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

A growing body of evidence suggests that angiotensin may have a functional role in growth and development, in addition to its classical role in the maintenance of body water homeostasis. Components of the renin-angiotensin system have been identified in the rat fetus. Because of the association between the renin-angiotensin system and hypertension, we quantified angiotensin receptor binding sites in the brains of spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats during perinatal development. Using in vitro receptor autoradiography we identified specific 125I-Sar1,Ile8 AII binding in several areas of the brains of perinatal rats of both strains and observed significant differences in the concentration of binding sites, at different ages in several brain nuclei. With the knowledge that components of the renin-angiotensin system appear early in development and are known to have an association with cellular growth, it is possible that an irregularity in this system occurring during neurogenesis could contribute to developmental abnormalities, as well as subsequent hypertension.
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PMID:Differences between perinatal angiotensin binding in the brains of SHR and WKY rats. 835 5

The renin-angiotensin system plays an important role in the regulation of blood pressure and fluid and electrolyte homeostasis. Components of this system, renin, angiotensin converting enzyme (ACE) angiotensinogen, angiotensin II and angiotensin II receptors have been found in many tissues including kidney, adrenal, blood vessels and in discrete brain regions. This suggests that in addition to circulating angiotensin II, endogenous tissue renin-angiotensin system may also be important in cardiovascular control and maintaining fluid balance. Inhibitors for ACE are used successfully in the treatment of hypertension and chronic heart failure. In experimental animals, these inhibitors are found to block ACE in the kidney, lung, adrenal, blood vessels and the forebrain circumventricular organs after oral administration. The time course of tissue ACE inhibition correlated closely with the blood pressure lowering effect of these drugs. Most ACE inhibitors are unable to penetrate the blood-brain and blood-testis barriers. However, the more lipophilic drugs do penetrate the blood brain barrier, especially after chronic administration. The potential use of inhibitors for renin and angiotensin II receptors for the treatment of hypertension are being explored. An inhibitor for the AT1 angiotensin receptor, losartan (CAS 124750-99-8), which has potent antihypertensive effect, demonstrated dose and time dependent inhibition of AT1 receptors in the kidney and adrenal. Losartan also crossed the blood-brain barrier after acute peripheral administration suggesting additional possible central sites of action.
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PMID:Localization of components of the renin-angiotensin system and site of action of inhibitors. 849 67

Obese spontaneously hypertensive rats (SHR) develop nephropathy with severe proteinuria, but lean littermates do not develop renal disease. Intrarenal angiotensin has been suggested to contribute to nephropathy in other experimental models. We examined the regulation of angiotensin receptors as a reflection of target tissue response to possible changes in the renin-angiotensin system. We visualized angiotensin receptors in kidneys of 6-8-month-old obese SHR and their lean littermates. Both obese and lean rats were hypertensive as determined by tail-cuff or by direct measurement. Histologic studies showed early glomerular sclerosis in obese but not lean rats. Autoradiographic visualization of angiotensin receptor binding sites in both obese and lean SHR showed glomeruli and medullary rays having the highest levels of binding with additional diffuse labeling in cortex and outer medulla. In obese rats, binding was reduced relative to lean littermates, particularly in the medulla, while intense binding in glomeruli was preserved. Loss of receptors did not reflect tissue damage, since the medulla showed no pathological changes. Biochemical assays of the binding of subtype-selective antagonists to 125I-angiotensin sites in intact sections showed that both losartan-sensitive and PD 123319-sensitive sites were decreased in nephrotic obese rats. We conclude that specific binding sites for angiotensin are decreased in obese SHR with early glomerular sclerosis, suggesting that angiotensin receptors may be regulated by pathogenic processes in this model of renal disease.
Hypertension 1993 Jun
PMID:Renal angiotensin receptor mapping in obese spontaneously hypertensive rats. 850 89

