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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of renin and angiotensinogen genes and their proteins were studied during the progression of diabetes using adult BioBreeding spontaneously diabetic rats at 1 day and 2-12 months of diabetes. The number of renin-stained cells per juxtaglomerular apparatus was determined by immunocytochemistry. Initially, at 2 months of diabetes the number of renin-stained cells per juxtaglomerular apparatus increased significantly (p less than 0.0001, 2 months versus resistant groups) and was followed by a decrease in the number and intensity of renin-stained cells after 12 months of diabetes (p = 0.007, 2 months versus 12 months). A significant negative correlation was observed between the number of renin-containing cells and the duration of diabetes (r = 0.99, p = 0.014). Immunoreactive angiotensinogen was restricted to the proximal tubule and appeared increased after 4 and 8 months of diabetes as compared with the 2- and 12-month diabetic groups. Renin messenger RNA (mRNA) levels increased with the onset of diabetes and decreased markedly during chronic diabetes. At 1 day of diabetes, renin mRNA levels were 700% higher than at 12 months of diabetes. Angiotensinogen mRNA levels were unchanged. We conclude that diabetes results in an initial increase in renin gene expression, and as the duration of diabetes lengthens, there is a progressive decrease in renin gene expression and in the number of cells containing renin. These findings suggest that as the duration of diabetes and the age of the animal lengthens, there is a decrease in the number of cells expressing the renin gene.
Hypertension 1992 Jan
PMID:Renin and angiotensinogen expression during the evolution of diabetes. 173 Apr 42

To investigate the vascular renin-angiotensin system in two-kidney, one clip (2K1C) hypertension, we measured angiotensinogen messenger RNA (mRNA) in the aorta and aortic and plasma angiotensin II (Ang II) concentration in 2K1C rats during early (4 weeks) and chronic (16 weeks) phases. Four weeks after clipping, there was no significant change in aortic angiotensinogen mRNA in both groups. However, the levels of plasma and aortic Ang II in 2K1C rats were significantly elevated compared with levels in control rats (p less than 0.05). Sixteen weeks after clipping, aortic angiotensinogen mRNA in 2K1C rats did not differ compared with the level in control rats. The aortic Ang II level in 2K1C rats was significantly increased compared with that in control rats (p less than 0.05), whereas there was no significant difference in the plasma Ang II level between the groups during this chronic phase. During both phases, morphological studies in 2K1C rats showed arteriosclerotic changes, with a significant increase in the wall-to-lumen ratio (p less than 0.01). The present study is the first to demonstrate an increase in vascular Ang II levels and concomitant morphological arteriosclerotic changes during both the early and chronic phases in 2K1C rats. Together with the results of our previous study that demonstrated an elevation of vascular renin activity during the early phase and increased vascular angiotensin converting enzyme activity during the chronic phase, we conclude that the elevated vascular renin activity and vascular angiotensin converting enzyme activity during each phase may play a dominant role in the increase in vascular Ang II observed during both phases.
Hypertension 1992 Feb
PMID:Possible role of the vascular renin-angiotensin system in hypertension and vascular hypertrophy. 173 96

