Heikki Vapaatalo

Clinical trial: multispecies probiotic supplementation alleviates the symptoms of irritable bowel syndrome and stabilizes intestinal microbiota

Background  Irritable bowel syndrome is the most common diagnosis in gastroenterology. Trials suggest certain probiotics to be beneficial.

Coffee, caffeine and blood pressure: a critical review

Objective: We review the published data relating to intake of coffee and caffeine on blood pressure in man. We also refer to studies on the possible mechanisms of actions of these effects of caffeine.Design: The MEDLINE and Current Contents databases were searched from 1966 to April 1999 using the text words ‘coffee or caffeine’ and ‘blood pressure or hypertension’. Controlled clinical and epidemiologic studies on the blood pressure effects of coffee or caffeine are reviewed. We also refer to studies on the possible mechanisms of action of these effects of caffeine.Results: Acute intake of coffee and caffeine increases blood pressure. Caffeine is probably the main active component in coffee. The pressor response is strongest in hypertensive subjects. Some studies with repeated administration of caffeine showed a persistent pressor effect, whereas in others chronic caffeine ingestion did not increase blood pressure. Epidemiologic studies have produced contradictory findings regarding the association between blood pressure and coffee consumption. During regular use tolerance to the cardiovascular responses develops in some people, and therefore no systematic elevation of blood pressure in long-term and in population studies can be shown.Conclusions: We conclude that regular coffee may be harmful to some hypertension-prone subjects. The hemodynamic effects of chronic coffee and caffeine consumption have not been sufficiently studied. The possible mechanisms of the cardiovascular effects of caffeine include the blocking of adenosine receptors and the inhibition of phosphodiesterases.

Nitric Oxide in Inflammation and Immune Response

This short review deals with the role of a recently found signalling molecule, nitric oxide (NO), in inflammatory and immune responses. NO regulates inflammatory erythema and oedema and has cytotoxic action against micro-organisms. In some instances (such as reperfusion injury) NO has cytoprotective properties. Production of large amounts of NO by activated macrophages accounts for their ability to suppress lymphocyte proliferation. NO synthesis in lymphocytes is questionable but cytokines secreted by activated lymphocytes regulate NO synthesis by macrophages. Constitutive NO synthase is activated in neutrophils in response to inflammatory stimuli and NO has diverse, often biphasic effects on neutrophil functions. Increased concentrations of nitrite and nitrate (metabolites of NO) are present in arthritic joints. NO is synthesized not only by migrated inflammatory cells but also by articular chondrocytes and inflamed synovial membrane. In the inflamed joint, NO regulates the synthesis of several inflammatory mediators and functions of inflammatory cells. In addition, NO seems to mediate some destructive effects of proinflammatory cytokines such as interleukin-1. In conclusion, NO regulates several humoral and cellular responses in inflammation, having both anti-inflammatory and proinflammatory properties depending on the type and phase of the inflammatory reaction.

Effect of long-term intake of milk products on blood pressure in hypertensive rats

The effect of long-term intake of two fermented milk products on the development of hypertension was compared in young spontaneously hypertensive rats (SHR). The products contained tripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), which have been shown to possess angiotensin converting enzyme (ACE) inhibitory activity. Six-week-old SHR were divided into four groups to receive orally ad libitum water, skim milk or two fermented milk poducts (fermented milk A or fermented milk B; the latter is commercially available in Japan with trade name Calpis) for 14 weeks. The calculated intake of IPP was 0.4 mg/d and 0.2 mg/d in the groups receiving fermented milk A and B, respectively, whereas the corresponding amounts for VPP were 0.6 mg/d and 0.3 mg/d. Systolic blood pressure (SBP) was monitored weekly by tail-cuff method. The development of hypertension was significantly attenuated in both groups receiving fermented milk products, whereas skim milk did not affect blood pressure. The effect was detectable after 6 weeks of treatment. At the end of the experiment, the lowest blood pressure level was found in the group receiving fermented milk A: the SBP was 21 mm Hg lower than in the group receiving water and 10 mm Hg lower than in the group receiving fermented milk B. This difference could be explained by larger intake of ACE inhibitory tripeptides in the group receiving fermented milk A as compared with fermented milk B.