Erythropoietin (EPO)-induced hypertension is a common complication of EPO usage. The hypothesis that erythropoietin is antinatriuretic and that the sodium retention is mediated by intrarenal angiotensin II production was tested. Experiments were performed in Wistar rat kidneys perfused for 60 min in an isolated system. A dose-response curve was performed for EPO at 0, 10, 100, 1,000, and 10,000 mU/mL. EPO administration resulted in a dose-dependent decrease in sodium excretion to a maximum of 50% at the 1,000 mU/mL dose. In a second experiment, kidneys from five groups were perfused: controls, EPO (100 mU/mL), captopril (50 ng/mL), captopril (50 ng/mL) plus EPO (100 mU/mL), and the angiotensin receptor antagonist losartan (1 nM) plus EPO (100 mU/mL). The administration of EPO resulted in an immediate decrease in average sodium excretion (30%) with no change in GFR or other renal function parameters. Pretreatment with captopril or losartan blocked the effect of EPO. Captopril alone had no effect on renal function. A final experiment demonstrated the ability of losartan (10 nM) to block the pressor effects of angiotensin II (0.01, 0.1, and 1 nM). It was concluded that EPO acts within the kidney to cause the production of angiotensin II, which mediates the increased reabsorption of sodium.
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PMID:Erythropoietin-induced antinatriuresis mediated by angiotensin II in perfused kidneys. 850 14

Despite the wide range of anti-hypertensive drugs currently available many more are being developed, including entirely novel classes of compounds. This is not entirely surprising as a minority of patients do not respond to existing agents or are unable to tolerate them at therapeutic doses. It is also true that hypertension represents a very large international market. This brief review deals with the following classes of agents which are at various stages of development: (1) angiotensin receptor antagonists of the AT1 subtype, the first of which has recently been marketed in the UK; (2) renin inhibitors, whose development has been hindered by the poor bioavailability of all but the most recent compounds; (3) imidazoline (I1) receptor agonists, centrally acting drugs with relatively little sedating activity; (4) potassium channel openers, which act as potent vasodilators; (5) neutral endopeptidase inhibitors which potentiate the actions of atrial natriuretic peptides; and (6) endothelin antagonists, which are still in pre-clinical development. The potential clinical significance of these compounds is discussed.
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PMID:New ideas for treating hypertension. 852 85

Chronic renal allograft dysfunction is often associated with hypertension, but it is unknown to what extent this affects graft structure and function. We investigated the effect of antihypertensive drug treatments on the course and histopathology of chronic renal allograft rejection in a rat model. Recipient animals were treated with a combination of reserpine, hydralazine and hydrochlorothiazide, the angiotensin converting enzyme inhibitor cilazapril, or the angiotensin II receptor blocker L158,809. Systemic blood pressures and tubular stop-flow pressures were measured on day 50 after transplantation; the histopathology was assessed semiquantitatively in kidneys not used for micropuncture studies. Grafts removed from untreated recipients showed inflammation and structural vascular and glomerular lesions consistent with chronic rejection. All treatment regimens decreased the systemic and glomerular capillary pressures and were associated with improved graft survival, decreased proteinuria and a tendency to improved graft function; the histopathology showed a significant amelioration of glomerular mesangiolysis and glomerulosclerosis but no effect was found on the tubulointerstitial lesions; the angiotensin receptor blocker also inhibited graft atherosclerosis. We conclude that hemodynamic and angiotensin II-mediated processes may play a pivotal role in the expression of immune-mediated glomerular lesions of chronic allograft dysfunction.
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PMID:Post-transplant hypertension and chronic renal allograft failure. 858 80

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.
Hypertension 1996 Mar
PMID:Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. 861 97

Although angiotensin II (Ang II) and the heptapeptide Ang-(1-7) differ by only one amino acid, the two peptides produce different responses in vascular smooth muscle cells. We previously showed that Ang II stimulated phosphoinositide hydrolysis, whereas Ang II and Ang-(1-7) released prostaglandins. We now report that Ang II and Ang-(1-7) differentially modulate rat aortic vascular smooth muscle cell growth. Ang-(1-7) inhibited [3H]thymidine incorporation in response to stimulation by fetal bovine serum, platelet-derived growth factor, or Ang II. The reduction in serum-stimulated thymidine incorporation by Ang-(1-7) depended on the concentration of the heptapeptide over the range of 1 nmol/L to 1 mumol/L, with a maximal inhibition of 60% by 1 mumol/L Ang-(1-7). Ang-(1-7) also inhibited the serum-stimulated increase in cell number to a maximum of 77% by 1 mumol/L Ang-(1-7). The attenuation of serum-stimulated thymidine incorporation by Ang-(1-7) was unaffected by antagonists selective for angiotensin type 1 (AT1) or type 2 (AT2) receptors; however, [Sar1,Ile1]Ang II and [Sar1,Thr2]Ang II were effective antagonists, indicating that growth inhibition by Ang-(1-7) was a result of angiotensin receptor activation. In contrast, Ang II stimulated [3H]thymidine incorporation in cultured vascular smooth muscle cells over the same concentration range, with a maximal stimulation of 314% at 1 mumol/L Ang II. Ang II also increased the total number of cells (to 145% of control), suggesting that enhanced thymidine incorporation was associated with vascular smooth muscle cell proliferation. The AT1 antagonist losartan or L-158,809 but not AT2 antagonists blocked [3H]thymidine incorporation by Ang II. These results suggest that Ang-(1-7) and Ang II exhibit opposite effects on the regulation of vascular smooth muscle cell growth. The inhibition of proliferation by Ang-(1-7) appears to be mediated by a novel angiotensin receptor that is not inhibited by AT1 or AT2 receptor antagonists.
Hypertension 1996 Jul
PMID:Angiotensin-(1-7) inhibits vascular smooth muscle cell growth. 867 48