Prorenin determination in rat plasma has been problematic from the outset. Consequently, its existence is questioned by some and its quantity by others, making it difficult for knowledge to advance as to its function relative to the renin system. The present study examines major variables in the determination of rat plasma prorenin and renin, notably different prorenin activation protocols involving blood samples obtained under various conditions from animals under different anesthetics. We found that a trypsin activation step with 5 mg/mL plasma, 60 min at 23 degrees C, followed by a PRA step of 10 min at 37 degrees C, resulted in the highest prorenin estimates, up to approximately 400 ng.mL-1.h-1 in terms of angiotensin I, as compared with published values of 0-190, based on other protocols. These estimates were obtained despite considerable destruction of angiotensinogen (renin substrate) by trypsin. Cryoactivation of prorenin was much less effective than in human plasma but, when followed by trypsin, it facilitated greater activation than with trypsin alone. Comparable fresh and fresh-frozen plasmas had similar prorenin-renin values, but lower values were observed in plasmas that had been repeatedly frozen and thawed. Conscious rats and those anesthetized with Inactin or ether had higher renins and prorenins than those anesthetized with methoxyflurane or halothane. Rats with kidneys in place during blood collection had higher renins (but not prorenins) than those whose kidneys were clamped off, suggesting that last-minute renin release during blood collection had occurred. We conclude that (i) trypsin generates increased renin, or renin-like, activity in plasma, suggesting activation of a precursor; (ii) on this basis, high prorenin levels exist in normal rat plasma; (iii) renin and prorenin levels are variously influenced by different anesthetics and blood handling procedures; (iv) variation in prorenin levels suggests that it is a dynamic (functional?) component of the renin system; (v) prorenin measurements are heavily influenced by methodological variations during the trypsin step or the subsequent PRA step; (vi) using standardized methodology, the rat can serve as a model for investigating the function of prorenin in normotension and hypertension.
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PMID:Activation and measurement of plasma prorenin in the rat. 175 34

The standard angiotensin I (Ang I) radioimmunoassay for renin activity determination is a useful clinical tool for the diagnosis of high renin levels in certain cases of hypertension. It depends upon the liberation of Ang I from human plasma angiotensinogen. We considered whether a commercially available synthetic tetradecapeptide (TDP), Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser, would produce authentic Ang I upon incubation with protease from human immunodeficiency virus type 1 (HIV-1). This peptide is also known to be cleaved by renin at the Leu-Leu bond to yield the decapeptide Ang I. When the TDP is incubated with the HIV-1 protease, the peptide is readily hydrolyzed. Product formation is linear with respect to time and enzyme concentration. HPLC analysis of reaction products showed two new peaks, as one would expect from the cleavage of a TDP into a decapeptide and a tetrapeptide. Amino acid analysis of HPLC-purified peaks confirmed that the HIV-1 protease cleaves TDP at the Leu10-Leu11 site to produce the desired decapeptide, Ang I. Production of Ang I by the HIV-1 protease, like human renin, is inhibited in the presence of a protease inhibitor. Implications of the discovery of an HIV-1 protease substrate that produces authentic Ang I are discussed in light of a screening assay for soluble HIV-1 protease inhibitors.
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PMID:Could angiotensin I be produced from a renin substrate by the HIV-1 protease? 179 23

To examine and characterize the vascular renin--angiotensin system in low-renin models of renal hypertension with and without the presence of overt renal insufficiency, we studied the formation and metabolism of angiotensin in isolated perfused rat hindquarter preparations. Rats with 5/6 nephrectomy (5/6NX) and rats with one-kidney, one clip (1K1C) hypertension were compared to sham operated (sham) animals. Angiotensin peptides in plasma or perfusate were characterized by high-performance liquid chromatography and radioimmunoassay (RIA). Plasma angiotensin II was lower, and blood pressure was higher in both experimental groups, compared to sham animals. Plasma angiotensinogen, measured by both direct and indirect RIA, was increased in both experimental groups. The spontaneous release of angiotensin I and angiotensin II from perfused hindquarters did not differ between the groups. Angiotensin I conversion was not different in 5/6NX or 1K1C groups compared with controls. Furthermore, angiotensin conversion was completely inhibited by captopril (1 mumol/l) in all groups. Renin-induced angiotensin release was significantly increased in 5/6NX as compared with sham rats, whereas there was no difference in renin-induced angiotensin release between 1K1C and sham animals. Angiotensin II degradation was significantly attenuated in 5/6NX rats when compared with sham rats (27.6% versus 53.9%, respectively, P less than 0.05) but was unaltered in 1K1C rats. Thus, in chronic uremic hypertension, renin-induced angiotensin formation was increased in the face of decreased angiotensin II degradation. These data suggest that vascular angiotensin may contribute to the elevated blood pressure observed in chronic renal failure. In 1K1C rats, vascular angiotensin formation and metabolism was unchanged despite suppressed plasma angiotensin II.
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PMID:Local angiotensin formation in hindlimbs of uremic hypertensive and renovascular hypertensive rats. 184 58