Probiotic supplementation improves tolerance to Helicobacter pylori eradication therapy--a placebo-controlled, double-blind randomized pilot study.

Background : H. pylori is the major cause of chronic gastritis, and a risk factor for peptic ulcer and gastric cancer.

α-Lactorphin lowers blood pressure measured by radiotelemetry in normotensive and spontaneously hypertensive rats

Abstract Cardiovascular effects of subcutaneous administration of synthetic α-lactorphin, a tetrapeptide (Tyr-Gly-Leu-Phe) originally derived from milk α-lactalbumin, were studied in conscious spontaneously hypertensive rats (SHR) and in normotensive Wistar Kyoto rats (WKY) with continuous radiotelemetric monitoring. α-Lactorphin dose-dependently lowered blood pressure (BP) without affecting heart rate in SHR and WKY. The lowest dose which reduced BP was 10 μg/kg, and the maximal reductions in systolic and diastolic BP (by 23 ± 4 and 17 ± 4 mm Hg, respectively) were observed at 100 μg/kg dose in SHR. No further reductions were obtained at a higher dose of 1 mg/kg. There were no significant differences in the BP responses to α-lactorphin between SHR and WKY. Naloxone (1 and 3 mg/kg s.c.), a specific opioid receptor antagonist, abolished the α-lactorphin-induced reduction in BP and reversed it into a pressor response, which provides evidence for an involvement of opioid receptors in the depressor action of the tetrapeptide.

Endothelial Dysfunction and Salt-Sensitive Hypertension in Spontaneously Diabetic Goto-Kakizaki Rats

Endothelial dysfunction is associated with hypertension, hypercholesterolemia, and heart failure. We tested the hypothesis that spontaneously diabetic Goto-Kakizaki (GK) rats, a model for type 2 diabetes, exhibit endothelial dysfunction. Rats also received a high-sodium diet (6% NaCl [wt/wt]) and chronic angiotensin type 1 (AT1) receptor blockade (10 mg/kg PO valsartan for 8 weeks). Compared with age-matched nondiabetic Wistar control rats, GK rats had higher blood glucose levels (9.3±0.5 versus 6.9±0.2 mmol/L for control rats), 2.7-fold higher serum insulin levels, and impaired glucose tolerance (all P <0.05). Telemetry-measured mean blood pressure was 15 mm Hg higher in GK rats (P <0.01) compared with control rats, whereas heart rates were not different. Heart weight– and kidney weight–to–body weight ratios were higher in GK rats (P <0.05), and 24-hour albuminuria was increased 50%. Endothelium-mediated relaxation of noradrenaline-precontracted mesenteric arterial rings by acetylcholine was impaired compared with the control condition (P <0.05), whereas the sodium nitroprusside–induced relaxation was similar. Preincubation of the arterial rings with the NO synthase inhibitor NG-nitro-l-arginine methyl ester and the cyclooxygenase inhibitor diclofenac inhibited relaxations to acetylcholine almost completely in GK rats but not in Wistar rats, suggesting that endothelial dysfunction can be in part attributed to reduced relaxation via arterial K+ channels. Perivascular monocyte/macrophage infiltration and intercellular adhesion molecule-1 overexpression were observed in GK rat kidneys. A high-sodium diet increased blood pressure by 24 mm Hg and 24-hour albuminuria by 350%, induced cardiac hypertrophy, impaired endothelium-dependent relaxation further, and aggravated inflammation (all P <0.05). The serum level of 8-isoprostaglandin F2&agr;, a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased 400% in GK rats on a high-sodium diet. Valsartan decreased blood pressure in rats fed a low-sodium diet and prevented the inflammatory response. In rats fed a high-sodium diet, valsartan did not decrease blood pressure or improve endothelial dysfunction but protected against albuminuria, inflammation, and oxidative stress. As measured by quantitative autoradiography, AT1 receptor expression in the medulla was decreased in GK compared with Wistar rats, whereas cortical AT1 receptor expression, medullary and cortical angiotensin type 2 (AT2) receptor expressions, and adrenal ACE and neutral endopeptidase expressions were unchanged. A high-sodium diet did not influence renal AT1, AT2, ACE, or neutral endopeptidase expressions. In valsartan-treated GK rats, the cortical and medullary AT1 receptor expressions were decreased in the presence and absence of a high-sodium diet. A high-sodium diet increased plasma brain natriuretic peptide concentrations in presence and absence of valsartan treatment. We conclude that hypertension in GK rats is salt sensitive and associated with endothelial dysfunction and perivascular inflammation. AT1 receptor blockade ameliorates inflammation during a low-sodium diet and partially protects against salt-induced vascular damage by blood pressure–independent mechanisms.

