on silica gel by flash column chromatography. The ability of the various sub-fractions obtained to induce cell death of MCF-7, MDA-MB-231, PC-3 and DU-145 cell lines was determined using the LDH assay. The dose-response effect and the EC50 values of the active sub-fraction, SC/D-F9, were determined. Apoptosis was detected using Annexin V antibody and propidium iodide staining and analysed by fluorescence microscopy and flow cytometry, while caspase 3/7 activity was detected using FLICA caspase inhibitor and analysed by fluorescence microscopy.ResultsSelected sub-fractions of the dichloromethane extract induced death of MCF-7, MDA-MB-231, PC-3 and DU-145 cells. The sub-fraction SC/D-F9, consistently killed breast and prostate cancer cell lines with low EC50 values but is non-cytotoxic to the normal breast epithelial cell line, MCF-10A. SC/D-F9 displayed relatively higher cytotoxicity compared to tamoxifen, paclitaxel, docetaxel and doxorubicin. Cell death induced by SC/D-F9 occurred via apoptosis with the involvement of caspase 3 and/or 7.ConclusionsA dichloromethane sub-fraction of S. crispus displayed potent anticancer activities in vitro that can be further exploited for the development of a potential therapeutic anticancer agent.

Blood pressure-lowering properties of chokeberry ( Aronia mitchurinii, var. Viking)

The blood pressure-lowering properties of lyophilized chokeberry juice and polyphenols were monitored using in vitro angiotensin-converting enzyme (ACE) inhibition measurement and a 10 day in vivo study with spontaneously hypertensive rats (SHR). Juice and polyphenols indicated weak ACE-inhibitory activity. The IC 50 values for polyphenols and juice were 1.5–2.5 and 4.5 mg dry matter/ml, respectively. In the SHR study the blood pressure-lowering effects of juice and polyphenol extract seemed to be short-term and were generally highest after 3 h from administration (50 mg/kg/day) when mean reductions in systolic blood pressure were 20 ± 8 and 15 ± 7 mm Hg, respectively. Corresponding mean decreases in diastolic blood pressure were 23 ± 6 and 13 ± 2 mm Hg in juice and polyphenol groups, respectively. It was concluded that both chokeberry juice and polyphenols had blood pressure-lowering effects. We hypothesize that chokeberry polyphenols enhance endothelial nitric oxide production with an ACE-independent mechanism, e.g. by activation of endothelial nitric oxidase enzyme; this is yet to be verified.

Manidipine reduces pro-inflammatory cytokines secretion in human endothelial cells and macrophages

The dihydropyridine calcium antagonists (DHP-CA), commonly used for the treatment of hypertension, may exert antiatherosclerotic activity independent of the blood-pressure lowering properties. The aim of this study was to evaluate the effect in cell culture of the third generation DHP-CA Manidipine on the release of interleukin-6 (IL-6) and interleukin-8 (IL-8) from human endothelial cells and human macrophages, in response to different pro-inflammatory signals. In endothelial cells, incubation with acetylated LDL (acLDL), oxidized LDL (oxLDL) or tumor necrosis factor-α (TNF-α), increased the release of IL-6 from 50% to 100%. Manidipine 1–5 μM was able to completely inhibit IL-6 production induced by either of these factors. In these cells TNF-α increased by about 4 times the secretion of IL-8 and Manidipine 5 μM reduced the amount of IL-8 in the culture media by about 40%. In human macrophages THP-1, treatment with different cytokines was able to stimulate by about 3-folds the release of IL-6 and Manidipine 1 μM showed a 25% inhibition on TNF-α-induced IL-6 secretion. In these cells, a combined treatment with multiple cytokines, induced IL-6 production of about 6-folds and Manidipine was able to reduce such inflammatory response by 30%. Our experiments highlighted the anti-inflammatory properties of Manidipine in either human endothelial cells or macrophages. The mechanism by which Manidipine exert this effect is not related to its blocking activity on calcium channels and it involves an inhibition of NF-κB activation, that, in analogy with what is observed for other DHP-CA, may be related to the high lipophilicity and the antioxidant activity of this compound.

