Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Besides its glomerular hemodynamic effects, nitric oxide (NO) inhibits platelet aggregation and mesangial cell proliferation, two mechanisms possibly involved in the pathogenesis of glomerulosclerosis (GS). Chronic NO synthase inhibition in the rat leads to marked arterial hypertension and promotes glomerular and interstitial injury, but only mild GS. In this study, NO synthase blockade by nitro-L-arginine methyl ester (L-NAME) was associated with 5/6 nephrectomy, a well-known model of GS. Sixty-eight adult male Munich-Wistar rats were distributed among four groups: SHAM (no renal ablation or drug treatment), NX (5/6 nephrectomy), NX+NAME (5/6 nephrectomy and chronic treatment with L-NAME, 5 mg/dL in drinking water) and NX+NAME+L (as in group NX+NAME but also receiving the angiotensin II receptor inhibitor Losartan potassium (L), 25 mg/dL in drinking water). One week after ablation, rats of Group NX showed moderate glomerular hypertension and hypertrophy. Although glomerular enlargement was also modest in Group NX+NAME, glomerular hypertension was particularly severe in this group. Both alterations were absent in Group NX+NAME+L. Only incipient glomerular and interstitial injury occurred at this phase. Three weeks after ablation, renal structural injury was still modest in Group NX. By contrast, Group NX+NAME exhibited marked GS, glomerular ischemic injury, interstitial expansion, and creatinine retention. Renal injury was largely prevented in Group NX+NAME+L. Tuft enlargement occurred in all groups but was most prominent in Group NX. NO synthase inhibition aggravates parenchymal injury and functional impairment in the remanent kidney by mechanisms that may involve glomerular hypertension and renin-angiotensin activation but that appear to be unrelated to glomerular enlargement.
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PMID:Chronic nitric oxide synthase inhibition aggravates glomerular injury in rats with subtotal nephrectomy. 753 72

Future directions in antihypertensive treatment will rely on our present experience with antihypertensive drugs, on new concepts of cardiovascular regulation and on novel antihypertensive agents. At present, we seek early detection of hypertension; treatment should focus on normalization of blood pressure, the reversal or prevention of left ventricular hypertrophy, associated coronary artery disease and on the prevention of, or reparation of, myocardial fibrosis and microangiopathy. Therefore, combination therapy is advisable in severe cases, and any monotherapy should focus on the pharmacological principles compatible with these goals. ACE inhibitors and calcium antagonists appear to meet these requirements. There are, in addition, novel drugs i.e. angiotensin II receptor antagonists and renin inhibitors, as well as therapeutic stimulation of endothelial nitric oxide by L-arginine, the inhibition of endothelin-1 mediated vasoconstriction, and potassium-channel openers. All are examined in this contribution to delineate the perspectives in antihypertensive therapy.
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PMID:Directions in antihypertensive treatment--our future from the past. 755 77

Twelve essential hypertensive patients were entered into a prospective study assessing the effect of losartan, a non-peptide specific angiotensin II receptor antagonist, on blood pressure, the renin-angiotensin-aldosterone axis and renal function. Specifically monitored prior to and following 12 weeks of therapy at 6 (peak) and 24 (trough) h after dosing, were blood pressure, plasma renin activity (PRA), plasma aldosterone, and plasma angiotensin II (Ang II), creatinine clearance and urinary albumin excretion (UAE). In this small sample of hypertensive patients, losartan monotherapy and losartan-hydrochlorothiazide (HCTZ) combination therapy were associated with modest reductions in systolic, diastolic and mean arterial BPs; significant changes were observed only at the peak dosing interval. Losartan, given as either monotherapy or combination therapy, was associated with an increase in the 'trough' values of PRA; significant changes in the 'trough' values of plasma Ang II and plasma aldosterone were not observed. In contrast, PRA and plasma Ang II were stimulated, and plasma aldosterone was depressed, 6 h after dosing. There were significant negative correlations between both PRA and plasma Ang II reactivity (difference between PRA or plasma Ang II values obtained 6 h after placebo dosing and 6 h after drug dosing) and the change in systolic, diastolic and mean arterial BPs. Of interest, losartan/HCTZ combination therapy was associated with a decrease in the creatinine clearance; UAE was not significantly altered. Losartan appears to be an effective anti-hypertensive agent in patients with mild to moderate hypertension. Its peak BP effect appears to be at the dosing interval corresponding to pharmacological blockade of angiotensin II receptors. Furthermore, this anti-hypertensive agent may be more efficacious in patients with a reactive renin-angiotensin system.
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PMID:Effects of losartan on the renin-angiotensin-aldosterone axis in essential hypertension. 759 5

