Blood pressure lowering effects of Lactobacillus helveticus fermented milk containing bioactive peptides Ile-Pro-Pro and Val-Pro-Pro; mechanistic, kinetic and clinical studies

The purpose of the present study was to evaluate the effects of Lactobacillus helveticus fermented milk (peptide milk) containing the casein-derived tripeptides Isoleucyl-prolyl-proline (Ile-Pro-Pro) and Valyl-prolyl-proline (Val-Pro-Pro) on blood pressure and vascular function in hypertensive subjects. The peptide milk lowered systolic and diastolic blood pressure in long-term use in hypertensive subjects when blood pressure was measured by using 24-hour ambulatory blood pressure measurement (ABPM). The blood pressure lowering effect was seen with the dose of 50 mg of tripeptides, and a tendency for lowering blood pressure was also observed when the dose was 5 mg. No adverse effects compared to the placebo group were reported or detected in laboratory analysis. The effect of the peptide milk on arterial stiffness was shown using two different methods, the ambulatory arterial stiffness index (AASI) and pulse wave analysis (PWA). According to the AASI, arterial stiffness was significantly reduced in the peptide milk group compared to the baseline level, but the difference was not significant compared to the placebo group. PWA showed that the peptide milk reduced arterial stiffness significantly compared to the placebo group. Endothelium-independent relaxation (nitroglycerin) and endothelium-dependent relaxation (salbutamol) did not differ between the groups. The blood pressure lowering mechanisms of the tripeptides and the kinetics of Ile-Pro-Pro were investigated using spontaneously hypertensive rats (SHR) and Sprague-Dawley rats. Previous studies have suggested that the blood pressure lowering effect of the tripeptides Ile-Pro-Pro and Val-Pro-Pro is based on angiotensin-converting enzyme inhibition, but the present findings did not agree with these previous studies. It was shown in SHR that calcium, potassium and magnesium may also have an important role in attenuating the development of hypertension as part of the peptide milk effect. In addition, the present study suggests indirectly that improved endothelial nitric oxide release capacity is not the mechanism by which peptide milk mediates its favourable circulatory effects. The kinetics of Ile-Pro-Pro were studied using adult Sprague-Dawley rats. The results showed that orally administered Ile-Pro-Pro is absorbed at least partly intact from the gastrointestinal tract. Radiolabelled Ile-Pro-Pro was distributed in different tissues and considerable radioactivity levels were found in tissues related to the renin-angiotensin system (RAS), adrenals, aorta and kidneys. Ile-Pro-Pro does not bind to plasma proteins, and therefore it is possible that its blood pressure lowering effect is mediated by free Ile-Pro-Pro. In conclusion, consumption of the peptide milk lowers blood pressure and reduces arterial stiffness in hypertensive subjects. Ile-Pro-Pro can be absorbed partly intact from the gastrointestinal tract and might accumulate in tissues related to the RAS. The precise blood pressure lowering mechanism of peptide milk remains to be studied.

Heidegger ja logos : Oleminen ja aika inhimillisen järjellisyyden uudelleentulkintana