To investigate the molecular mechanism of sustained hypertension in two-kidney, one clip (2K1C) hypertensive rats, possible changes in renin gene expression in the kidney and angiotensinogen in the liver were studied. In 2K1C rats 4 weeks after clipping, the plasma renin and angiotensin II levels were significantly higher than those in sham-operated rats, but the plasma angiotensinogen levels were similar in the two groups. At this time, expression of the renin gene in the ischaemic kidney of 2K1C rats was 2.6-times that in sham-operated rats (P less than 0.05), but expressions of the angiotensinogen gene were similar in the two groups. Sixteen weeks after clipping, the plasma renin and angiotensin II levels in 2K1C rats were not significantly higher than those in sham-operated controls, but expression of the renin gene in the kidney was still 2.2-times higher in 2K1C rats than in controls (P less than 0.05). The plasma angiotensinogen level was significantly higher in 2K1C rats than in controls (P less than 0.05), and expression of the angiotensinogen gene in the liver was 2.9-times higher in 2K1C rats than in controls (P less than 0.01). These results indicate that the roles of the renin-angiotensin system in maintenance of hypertension in 2K1C rats differ in the acute and chronic phases: in the acute phase, over-expression of the renal renin gene coupled to increased renin secretion plays the major role in elevating the blood pressure; in the chronic phase, a counter-regulatory mechanism may affect the post-transcriptional fate of renin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in gene expression of the renin-angiotensin system in two-kidney, one clip hypertensive rats. 184 37

1. In view of a recent interesting hypothesis that the vascular renin-angiotensin system (RAS) plays an important role in the maintenance of hypertension, we examined the effect of delapril (DP), a newly developed angiotensin converting enzyme inhibitor (ACEI), on angiotensin II (Ang II) release from isolated perfused hind legs of spontaneously hypertensive rats (SHR) in comparison with normotensive rats of Wistar-Kyoto strain (WKY). 2. Male SHR and WKY were given DP orally (10 mg/kg per day) for 2 weeks. Isolated hind legs of these rats were perfused with angiotensinogen-free Krebs-Ringer solution, and Ang II released into the perfusate was determined directly by extraction with Sep-Pak C18 cartridges connected to the perfusion system. 3. Delapril produced a sustained antihypertensive action in SHR but not in WKY. The spontaneous release of Ang II in SHR was 112.9 +/- 17.6 pg during the first 30 min of perfusion, which was somewhat greater than that in WKY (96.5 +/- 9.8 pg). An active metabolite of DP, delapril diacid (DPD), when added to the perfusion medium, suppressed the Ang II release in a dose-dependent manner in the two strains. Oral pretreatment of DP for 2 weeks suppressed the Ang II release by 60% in WKY and more pronouncedly by 73% in SHR. 4. These results suggest the presence of a functional RAS in vascular tissues which contributes to the maintenance of vascular tone of SHR, and that ACEI including DP exerts their antihypertensive effect through inhibition of vascular Ang II release in this animal model of human hypertension.
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PMID:Effect of delapril on the vascular angiotensin II release in isolated hind legs of the spontaneously hypertensive rat: evidence for potential relevance of vascular angiotensin II to the maintenance of hypertension. 195 33

