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Increased plasma aldosterone concentration is significantly associated with dementia, which is accentuated by diabetes mellitus (DM). Angiotensin II (AngII) deteriorates cognitive function through neuronal degradation. Lipoproteins, a major source of cholesterol for aldosterone biosynthesis, undergo glycoxidative modifications in the presence of hyperglycemia. We hypothesize that there would be a pathophysiological link between diabetically-modified lipoproteins, angiotensin II, and increased plasma aldosterone concentration for induction of cognitive impairment. Glycoxidized lipoproteins produce significantly more aldosterone from AngII-sensitized adrenocortical cells compared to their native counterparts. The elucidation of signaling mechanisms revealed that modified lipoproteins follow the similar signaling mechanism like AngII for adrenocortical aldosterone release via ERK1/2 and Janus kinase-2 (Jak-2)-mediated pathways. The enhanced aldosterone release from AngII-sensitized adrenocortical cells induced by glycoxidatively modified lipoproteins may play a crucial role in cognitive dysfunction in diabetic individuals along with AngII via a prevailing mode of signaling cascade involving ERK1/2- and Jak-2-dependent pathways., Competing Interests: Conflicts of interest: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Angiotensin II (ANG II) is an important factor for the progression of renal diseases. ANG II has many pleiotropic effects on the kidney such as pro-inflammatory and profibrotic actions besides the well-known blood pressure-increasing effect., Novel Knowledge: Organs have local ANG II-generating systems that work independently from their classic systemic counterpart. Renal proximal tubular cells could generate and secrete ANG II into the urine in concentrations that are 10,000 times higher than those found in serum. These local systems are only incompletely blocked by currently used doses of ACE inhibitors or AT(1) antagonists. There are other enzyme systems besides ACE that contribute to the formation of ANG II. Alternative pathways generate peptides such as angiotensin 1-7 that have antagonistic effect compared with ANG II. Degradation products of ANG II such as angiotensin IV bind at separate receptors and could mediate fibrosis. The discovery of AT(1) receptor dimers and agonistic antibodies against AT(1) receptors contributes to the complexity of the system., Clinical Relevance: The complexity of the renin-angiotensin-aldosterone system (RAAS) implies that dual blockade with ACE inhibitors and AT(1) receptor antagonists makes sense for pathophysiological reasons. First clinical studies have shown that such as dual therapy reduces progression of chronic renal disease more efficiently that the respective monotherapies in certain risk populations. This shows that novel pathophysiological data could lead to innovative clinical treatment strategies.

Atrial fibrillation (AF) is the most common clinical arrhythmia and one of the most important factors for embolic stroke. In recent years, a tremendous amount has been learned about the pathophysiology and molecular biology of AF. Thus, pharmacologic interference with specific signal transduction pathways appears promising as a novel antiarrhythmic approach to maintain sinus rhythm and to prevent atrial clot formation. This review highlights the underlying molecular biology of atrial fibrillation, which may also be relevant for AF therapy.

ACE (Angiotensin Converting Enzyme) inhibitors and angiotensin II type 1 receptor antagonists increase the effective renal plasma flow dose dependently, whereas glomerular filtration rate does not change. Both substances reduce dose dependently arterial blood pressure, glomerular capillary pressure and proteinuria and are probably comparably renoprotective due to haemodynamic and non-haemodynamic (e.g. antiproliferative) effects. These data indicate that the renoprotective effects of ACE inhibitors and angiotensin II receptor antagonists are the results of inhibition of angiotensin II and not due to inhibition of bradykinin degradation. Several studies suggest an additive renoprotective effect of ACE inhibitors and angiotensin II receptor antagonists. However, controlled clinical studies are lacking. Experimental data suggest that the combination of AT1 and AT2 receptor blockers or treatment with ACE inhibitors reduce more effectively inflammatory cell infiltration into the kidney than angiotensin II type 1 receptor antagonists alone. Long-term clinical trials using angiotensin II type 1 receptor antagonists are needed before these substances can be recommended as comparably renoprotective as ACE inhibitors.