Low vs. Higher-Dose Dark Chocolate and Blood Pressure in Cardiovascular High-Risk Patients

Dark chocolate may have blood pressure-lowering properties. We conducted a prospective randomized open-label blinded end-point design trial to study a potential dose dependency of the presumed antihypertensive effect of dark chocolate by directly comparing low vs. higher doses of dark chocolate over the course of 3 months. We enrolled a total of 102 patients with prehypertension/stage 1 hypertension and established cardiovascular end-organ damage or diabetes mellitus. Patients were randomly assigned to receive either 6 or 25 g/day of flavanol-rich dark chocolate for 3 months. The difference in 24-h mean blood pressure between groups was defined as the primary outcome measure. Significant reductions in mean ambulatory 24-h blood pressure were observed between baseline and follow-up in both groups (6 g/day: -2.3 mm Hg, 95% confidence interval -4.1 to -0.4; 25 g/day: -1.9 mm Hg, 95% confidence interval -3.6 to -0.2). There were no significant differences in blood pressure changes between groups. In the higher-dose group, a slight increase in body weight was noted (0.8 kg, 95% confidence interval 0.06 to 1.6). The findings are consistent with the hypothesis that dark chocolate may be associated with a reduction in blood pressure (BP). However, due to the lack of a control group, confounding may be possible and the results should be interpreted with caution.

A Human Atrial Natriuretic Peptide Gene Mutation Reveals a Novel Peptide With Enhanced Blood Pressure-Lowering, Renal-Enhancing, and Aldosterone-Suppressing Actions

We sought to determine the physiologic actions and potential therapeutic applications of mutant atrial natriuretic peptide (mANP). The cardiac hormone atrial natriuretic peptide (ANP) is a 28-amino acid (AA) peptide that consists of a 17-AA ring structure together with a 6-AA N-terminus and a 5-AA C-terminus. In a targeted scan for sequence variants within the human ANP gene, a mutation was identified that results in a 40-AA peptide consisting of native ANP((1-28)) and a C-terminal extension of 12 AA. We have termed this peptide mutant ANP. In vitro 3',5'-cyclic guanosine monophosphate (cGMP) activation in response to mANP was studied in cultured human cardiac fibroblasts known to express natriuretic peptide receptor A. The cardiorenal and neurohumoral properties of mANP compared with ANP were assessed in vivo in normal dogs. We observed an incremental in vitro cGMP dose response with increasing concentrations of mANP. In vivo with high-dose mANP (33 pmol/kg/min), we observed significantly greater plasma cGMP activation, diuretic, natriuretic, glomerular filtration rate enhancing, renin-angiotensin-aldosterone system inhibiting, cardiac unloading, and blood pressure lowering properties when compared with native ANP. Low-dose mANP (2 pmol/kg/min) has natriuretic and diuretic properties without altering systemic hemodynamics compared with no natriuretic or diuretic response with low-dose native ANP. These studies establish that mANP activates cGMP in vitro and exerts greater and more sustained natriuretic, diuretic, glomerular filtration rate, and renal blood flow enhancing actions than native ANP in vivo.

Hypertension and the bradykinin system

The blood pressure-lowering property of the brady-kinin system has been documented for more than eight decades. The bradykinin system is involved in the mediation and modulation of the vasoconstrictor renin-angiotensin system and the vasodilators prostaglandin, prostacyclin, and nitric oxide in regulating sodium water balance, renal and cardiac hemodynamics, and blood pressure. Reduced activity of the bradykinin system has been observed in various hypertensive situations in both clinical and experimental models of hypertension. Antihypertensive properties of the angiotensin-converting enzyme or kininase II inhibitors are primarily mediated via the bradykinin-releasing pathway, which may also cause regression of left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate for treating hypertension and cardiovascular and renal diseases. In addition, stable bradykinin agonists may also be available in the future as therapeutic agents for cardio-vascular and renal disorders.

Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure.

We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure-lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 x 10(-70)), rs198358 (P = 8 x 10(-30)) and rs632793 (P = 2 x 10(-10)), and of plasma B-type natriuretic peptide with rs5068 (P = 3 x 10(-12)), rs198358 (P = 1 x 10(-25)) and rs632793 (P = 2 x 10(-68)). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found to be associated with lower systolic (P = 2 x 10(-6) and 6 x 10(-5), respectively) and diastolic blood pressure (P = 1 x 10(-6) and 5 x 10(-5)), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79-0.92, P = 4 x 10(-5); OR = 0.90, 95% CI = 0.85-0.95, P = 2 x 10(-4), respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension.