The existence of a local cardiovascular renin-angiotensin system (RAS) is often invoked to explain the long-term beneficial effects of RAS inhibitors in heart failure and hypertension. The implicit assumption is that all components of the RAS are synthesized in situ, so that local angiotensin II formation may occur independently of the circulating RAS. Evidence for this assumption however is lacking. The angiotensin release from isolated perfused rat hearts or hindlimbs depends on the presence of renal renin. When calculating the in vivo angiotensin production at tissue sites in humans and pigs, taking into account the extensive regional angiotensin clearance by infusing radiolabeled angiotensin I or II, it was found that angiotensin production correlated closely with plasma renin activity. Moreover, in pigs the cardiac tissue levels of renin and angiotensin were directly correlated with their respective plasma levels, and both in tissue and plasma the levels were undetectably low after nephrectomy. Similarly, rat vascular renin and angiotensin decrease to low or undetectable levels within 48 h after nephrectomy. Aortic renin has a longer half life than plasma renin, suggesting that renin may be bound by the vessel wall. In support of this assumption, both renin receptors and renin-binding proteins have been described. Like ACE, renin was enriched in a purified membrane fraction prepared from cardiac tissue. Binding of renin to cardiac vascular membranes may therefore be part of a mechanism by which renin is taken up from plasma. It appears that the concept of a local RAS needs to be reassessed. Local angiotensin formation in heart and vessel wall does occur, but depends, at least under normal circumstances, on the uptake of renal renin from the circulation. Tissues may regulate their local angiotensin concentrations by varying the number of renin receptors and/or renin-binding proteins, the ACE level, the amount of metabolizing enzymes and the angiotensin receptor density.
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PMID:Local renin-angiotensin systems. 873 48

The actions of angiotensin II in the cardiovascular system are transmitted by two known and possibly some unknown angiotensin receptor types. AT1 and AT2 both correspond to G-protein-coupled receptors with seven hydrophobic transmembrane domains, several N-glycosylation sites and a potential G-protein binding site. Cloning of coding regions and promoter sequences contributed to the understanding of receptor protein function and regulation. Angiotensin receptors with atypical binding properties for the known AT1- and AT2-specific ligands are expressed on human cardiac fibroblasts and in the human ulcrus. In several animal models, receptors with high affinity for angiotensin (1-7) have been described. AT1 stimulation is mediated by the generation of phospholipid-derived second messengers, activation of protein kinase C, the MAPkinase pathway and of immediate early genes. Recently, phosphorylation and dephosphorylation of tyrosine kinases have been associated with AT1- and AT2-mediated signal transduction. ATR are regulated by phosphorylation, internalization, modification of transcription rate and mRNA stability. Regulation is highly cell and organ specific and includes upregulation of ATR in some pathophysiological situations where the renin angiotensin system is activated. Whereas the function of AT1 in the cardiovascular system is relatively well established, there is little information regarding the role of AT2. Recent hypotheses suggest an antagonism between AT1 and AT2 at the signal transduction and the functional level. Transgenic animal models, particularly with targeted disruption of the AT1 and AT2 genes, suggest the contribution of both genes to blood pressure regulation. Genetic polymorphisms have been described in the AT1 and AT2 gene or neighbored regions and are used to analyze the association between gene defects and cardiovascular diseases. AT1 antagonists are now being introduced into the treatment of hypertension and potentially heart failure, and more interesting pharmacological developments are expected from the ongoing basic studies.
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PMID:Molecular biology of angiotensin receptors and their role in human cardiovascular disease. 877 61


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