Unlabelled: Chronic renal failure is the consequence of progressive glomerulosclerosis and tubulo-interstitial fibrosis. The initiating hallmark of nephrosclerosis represents nephronal hypertrophy, due to an accumulation of proteins in the glomeruli and tubulointerstitium. From experimental and clinical investigations the conclusion can be drawn that the disturbed intrarenal protein balance with the consequent nephronal hypertrophy is at least partly the result of reduced protein degradation. Potential factors involved in impaired renal proteinase activities are cytokines like transforming growth factor beta 1 (TGF-beta 1), angiotensin II and advanced glycation endproducts (AGEs)., Conclusion: Nephrosclerosis as the common histological endpoint of chronic renal insufficiency is the result of an interaction between many pathogenetic factors. Its growing understanding implies the possibility of new therapeutic options to retard the progressive course of chronic renal failure.

The beneficial cardiovascular effects of ACE inhibitors are thought to be based primarily on a reduction in vascular angiotensin II formation. However, since ACE also degrades the potent endothelium-dependent vasodilator bradykinin, it has been proposed that the local accumulation of this peptide in the vascular wall represents an additional mechanism by which ACE inhibitors exert their cardiovascular effects. In this context it has been demonstrated that incubation of cultured endothelial cells with ACE inhibitors leads to an enhanced formation of nitric oxide (NO) and prostacyclin (PGI2). This effect is believed to be the consequence of an accumulation of endothelium-derived bradykinin in the vicinity of the endothelial cells. Moreover, by virtue of an as yet unidentified mechanism, ACE inhibitors may also enhance the potency of bradykinin at the receptor level and/or activate the B2-kinin receptor following pre-exposure to bradykinin. Both of these effects may enhance or sustain the bradykinin-induced formation of NO and PGI2 by the endothelium. ACE inhibition also leads to the accumulation of angiotensin I which can be metabolized to angiotensin-(1-7) by another endothelial enzyme, the neutral endopeptidase 24.11. Activating an as yet unidentified receptor, angiotensin-(1-7) (but not other known angiotensin peptides) stimulates endothelial NO release in coronary arteries from different species as well as in the isolated perfused rat heart. This effect also seems to involve the release of vasoactive kinins from the endothelium. The shift in angiotensin I metabolism towards an enhanced formation of angiotensin-(1-7) in the presence of an ACE inhibitor may thus also contribute to the hypotensive action of this class of compounds.

While nitrates have been in clinical use for more than 100 years, their mode of action is of rather recent discovery. Nitrates act by the release of the free radical NO (nitric oxide) which stimulates the cyclic guanosine monophosphate as vasodilatator and as inhibitor of platelet function. The endogenous nitrate NO is derived from L-arginine catalyzed by nitric oxide synthase, a recently cloned enzyme. Nitrates and other nitro-vasodilatators act similarly to the endogenous nitrate, whereby a basal release of NO in the vascular wall reduces the effect of nitro-vasodilatators. Therefore, drugs are particularly effective in endothelium-free vessel segments and in veins, where the basal release of NO is low. A recently discovered effect of nitro-vasodilatators is the inhibition of thrombin and angiotensin II-induced production of endothelin. Insofar the L-arginine/NO metabolism acts as an important regulator in the vessel wall and has a protective role in the circulation by its antispastic and antithrombotic principle.

The renin angiotensin system is an important system for the regulation of blood pressure and salt and water homeostasis. As a pathogenetic factor it is involved in the development of several forms of renal hypertension and, furthermore, it participates in the pathogenesis of primary and secondary hypertension. The regulation of the activity of the system is under the control of neuronal and hormonal mechanisms and depends on blood pressure and plasma concentrations of sodium chloride. With the development of converting enzyme inhibitors and their vasodilator, diuretic and sympatholytic actions a new important antihypertensive principle for lowering blood pressure was found. In this context also local renin angiotensin systems which have been described for several tissues have to be discussed as a possible target of action for converting enzyme inhibitors.

The pathogenesis of cardiopulmonary insufficiency in intensive-care patients is reviewed, with special reference to the development of interstitial pulmonary oedema. Measures designed to control the condition and compensate for the increased post-operative and post-traumatic calorie and aminoacid requirements are: 1. restricted fluid intake; 2. digitalization and administration of diuretics; 3. administration of highly concentrated human albumin. Potential pulmonary reactions to, and possible beneficial effects of, parenteral fat administration are discussed.

