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Although the use of angiotensin converting enzyme inhibitors (ACE-Is) in clinical practice brought the great chance to recognize the RAS role in the physiology and pathology, there are still many questions which we cannot answer. This article reviews actually known pathways of angiotensin II (Ang II) and other peptides of renin-angiotensin system (RAS) production and their physiological significance. The various carboxy- and aminopeptidases generate a range of peptides, like Ang II, Ang III, Ang IV, Ang-(1-7) and Ang-(1-9) possessing their own and known biological activity. In this issue especially the alternative pathways of Ang II synthesis involving enzymes other than angiotensin-converting enzyme (ACE) are discussed. We present many evidences for the significance of a new pathway of Ang II production. It has been clearly shown that Ang I may be converted to Ang-(1-9) by angiotensin-converting enzyme-related carboxypeptidase (ACE-2) and then into Ang II in some tissues, but the enzymes responsible for this process are unknown till now. Although there are many data proving the existence of alternative pathways of Ang II production, we can still block only ACE and angiotensin receptor 1 (AT1) in clinical practice. It seems that a lot needs to be done before we can wildly complexively control RAS and treat more effectively cardiovascular disorders such as hypertension or heart failure.
Recent study demonstrated that duodenal HCO3- secretion is affected by modulation of the renin-angiotensin system. We examined the effects of enalapril (angiotensin-converting enzyme (ACE) inhibitor) or losartan (angiotensin AT1 receptor antagonist) on duodenal HCO3- secretion in rats and investigated the mechanisms involved in the renin-angiotensin system-related HCO3- response. A proximal duodenal loop was perfused with saline, and HCO3- secretion was measured at pH 7.0 using a pH-stat method and by adding 2 mM HCl. Enalapril increased the HCO3- secretion in a dose-dependent manner, with a decrease in arterial blood pressure (MBP), and these effects were significantly attenuated by pretreatment with indomethacin, L-NAME and FR172357 (a selective bradykinin B2 receptor antagonist). Although losartan alone did not affect the HCO3- secretion, despite reducing MBP, the agent dose-dependently increased the HCO3- secretion in the presence of angiotensin II, and this response was totally antagonized by prior administration of FR172357, indomethacin and L-NAME. Bradykinin also dose-dependently increased the HCO3- secretion with no change in MBP, though transient, and again the effects were blocked by indomethacin, L-NAME and FR172357. Both prostaglandin (PG) E2 and the nitric oxide (NO) donor NOR-3 also increased the HCO3- secretion, the latter effect being inhibited by indomethacin. These results suggest that both an ACE inhibitor and AT1 antagonist (in the presence of angiotensin II) increase duodenal HCO3- secretion via a common pathway, involving bradykinin, NO and PGs. It is also assumed that bradykinin releases NO locally, which in turns stimulates HCO3- secretion mediated by PGs.
Introduction. Numerous studies have focused on the association between I/D ACE and physical fi tness; however, this association in professional hockey players has never been recognized. Aim of the Study. The study examined the distribution of Alu insertion (I)/deletion (D) angiotensin converting enzyme (ACE) genotypes in elite male professional fi eld hockey players. Material and Methods. The effect of Alu insertion (I)/deletion (D) angiotensin converting enzyme (ACE) genotypes on motor skills and maximal oxygen uptake (VO₂max) in 47 elite male fi eld hockey players was studied. Genotyping for ACE I/D was performed using a polymerase chain reaction on DNA from leucocytes. The studied motor skills such as speed – 20 m run, power – vertical jump, recovery – step-test, speed endurance (15 x 20 m) shuttle run, were established using functional tests. The VO₂max was measured during progressive exercise test till exhaustion. Results. The authors do not confi rm some literature data that D allele favours endurance ability. We did not detect signifi cant genotype effects of ACE on the analyzed traits; how-ever a tendency for decreased performance of individuals with the DD genotype was noted for vertical jump, power peak and power. Conclusions. Analysis of the genetic profi le of ACE I/D may provide supplemetary information on a player’s predispositions to exercise with specifi c energy requirements.