Käsilläolevan tutkielman kohteena on Martin Heideggerin (1889–1976) tulkintatyö, jonka hän varhaisessa ajattelussaan (1919–1927) kohdisti kreikkalaisen filosofian keskeiseen käsitteeseen logos: ”järki”, ”puhekyky”. Tutkielman tavoitteena on selvittää, miten Heidegger tulkitsi tätä käsitettä ja mikä merkitys Heideggerin tulkintatyöllä oli hänen pääteoksensa Sein und Zeit (1927, suom. Oleminen ja aika) kannalta. Työn keskeinen näkemys on, että Heideggerin ajattelu on nähtävä kreikkalaisen järjellisyyskäsityksen kriittisenä arviointina ja uudelleentulkintana. Heideggerin filosofia pohjautui vahvasti näkemykselle, jonka mukaan ajattelumme on hyvin perustavassa mielessä kiinni perinteessä ja sen välittämissä käsityksissä ja tulkinnoissa. Heideggerin mukaan filosofinen tutkimus ei voi koskaan täysin ennakkoluulotonta ja tämän vuoksi kaiken ajattelun on päästävä selville oman tilanteensa historiallisuudesta ja satunnaisuudesta; tieteellinen filosofia ei voi valita systemaattisen ja historiallisen lähestymistavan välillä, vaan sen on oltava olemuksellisesti molempia. Vuosina 1919–1929 Heideggerin historiallisen tulkintatyön ensisijaisena kohteena oli kreikkalainen filosofia, erityisesti Aristoteleen ajattelu. Heideggerin mukaan Aristoteles ei ollut ensimmäinen filosofista ajattelua harjoittanut henkilö, mutta Heidegger näki Aristoteleen tuotannon tiivistävän yhteen länsimaisen ajattelun keskeisimmät ennakkokäsitykset. Tutkielmassa seurataan Heideggerin pyrkimystä tulkita inhimillisen järjellisyyden ilmiötä, jonka juuret Heidegger paikansi Aristoteleen ihmismääritelmään zōon logon ekhon (”järjellinen eläin”). Aristotelesta seurannut skolastinen filosofia omaksui tämän määritelmän muodossa animal rationale, mutta Heidegger painotti, että tällä käännöksellä oli taipumus sivuuttaa se perusta, joka oli vielä ominainen kreikkalaiselle järjen käsitteelle. Sillä Aristoteleelle ja kreikkalaiselle ajattelulle logos ei merkinnyt ainoastaan haluihin ja tunteisiin rinnastuvaa mielen sisäistä kykyä vaan ennen kaikkea yhteisöllisesti jaettua tulkintaa ympäröivästä todellisuudesta. Tämä tulkinta ilmenee jokapäiväisesti keskustelun ja kommunikaation yhteydessä, mutta se on myös olennainen osa tapaamme jäsentää ympäröivää todellisuutta merkitykselliseksi. Heidegger kuitenkin argumentoi, että kreikkalainen ajattelu näki tämän kielellis-diskursiivisen käsittämisen alisteisena inhimillisen kokemuksen perustaville tavoille olla suhteessa todellisuuteen: puhtaalle aistihavainnolle (aisthēsis) sekä intuitiiviselle tajuamiselle (noein). Tutkielma koostuu neljästä luvusta sekä lyhyestä johdannosta. Ensimmäinen luku käsittelee Heideggerin filosofian kantavaa teemaa, kysymystä olemisen mielestä – sekä tämän kysymyksen perustaa kreikkalaisessa ajattelussa. Tämän jälkeen luodaan katsaus Heideggerin fenomenologiseen metodiin, sen ensisijaiseen kohdealueeseen inhimillisessä kokemuksessa sekä fenomenologisen tutkimuksen historialliseen ulottuvuuteen. Toisessa luvussa esitetään puolestaan Heideggerin tulkinta käsitteestä logos. Tulkinnan ymmärtämiseksi on välttämätöntä esittää tiivistetysti Heideggerin tulkinta kreikkalaisesta totuuden käsitteestä. Heideggerin mukaan kreikkalainen ajattelu ymmärsi totuuden monitasoisena ilmiönä, jonka perustavin käyttöyhteys on löydettävissä todellisuuden ilmiöstä. Kolmannessa luvussa pureudutaan niihin piirteisiin, joiden valossa Aristoteles Heideggerin mukaan tulkitsi kielen ja kokemuksen välistä suhdetta. Neljännessä luvussa esitetään, mitä edellä esitetyt oivallukset merkitsivät Heideggerin oman filosofisen projektin kannalta, erityisesti inhimillistä olemassaoloa (Dasein) selvittäneen fundamentaaliontologian kannalta.