A central stimulatory effect of angiotensin II (AII) on the secretion of arginine-vasopressin (AVP) has been described. The competitive blocker of AII, saralasin (SAR) has been used for diagnostic purposes in angiotensin-dependent hypertension. In addition SAR has a partially agnoistic effect. The aim of the present study was to demonstrate whether AVP-levels can be influenced during SAR-induced renin stimulation. In 9 patients with essential hypertension blood pressure dropped significantly under SAR (10 microgram/kg/min over a 30 min period). Before and after SAR plasma renin activity (PRA) and AVP were measured by RIA, SAR evoked significantly increments of PRA in all patients and of AVP in 6 patients. The increased serum concentrations of AVP following SAR may be explained either by the depressor effect of SAR, its diminished concentration at the central receptor, or a partial AII-agonistic effect.

1. Angiotensin II (A II) and angiotensin (3--8)-hexapeptide (H) were measured by radioimmunoassay in arterial and venous plasma before and during infusion of angiotensin II-amide in five normotensive subjects, both in sodium-replete and sodium-depleted states. The separation of the oligopeptides was performed by thin layer chromatography. 2. Before sodium-depletion the mean ratio of arterial to venous A II was 1.14+/-0.11:1, corresponding to an A II-extraction of approximately 12% during a single forearm passage. Infusion of A II-amide increased extraction of A II. The mean ratio of arterial to venous A II increased to 1.68+/-0.3:1, corresponding to an extraction of approximately 39% when 8 ng-min-1-kg-1 were infused. 3. Sodium depletion increased arterial and venous concentrations of A II and H. During infusion of angiotensin II-amide the arterial and venous concentrations of A II and H increased approximately parallel to the concentrations before sodium depletion. The extraction of A II did not differ significantly in both states. 4. The augmented extraction extraction of A II observed during infusion of angiotensin II-amide suggest an overproportional increase of the metabolism of A II under the latter condition. Sodium depletion, however, does not appear to cause a percent change in A II metabolism.

In about 15% of cases hypertension is caused by renal diseases, including unilateral and bilateral parenchymatous nephropathies, renal artery stenosis and renin producing tumors. Important pathogenic determinants are the sodium volume status and the renin angiotensin system. The level of the blood pressure may also depend on the duration of hypertension. An increase in peripheral resistance plays a more important role than an increase in cardiac index. Simultaneous determination of the renin activity in both renal veins is of decisive importance in the diagnosis of renal artery stenosis. Drug treatment of renal hypertension is not essentially different from that of essential hypertension. Surgical procedures include revascularization, uninephrectomy and, in uncontrollable hemodialysis patients, binephrectomy.

Current pathogenetic concepts regarding renal hypertension are reviewed. Alterations of the renin-angiotensin-aldosterone system (RAA) on the one hand, and disturbances of NaCl and water metabolism on the other, represent the dominant factors in renal hypertension. The present view of the reactions within the RAA system and of its activators, inhibitors or antagonists is described schematically. The angiotensin II-antagonist 1-sar-8-ala-angiotensin II (Saralasin), when infused in a patient with angiotensinogenic hypertension, induces normalization of the blood pressure during the course of the infusion. The Saralasin infusion test may be of assistance in detecting cases with angiotensinogenic hypertension. The pressor(s) and the extracellular fluid volume appear to be the decisive pathogenetic factors in renal hypertension. As long as the functioning renal mass is sufficient to excrete water and salt normally or in excess, as is the case when the renal perfusion pressure in hypertension is elevated, the pressor is the dominating factor besides other, so far hypothetical mechanism such as the neurogenic. A critical reduction of the renal mass will enhance fluid and salt retention. Thus, an increase in extracellular fluid volume and blood volume will emerge as a major factor inducing hypertension. As a consequence of the volume gain and salt retention, renin secretion may slow down. The possibility is mentioned that the absence or ineffectiveness of renal depressor substances (prostaglandins) may be involved in renal hypertension. Finally, two hypotheses are presented which may explain the finding of LARAGH et al., who grouped their essential hypertensives into 'high, normal and low renin hypertensives'.