Treatment recommendations to prevent myocardial ischemia and infarction in patients undergoing vascular surgery

During major vascular surgery (MVS), patients are at high risk for developing unrecognized myocardial infarction (MI) and myocardial ischemia. In reducing postoperative morbidity and mortality, preoperative cardiac risk stratification and adequate medical therapy play a pivotal role. Based on literature and current opinions, medical treatment should comprise at least a combination of beta-blockers, aspirin, and statins. beta-Blockers exert their beneficial effects predominantly through heart rate control, leading to reduced oxygen demand during surgery. A heart rate between 65 and 70 bpm should be achieved. Irrespective of their lipid-lowering effects, statins seem to improve postoperative cardiac outcome by stabilizing coronary artery plaques, thereby preventing atherosclerotic plaque rupture. Aspirin reduces platelet activation and vasoconstriction, thereby limiting ischemic events and reducing nonfatal MI by 34%. Adding clopidogrel to low-dose aspirin might be beneficial toward postoperative cardiac outcomes; however, the effect on the incidence of postoperative bleeding complications may be a problem for future studies to resolve. Whereas beta-blockers inhibit the effect of catecholamines, alpha(2)-agonists inhibit catecholamine release and may be used in the perioperative setting when beta-blockers are contraindicated. Despite the blood pressure-lowering effect and anti-inflammatory properties of angiotensin-converting enzyme inhibitors, the literature does not support their use in patients undergoing MVS. The possible use of calcium antagonists before MVS should be further evaluated in high-risk patients with contraindications to beta-blockers, such as asthma, conduction abnormalities, or a history of stroke. Although nitrates are widely used for treating angina pectoris, the beneficial effect of their use in patients undergoing MVS remains controversial. Therefore, nitrates are not routinely used in the perioperative setting. The current American College of Cardiology/American Heart Association guidelines do not recommend prophylactic coronary revascularization before noncardiac surgery in patients with stable coronary artery disease.

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 organismAspergillus 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.

Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite

Diets rich in fruits and vegetables reduce blood pressure (BP) and the risk of adverse cardiovascular events. However, the mechanisms of this effect have not been elucidated. Certain vegetables possess a high nitrate content, and we hypothesized that this might represent a source of vasoprotective nitric oxide via bioactivation. In healthy volunteers, approximately 3 hours after ingestion of a dietary nitrate load (beetroot juice 500 mL), BP was substantially reduced (Delta(max) -10.4/8 mm Hg); an effect that correlated with peak increases in plasma nitrite concentration. The dietary nitrate load also prevented endothelial dysfunction induced by an acute ischemic insult in the human forearm and significantly attenuated ex vivo platelet aggregation in response to collagen and ADP. Interruption of the enterosalivary conversion of nitrate to nitrite (facilitated by bacterial anaerobes situated on the surface of the tongue) prevented the rise in plasma nitrite, blocked the decrease in BP, and abolished the inhibitory effects on platelet aggregation, confirming that these vasoprotective effects were attributable to the activity of nitrite converted from the ingested nitrate. These findings suggest that dietary nitrate underlies the beneficial effects of a vegetable-rich diet and highlights the potential of a "natural" low cost approach for the treatment of cardiovascular disease.

Occurrence of the Angiotensin-Converting Enzyme–Inhibiting Tripeptides Val-Pro-Pro and Ile-Pro-Pro in Different Cheese Varieties of Swiss Origin

The contents of the 2 antihypertensive peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) were determined in 101 samples from 10 different Swiss cheese varieties using HPLC with subsequent triple mass spectrometry. In the category of extra hard and hard cheeses, the Protected Denomination of Origin cheeses Berner Alpkäse and Berner Hobelkäse, L’Etivaz à rebibes, Le Gruyère, Sbrinz, Emmentaler (organic and conventional) and in the category of semihard cheeses, the varieties Tilsiter, Appenzeller 14 fat and full fat, Tête de Moine, and Vacherin fribourgeois were screened in the study. The average concentration of the sum of VPP and IPP in the screened cheese varieties varied to a large extent, and substantial variations were obtained for individual samples within the cheese varieties. The lowest average concentration of the 2 tri-petides was found in L’Etivaz à rebibes (n = 3) at 19.1mg/kg, whereas Appenzeller 14 fat (n = 4) contained the greatest concentration at 182.2mg/kg. In individual samples, the total concentration of VPP and IPP varied between 1.6 and 424.5mg/kg. With the exception of a 10-yr-old cheese, VPP was always present at greater concentrations than IPP. Milk pretreatment, cultures, scalding conditions, and ripening time were identified as the key factors influencing the concentration of these 2 naturally occurring bioactive peptides in cheese. The results of the present study show that various traditional cheese varieties contain, on average, similar concentrations of the 2 antihypertensive peptides to the recently developed fermented milk products with blood pressure–lowering property. This may serve as a basis for the development of a functional cheese with blood pressure–lowering property.