Milk casein-derived tripeptides : A special focus on blood pressure and vascular function

Increased consumption of low-fat milk products is inversely associated with the risk of hypertension. The beneficial effect of milk on blood pressure is attributed to high calcium and potassium content but also to specific peptide sequences, which are cleaved from milk protein during gastrointestinal digestion, fermentation of milk with proteolytic starter cultures or enzymatic hydrolysis. Milk products fermented with Lactobacillus helveticus contain casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro), which have been shown to possess antihypertensive effects in humans and in experimental animals. The aim of the present series of studies was to investigate the effects of tripeptides Ile-Pro-Pro and Val-Pro-Pro or fermented milk products containing them on vascular function and blood pressure and to elucidate the mechanisms behind them by using different experimental models of hypertension. Another aim was to characterize the acute effects of tripeptides on blood pressure and arterial stiffness in mildly hypertensive humans. Ile-Pro-Pro and Val-Pro-Pro or fermented milk products containing them attenuated the development of hypertension in two experimental models of hypertension, spontaneously hypertensive rat (SHR) and type 2 diabetic Goto-Kakizaki (GK) rat fed with high-salt diet. Significant differences in systolic blood pressure (SBP) were seen after 8 weeks treatment with tripeptide-containing products compared to control product. Plant sterols did not enhance this effect. Two differently produced tripeptide powders produced a similar attenuating effect on SBP in SHR. In mildly hypertensive subjects, a single administration of tripeptide- and plant sterol-containing fermented milk product decreased both SBP and diastolic blood pressure (DBP) over a period of 8 hours. Protective effect of tripeptides Ile-Pro-Pro and Val-Pro-Pro and fermented milk products containing them on vascular function was demonstrated in in vitro studies and long-term experimental studies. The effect was shown to be endothelium-dependent and possibly involving endothelium-derived hyperpolarizing factor (EDHF). In the clinical study, single administration of tripeptide-containing fermented milk product did not affect measures of arterial stiffness. Long-term treatment with fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro inhibited angiotensin-converting enzyme (ACE) and decreased aldosterone levels thus showing beneficial effects on the renin-angiotensin system (RAS) in SHR and GK. No changes in the components of RAS were observed by the single administration of the same product in mildly hypertensive subjects. Increased levels of cGMP, NOx and citrulline suggest increased nitric oxide (NO) production by the tripeptides. Taken together, Ile-Pro-Pro and Val-Pro-Pro -containing products attenuate the development of hypertension after long-term treatment in experimental models of hypertension and possess an acute antihypertensive effect in mildly hypertensive subjects. In addition, these tripeptides show endothelium-mediated beneficial effects on vascular function. Attenuation of blood pressure increase by the tripeptides in experimental animals involves RAS, but its role in the antihypertensive effect in humans remains to be elucidated.

Direct and Inverse Scattering for Beltrami Fields

We consider an obstacle scattering problem for linear Beltrami fields. A vector field is a linear Beltrami field if the curl of the field is a constant times itself. We study the obstacles that are of Neumann type, that is, the normal component of the total field vanishes on the boundary of the obstacle. We prove the unique solvability for the corresponding exterior boundary value problem, in other words, the direct obstacle scattering model. For the inverse obstacle scattering problem, we deduce the formulas that are needed to apply the singular sources method. The numerical examples are computed for the direct scattering problem and for the inverse scattering problem.

Direct and Inverse Scattering for Beltrami Fields

We consider an obstacle scattering problem for linear Beltrami fields. A vector field is a linear Beltrami field if the curl of the field is a constant times itself. We study the obstacles that are of Neumann type, that is, the normal component of the total field vanishes on the boundary of the obstacle. We prove the unique solvability for the corresponding exterior boundary value problem, in other words, the direct obstacle scattering model. For the inverse obstacle scattering problem, we deduce the formulas that are needed to apply the singular sources method. The numerical examples are computed for the direct scattering problem and for the inverse scattering problem.