We have previously demonstrated that chronic exposure to low-dose of mercury induced endothelial dysfunction and increased vasoconstrictor responses. The aim of this work was to investigate if mercury exposure alters contractile prostanoids production from cyclooxygenase-2 (COX-2) and its contribution to phenylephrine responses. For this, aortic segments from 3-month old Wistar rats daily treated with HgCl2 (1st dose 4.6 µg/kg, subsequent dose 0.07 µg/kg/day, i.m.) or vehicle for 30 days were used. Mercury treatment did not affect systolic blood pressure but increased phenylephrine-induced vasoconstriction. The non selective COX inhibitor, indomethacin (10 µmol/l) reduced the response to phenylephrine more in aortic segments from mercury-treated than control rats. The selective COX-2 inhibitor NS 398 (1 µmol/l), the thromboxane A2/prostaglandin H2 receptor (TP) antagonist SQ 29,548 (1 µmol/l), the TXA2 synthase inhibitor furegrelate (1 µmol/l), the EP1 receptor antagonist SC 19220 (1 µmol/l) and the AT1 receptor antagonist losartan (10 µmol/l) reduced phenylephrine response only in vessels from mercury-treated rats. TXA2 and PGE2 levels were greater in the incubation medium of vessels from treated than untreated rats; NS 398 decreased these levels only in the mercury group. COX-2 protein was localized in adventitial and endothelial cells. Aortic COX-2 mRNA expression and plasma angiotensin converting enzyme activity were greater in mercury-treated rats. These results suggest that treatment with low doses of mercury increases the release of COX-2-derived vasoconstrictor prostanoids and its participation in phenylephrine responses. The increased activation of the renin-angiotensin system after mercury treatment might be associated to this increased COX-2 activity.
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Kaempferol, but not resveratrol inhibits angiotensin converting enzyme

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Inhibition of angiotensin converting enzyme (ACE) has proved to be beneficial in the treatment of various cardiovascular disorders. The aim of this study was to evaluate ACE inhibitory potential of two polyphenolic compounds with different structures: resveratrol (present in high quantities in French wine) and kaempferol (abundant in greens), using method of liquid chromatography coupled with electrospray ionization mass spectrometry (LC-ESI-MS) for ex vivo measurement of angiotensin I to angiotensin II conversion by ACE in aortic tissue of Wistar-Kyoto rats. In this setting, kaempferol (10-30-100 µM), but not resveratrol (10-30-100 µM) appeared to inhibit dose-dependently conversion of Ang I to Ang II. Although the mechanism of ACE inhibition by kaempferol remains to be elucidated, this observation may help in search or designing of new classes of ACE inhibitors.
The effects of the angiotensin converting enzyme inhibitors benazepril (B), enalapril (E), and ramipril (R) on the function, geometry, and dimensions of the left ventricle (LV) in the dogs with naturally acquired severe mitral regurgitation (MR) were evaluated by echocardiography. Thirty-two dogs, aged 8-16 years and weighing 10-12 kg, with fractional shortening (FS) >50% were included into the study. Benazepril (0.5mg/kg/d), enalapril (0.5mg/kg/d), and ramipril (0.5mg/kg/d) were administered orally to B, E, and R groups, respectively. Furosemide (2mg/kg/d) was administered orally for conventional heart failure therapy. Physical, radiographic, electrocardiographic, and echocardiographic examinations were performed before treatment and on day 7 after the treatment. A decrease in the left ventricle end diastolic diameter (LVEDd) in groups E and R and in end diastolic volume (EDV) in group E was considerable during the subacute period (P<0.05). The stroke volume (SV) significantly decreased in groups E and R (P<0.01), whereas group B dogs had a mild decrease (P<0.05). FS and ejection fraction (EF) that were higher before treatment decreased significantly in all groups after the treatment (P<0.001). Differences in SV, FS, and EF were not statistically significant between groups. It was detected that LV was remodelled as a result of the effects of enalapril and ramipril on LVEDd and also EDV was decreased by enalapril. Furthermore, it was observed that these ACE inhibitors were effective on geometry, dimensions, and functions on LV of the dogs with severe MR, and enalapril was found to be the most effective agent, followed by ramipril and benazepril.
Hypoxia is regarded as an important physiological factor that controls nephrogenesis. We investigated whether the renin-angiotensin-aldosterone system (RAAS) affects hypoxia-related target genes in developing kidneys. Newborn rat pups were treated with enalapril (30 mg/kg/d) or spironolactone (200 mg/kg/d) for 7 days. Tissue hypoxia was assessed by the uptake of a hypoxyprobe-1, pimonidazole (200 mg/kg), and the expression of hypoxia-responsive genes. In the enalapril group, hypoxia-inducible factor (HIF)-1, HIF-2, and Ets-1 protein expression were not changed, compared to the control group. In the spironolactone group, HIF-1 and Ets-1 protein expression were significantly increased by immunoblots and immunohistochemistry, whereas HIF-2 protein expression was not changed, compared to the control group. In the enalapril group, the immunoactivity of pimonidazole was not significantly different from that of the controls. However, in the spironolactone group, pimonidazole staining demonstrated that the cortex and medulla underwent severe hypoxia. In summary, our data showed that aldosterone inhibition in the developing kidney augmented the hypoxic responses, and up-regulated the expression of key mediators of hypoxia including HIF-1 and Ets-1. Angiotensin II inhibition did not affect hypoxia-related alterations in the developing kidney. The components of RAAS may differentially modulate renal hypoxia and its related target genes in the developing rat kidney.
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