Effects of probiotic therapy on the activity and activation of mild rheumatoid arthritis-a pilot study

Objective: To study the effects of Lactobacillus rhamnosus GG (LGG) on rheumatoid arthritis (RA). Methods: Twenty‐one RA patients were randomised to receive 2 capsules of LGG or a placebo twice daily in double‐blind fashion for 12 months. Arthritis activity was evaluated by clinical examination, HAQ index, and laboratory tests (e.g. ESR, CRP, pro‐ and anti‐inflammatory cytokines). Results: There were no statistical differences in the clinical parameters, biochemical variables and HAQ index between the study groups over the intervention period. The mean number of tender and swollen joints decreased from 8.3 to 4.6 in the Lactobacillus group and from 5.5 to 4.8 in the placebo group (p=0.41). According to the global assessment the RA activity was reduced in 71% (LGG group) vs. 30% (controls) (p=0.15). Serum IL‐1β increased slightly in the LGG group (p=0.07), but no differences were seen in IL‐6, TNF‐α, MPO, IL‐10 or 1L‐12. Conclusions: Although there were no statistical significant differences in the activity of RA, more subjects in the LGG group reported subjective well being. More studies on the effects of probiotic bacteria in RA are needed.

Endothelial Dysfunction and Xanthine Oxidoreductase Activity in Rats With Human Renin and Angiotensinogen Genes

We examined whether xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, is involved in the onset of angiotensin (Ang) II–induced vascular dysfunction in double-transgenic rats (dTGR) harboring human renin and human angiotensinogen genes. In 7-week-old hypertensive dTGR, the endothelium-mediated relaxation of noradrenaline (NA)-precontracted renal arterial rings to acetylcholine (ACh) in vitro was markedly impaired compared with Sprague Dawley rats. Preincubation with superoxide dismutase (SOD) improved the endothelium-dependent vascular relaxation, indicating that in dTGR, endothelial dysfunction is associated with increased superoxide formation. Preincubation with the XOR inhibitor oxypurinol also improved endothelium-dependent vascular relaxation. The endothelium-independent relaxation to sodium nitroprusside was similar in both strains. In dTGR, serum 8-isoprostaglandin F2&agr;, a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased by 100%, and the activity of XOR in the kidney was increased by 40%. Urinary nitrate plus nitrite (NOx) excretion, a marker of total body NO generation, was decreased by 85%. Contractile responses of renal arteries to Ang II, endothelin-1 (ET-1), and NA were decreased in dTGR, suggesting hypertension-associated generalized changes in the vascular function rather than a receptor-specific desensitization. Valsartan (30 mg/kg PO for 3 weeks) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. Valsartan also normalized serum 8-isoprostaglandin F2&agr; levels, renal XOR activity, and, to a degree, NOx excretion. Thus, overproduction of Ang II in dTGR induces pronounced endothelial dysfunction, whereas the sensitivity of vascular smooth muscle cells to nitric oxide is unaltered. Ang II–induced endothelial dysfunction is associated with increased oxidative stress and vascular xanthine oxidase activity.

Angiotensin II induces connective tissue growth factor gene expression via calcineurin-dependent pathways.

Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis. Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGFbeta(1), collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cell-mediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and calcineurin-dependent pathways.