Thesis (doctoral)--Ludwig Maximilians-Universität zu München, 1979.

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In 2008 the global prevalence of hypertension [high blood pressure (BP), systolic ≥140 mmHg and/or diastolic ≥90 mmHg] was around 40% in adults > 25 yrs of age, according to the 2013 WHO statistics. Hypertension is a major risk factor for myocardial infarction, heart failure and stroke. Currently, around 20% of the Canadian population is affected by hypertension. Hypertension is more closely associated with diabetes. More than two thirds of people with diabetes have hypertension, alongwith increased activity of the renin angiotensin aldosterone (RAAS) system. The RAAS plays a major role in maintaining fluid balance, vascular tone and BP. The components of the RAAS include the hormone renin, which cleaves angiotensinogen, a circulating inactive peptide into angiotensin I. Angiotensin converting enzyme (ACE) converts angiotensin I into the active peptide angiotensin II (Ang II). Ang II causes vasoconstriction, sodium reabsorption from the kidney tubules and also release of the hormone, aldosterone, from the adrenal cortex. The epidemic of hypertension, diabetes and obesity is widely attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. However, the underlying molecular mechanisms are far from clear. A high fructose diet increases BP in Sprague-Dawley (SD) rats; along with elevated plasma and aortic levels of methylglyoxal (MG). MG is a reactive dicarbonyl compound mainly formed as an intermediate during glycolysis. Small amounts of MG are also formed during amino acid (threonine) and fatty acid metabolism. MG reacts with certain proteins to form irreversible advanced glycation end products (AGEs). MG has high affinity for arginine, lysine and cysteine. Plasma MG levels are increased in hypertensive rats and diabetic patients. However, it is not yet clear whether MG is the cause or effect of hypertension. Moreover, safe and specific MG scavengers are not available. The aim of the project was to determine the effect of MG and a high fructose diet on the RAAS and the BP in male SD rats. The hypothesis that L-arginine, and its inactive isomer D-arginine, can efficiently scavenge MG in vitro, was also tested. Male SD rats were treated with a continuous infusion of MG with a subcutaneous minipump for 4 weeks, or with a high fructose diet (60% of total calories) for 16 weeks. We also used isolated aortic rings from 12 week old normal male SD rats to study endothelial function. Organs / tissues, cultured human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs) were used for molecular studies. HPLC, Western blotting and Q-PCR were used to measure MG, reduced glutathione (GSH), proteins and mRNA, respectively. siRNA for angiotensinogen and the receptor for advanced glycation endproducts (RAGE) were used to study mechanisms. MG treated rats developed a significant increase in BP and plasma levels of aldosterone, renin, angiotensin and catecholamines. MG level, and protein and mRNA for angiotensin, AT1 receptor, adrenergic α1D receptor and renin were significantly increased in the aorta and/or kidney of MG treated rats, a novel finding. Alagebrium, a MG scavenger and AGEs breaker, attenuated the above effects of MG. Treatment of cultured VSMCs with MG or high glucose (25mM) significantly increased cellular MG, and protein and mRNA for nuclear factor kappa B (NF-κB), angiotensin, AT1 and α1D receptors, which were prevented by inhibition of NF-κB, and by alagebrium. Silencing of mRNA for RAGE prevented the increase in NF-kB induced by MG. Silencing of mRNA for angiotensinogen prevented the increase in NF-κB, angiotensin, AT1 and α1D receptors’ protein. Fructose treated rats developed a significant increase in BP. MG level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of fructose and MG were attenuated by metformin, a MG scavenger and AGEs inhibitor. In experiments to test the MG scavenging action of arginine, both D-arginine and L-arginine prevented the attenuation of acetylcholine-induced endothelium-dependent vasorelaxation by MG and high glucose. However, the inhibitory effect of the NOS inhibitor, Nω-nitro-L-arginine methyl ester, on vasorelaxation was prevented only by L-arginine, but not by D-arginine. MG and high glucose increased protein expression of arginase, a novel finding, and also of NADPH oxidase 4 and NF-κB, and production of reactive oxygen species in HUVECs and VSMCs, which were attenuated by D- and L-arginine. However, D- and L-arginine did not attenuate MG and high glucose-induced increased arginase activity in VSMCs and the aorta. D- and L-arginine also attenuated the increased formation of the MG-specific AGE, Nε-carboxyethyl lysine, caused by MG and high glucose in VSMCs. In conclusion, MG activates NF-κB through RAGE and thereby increases renin angiotensin levels, a novel finding, and a probable mechanism of increase in BP. There is a strong association between elevated levels of MG, RAGE, NF-κB, mediators of the RAAS and BP in high fructose diet fed rats. Arginine attenuates the increased arginase expression, oxidative stress, endothelial dysfunction and AGEs formation induced by MG and high glucose, by an endothelial NOS independent mechanism.

Thesis (doctor of medicine)--Aarhus Universitet, 1980. / Text in English with summaries in English and Swedish. Spine title: Renin and sodium in renal hypertension.

and key words Enhanced activation of renin-angiotensin system (RAS) and endothelin system (ES) plays the key pathophysiological role in the progression of hypertension and the chronic kidney disease (CKD). The aim of this study was to verify wheter the combined inhibition RAS and selective inhibition ETA receptor for endothelin 1 (ET-1) will show additive renoprotective effects in experimental model CKD. This therapeutic aproach was tested on the transgenic rats with mouse renin gen (TGR), to whome ablation nephrectomy (5/6 NX) was done in the age of 6 weeks. After next 6 weeks the relevant treatment was given in drinking-water: dual RAS blockade (trandolapril 6mg/L + losartan 100mg/L) or the combination of dual RAS blockade + inhibitor of ETA receptor (atrasentan 25mg/L). Results of the first series show 100 % mortality in untreated rats with 5/6 NX to the 30th week. Both type of treatments increased the survival rate up to 30 % in 5/6 NX TGR after the 50th week. In the second series influence of treatments on the blood pressure (BP) was monitored in 5/6 NX TGR, which had systolic BP over 210 mmHg. Both treatments decreased BP to the level normotensive rats and reduced heart hypertrophy. In the third series the results showed that treatment significantly decreased renal level of angiotensin II...

Part I. The aldosterone synthase gene (CYP11B2) polymorphism T-344C in blood pressure and left ventricular hypertrophy. BACKGROUND: Aldosterone is a key cardovascular hormone, it significantly influences volume, pressure and electrolyte balance. Aldosterone plays an important role in development of left ventricular (LV) hypertrophy and myocardial fibrosis. The aldosterone synthase gene (CYP11B2) is an important candidate gene region in essential hypertension. DESIGN AND METHODS: We assessed the influence of the T-344C polymorphism of aldosterone synthase - the rate-limiting enzyme in aldosterone biosynthesis - on the structure of the left ventricle in young normotensive men. The population included 113 normotensive mid-European Caucasian men aged 18-40 years (mean 27 +/- 5 years). We also studied the association of -344T/C polymorphism of the CYP11B2 gene with the presence and severity of hypertension in 369 individuals, of whom 213 were hypertensive patients (139 controlled hypertensive, 74 resistant hypertensive) and 156 were healthy normotensive subjects. The genotype was assessed using polymerase chain reaction with subsequent cleavage with restriction enzyme HAEIII (restriction fragment length polymorphism method) and visualization with ethidium bromide. Plasma renin activity (PRA) and plasma...