A H Danser

..A local renin-angiotensin system in the heart is often invoked to explain the beneficial effects of ACE inhibitors in heart failure. The heart, however, produces little or no renin under normal conditions...

..e., immediate binding of angiotensin II to its receptors with minimal loss into the extracellular space...

..with the local generation or effects of angiotensin II), and (5) to what degree do differences in tissue angiotensin generation underlie the association between cardiovascular diseases and renin-angiotensin system gene polymorphisms?..

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..ACE inhibitors potentiate BK independent of their effect on BK metabolism...

..Here we quantify ACE genotype-related Ang I to Ang II conversion in the human forearm and leg using non-pressor 125I-Ang I infusions...

..In addition, the role of alternative angiotensin-generating enzymes (cathepsin, chymase) and the possibility of (pro)renin uptake from the circulation is evaluated...

..To overcome this problem, we now infused 125I-angiotensin I directly into the renal artery...

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..To study whether the vasorelaxant effect of bradykinin in the coronary vascular bed depends on the release of NO from preformed pools and/or de-novo synthesis of NO resulting from bradykinin-induced stimulation of NO synthase...

..Plasma renin concentrations are an important factor in cardiovascular risk profiling...

..RVC, at baseline or with ANG II, was not affected by PD123319 in infarcted and sham animals. In conclusion, coronary but not renal AT(2) receptor stimulation results in vasodilation, and this effect is enhanced in infarcted rats...

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..CONCLUSIONS: In the intact rat heart, ACE is the main contributor to angiotensin I to angiotensin II conversion, both in the coronary vascular bed and the interstitium. Cardiac ACE is not limited to the coronary vascular endothelium...

..The inhibitory effects of Ang-(1-7) are limited to the ACE C-domain, raising the possibility that Ang-(1-7) synergistically increases the blood pressure-lowering effects of N-domain-specific ACE inhibitors...

..The inconsistent results obtained with L-NAME suggest that it depends on NO synthesized de novo and/or NO from storage sites...

..Most likely, therefore, in the absence of angiotensinogen synthesis or endocytosis, M6P receptor-mediated prorenin internalization by endothelial cells represents prorenin clearance...

..We propose the existence of a low-Ang II vascular system-related interstitial compartment that is separate from tubular fluid, where, according to micropuncture studies, Ang II levels might be high...

..In conclusion, AT(2)-Rs modulate cardiac hypertrophy in women with HCM, independently of the circulating renin-angiotensin system. These data support the contention that AT(2)-Rs mediate antitrophic effects in humans...

..CONCLUSIONS: Acute vasoconstriction by Ang II is not mediated via superoxide generated through NAD(P)H oxidase and/or XO activation. Such activation, if occurring, rather results in the generation of the vasodilator H2O2...

..Ultimately, this could lead to the development of (pro)renin receptor blockers (i.e., drugs that not only prevent tissue angiotensin generation but also inhibit renin- or prorenin-induced effects)...

..This review discusses several approaches to guide angiotensin-converting enzyme-inhibition therapy to more specific groups of patients that are most likely to benefit...

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..ACE-inhibitor users with at least one copy of the 235T-allele of the AGT gene might have an increased risk of MI and stroke...

..The review ends with a brief overview of the available (pre)clinical aliskiren data and a description of its safety profile...

..Here, we evaluated the kinetics of renin/prorenin binding to the recently discovered human (pro)renin receptor (h(P)RR), and the idea that such binding underlies tissue angiotensin generation...

..The review ends with the concept that prorenin rather than renin determines tissue angiotensin generation...

..We also investigated whether aliskiren affects (pro)renin binding to its receptors, using rat aortic vascular smooth muscle cells (VSMCs) overexpressing the h(P)RR...

..This review provides an update on the sources of (pro)renin in the body, lists the known stimulants and inhibitors of its production, and discusses the concept that prorenin rather than renin determines tissue angiotensin generation...

..CONCLUSIONS: Circulating (pro)renin, angiotensinogen, ANG I and ANG II enter the interstitium via diffusion, and interstitial ANG II generation is mediated, at least in part, by basolaterally located endothelial ACE...

..In the present study, mice lacking tissue-bound angiotensin converting enzyme (t-ACE -/-) were used to investigate the importance of t-ACE during cardiac remodeling after myocardial infarction...

..Taken together, our results do not support the concept of Ang II generation in cardiomyocytes following intracellular prorenin activation...

..e., the Ace allele of the normotensive Wistar-Kyoto (WKY) rat, in the hypertensive background of stroke-prone spontaneously hypertensive (SHRSP) rats...

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..Our data do not support angiotensin generation by truncated prorenin...

..5. Interstitial, rather than circulating Ang II determines vasoconstriction. Arterial Ang I, resulting in high interstitial Ang II levels via its local conversion by ACE, may be of greater physiological importance than arterial Ang II...

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..Intracellular angiotensin II generation is unlikely to occur, in particular because angiotensinogen is not available in the cytosol...

..We hypothesized that angiotensin-converting enzyme inhibition (ACE-I) during left ventricular assist device (LVAD) support in patients with end-stage heart failure prevents potentially deleterious effects on the extracellular matrix...

..This finding raises the need for studies determining the benefit of aldosterone blockade in HCM...

..These effects are specific and involve PKC and ERK 1/2, respectively. Furthermore, they occur in a nongenomic manner, and require pathological aldosterone concentrations...

..Lack of significant effects on the RV suggest that hemodynamic unloading of the LV (not provided to the RV) might be the primary factor that regulates these extracellular matrix changes...

..The rapid, mineralocorticoid receptor-independent kinetics of aldosterone suggest that its accumulation in the heart involves cell surface binding rather than internalization...

..MR blockade reduces infarct size and increases LVP recovery following coronary artery occlusion. The MR-related phenomena may underlie, at least in part, the beneficial actions of spironolactone in heart failure...

..The sessions were divided into basic, clinical and population science. The abstracts have been published in a supplement to Circulation (2004) 110(7)...

..It is eventually concluded that angiotensin generation at tissue sites occurs extracellularly, most likely on the cell surface...

..The levels of angiotensin-(1-7) are increased during ACE inhibition, and most studies suggest that its hypotensive effects are mediated in a bradykinin-dependent manner...

..The objective of this study was to investigate ACE- and chymase-dependent angiotensin I-to-II conversion in human coronary arteries (HCAs)...

..Some of these effects occur via or in synergy with angiotensin II, and involve a non-MR-mediated mechanism. This raises the possibility that aldosterone synthase inhibitors might exert beneficial effects on top of MR blockade...