The renin-angiotensin system (RAS) is an important modulator of blood pressure and fluid balance. The clinical success of angiotensin converting enzyme inhibitors (ACEIs) in the treatment of hypertension has stimulated the search for antagonists of renin. Because renin is highly specific for its substrate, angiotensinogen, renin inhibitors may emerge as clinically preferable alternatives to ACEIs, which affect multiple biological systems, including bradykinin and prostaglandin metabolism. Recent advances in renin inhibitor chemistry have produced highly specific and potent, transition-state analogs of angiotensinogen. Several compounds (e.g., enalkiren, ditekiren, CGP 38560A, and RO 42-5892) have been tested in man. These renin inhibitors produce dose-dependent decreases in plasma renin activity (PRA) which are dissociated from the dose-dependent decreases in blood pressure (BP). Potential explanations for this dissociation include methodologic errors in PRA assays and alternate sites or mechanisms of drug action, including inhibition of noncirculating tissue renin. A prolonged hypotensive effect is seen following single doses of enalkiren and RO 42-5892, and repeated dosing with enalkiren results in sustained hypotensive effect without tachyphylaxis. Renin inhibitors can reduce blood pressure irrespective of baseline renin status and sodium balance. However, high-renin patients generally respond more vigorously, and the hypotensive response is enhanced by sodium depletion. In general, renin inhibitors have been safe and well tolerated in limited clinical studies. New generation renin inhibitors with higher potency and greater oral bioavailability may join the antihypertensive armamentarium.
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PMID:Renin inhibitors in hypertension. 195 44

Accumulating evidence suggests an important role of vascular renin-angiotensin system (RAS) in the local control of arterial tone. To further gain insight into the significance of vascular RAS in hypertension, we investigated the relationship between the antihypertensive action of delapril, a newly developed converting enzyme inhibitor (CEI), and its effects on vascular angiotensin II (Ang II) release in spontaneously hypertensive rats (SHR). Male SHRs were given delapril or its active metabolite (5-hydroxydelapril diacid; 5-hydroxy-DPD) orally (10 mg/kg/day) for 2 weeks. Isolated hind legs of these rats were perfused with angiotensinogen-free Krebs-Ringer solution, and Ang II released into the perfusate was directly determined by extraction with Sep-Pak C18 cartridges connected to the perfusion system. Both delapril and 5-hydroxy-DPD produced a sustained antihypertensive action. The spontaneous release of Ang II from isolated perfused hind legs of control SHRs was about 50 to 110 pg during the first 30 min of perfusion, and it remained stable up to 3 h. Another active metabolite, delapril diacid (DPD), when added to the perfusion medium (10(-9) to 5 x 10(-5) mol/L), suppressed the Ang II release in a dose-dependent manner. The maximal percent inhibition of Ang II released evoked by DPD (5 x 10(-6) mol/L) was approximately 51%. Oral pretreatment of either delapril or 5-hydroxy-DPD for 2 weeks suppressed the Ang II release by 61% and 73% for delapril and 5-hydroxy-DPD, respectively. These results suggest the presence of a functional RAS in vascular tissues, and that delapril exerts its antihypertensive effect through inhibition of vascular Ang II release in SHRs.
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PMID:The antihypertensive mechanism of delapril, a newly developed converting enzyme inhibitor, is related to the suppression of vascular angiotensin II release in the spontaneously hypertensive rat. 200 51

The brain's renin-angiotensin system in integrally involved in the regulation of blood pressure and fluid/mineral metabolism. Enhanced activity of the angiotensin system in the brain has been implicated as a possible source of the hypertension and the elevated salt appetite of the spontaneously hypertensive rat, as compared with the Wistar-Kyoto rat. This study tested whether these inbred strains of hypertensive and normotensive rats differ in central or peripheral expression of the gene coding for angiotensinogen, the prohormone for the angiotensin peptides. Angiotensinogen messenger RNA was measured in the brain by in situ hybridization and in the liver by Northern blot analysis, using a synthetic oligonucleotide. There was a 28% greater expression of the angiotensinogen gene in the region of the anteroventral hypothalamus, preoptic area, and medial septum of the hypertensive strain. There were no differences between strains in liver angiotensinogen gene expression. These results are consistent with the possibility that enhanced elaboration of the angiotensin prohormone in the brain contributes, in part, to the hypertension or the elevated salt appetite of the spontaneously hypertensive rat.
Hypertension 1991 Apr
PMID:Brain and liver angiotensinogen messenger RNA in genetic hypertensive and normotensive rats. 201 75


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