The growing list of vasoactive substances known to be involved in blood pressure control provides new targets for antihypertensive drugs. Currently under development are alternative strategies for blockade of the renin-angiotensin system (e.g., renin inhibition and angiotensin II receptor antagonism) that may have fewer side effects than angiotensin-converting-enzyme inhibition, and antagonists to other vasocontrictor peptides, such as endothelin and vasopressin. Novel strategies to enhance the effects of endogenous vasodilators, such as natriuretic peptides and nitric oxide, are also being explored.
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PMID:Beyond ACE inhibition: new developments in drug therapy for hypertension. 760 80

The acute renal tubular effects of two pharmacologically distinct angiotensin II receptor antagonists have been evaluated in normotensive volunteers on various salt diets. In the first study, the renal response to a single oral dose of losartan (100 mg) was assessed in subjects on a low (50 mmol Na/d) and on a high (200 mmol Na/d) salt intake. In a second protocol, the renal effects of 50 mg irbesartan were investigated in subjects receiving a 100 mmol Na/d diet. Both angiotensin II antagonists induced a significant increase in urinary sodium excretion. With losartan, a modest, transient increase in urinary potassium and a significant increase in uric acid excretion were found. In contrast, no change in potassium and uric acid excretions were observed with irbesartan, suggesting that the effects of losartan on potassium and uric acid are due to the intrinsic pharmacologic properties of losartan rather than to the specific blockade of renal angiotensin II receptors. Assessment of segmental sodium reabsorption using lithium as a marker of proximal tubular reabsorption demonstrated a decreased distal reabsorption of sodium with both antagonists. A direct proximal tubular natriuretic effect of the angiotensin II antagonist could be demonstrated only with irbesartan. This apparent discrepancy allowed us to reveal the importance of acute water loading as a possible confounding factor in renal studies. The results of the present analysis show that acute water loading per se may enhance renal sodium excretion and hence modify the level of activity of the renin-angiotensin system expected from a given sodium diet. Since acute water loading is a common practice in clinical renal studies, this confounding factor should be taken into account when investigating the renal effects of vasoactive systems.
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PMID:Studies of the renal effects of angiotensin II receptor blockade: the confounding factor of acute water loading on the action of vasoactive systems. 761 Dec 41

The renin-angiotensin system (RAS) participates in both cardiovascular homeostasis and diseases. Angiotensin converting enzyme (ACE) inhibitors have been used very successfully in the treatment of hypertension and heart failure. The therapeutic effectiveness of these drugs has been ascribed to their action in limiting the activity of the RAS and suggests that other pharmacological mechanisms that block this system, such as angiotensin II receptor inhibitors, could also be of benefit. Some properties of angiotensin II receptor inhibitors offer potential advantages over ACE-inhibitors. ACE acts on other substrates in addition to angiotensin I (i.e. bradykinin) so that more specific inhibition of the RAS can be achieved with selective angiotensin II antagonists. Data on the existence of both circulating and tissue RAS have been reported, and non-ACE pathways for angiotensin II production have also been described. So, by inhibiting the interaction of the biological active peptide at its receptor level, an angiotensin II receptor antagonist will inhibit the RAS independently of the source or route of angiotensin II synthesis. Peptide angiotensin II antagonists were first reported 20 years ago and the best studied was saralasine; they are potent and selective blockers of angiotensin II responses, but their lack of oral activity, short duration of action and the concomitant partial agonistic activity limited their clinical use. Now are available nonpeptide angiotensin II antagonists with attributes appropriate for clinical development. The preliminary evaluation of these new selective nonpeptide angiotensin II antagonists show their potential therapeutic role in many cardiovascular diseases in which the RAS is involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Clinical pharmacology of angiotensin II antagonists]. 763 4

Angiotensin converting enzyme (ACE) inhibitors have been shown to improve morbidity and mortality in patients with heart failure. However, despite the demonstrated clinical benefits many physicians are reluctant to prescribe ACE-inhibitors to the mostly elderly heart failure patients due to concern for side effects which may be related to ACE-inhibitor-induced bradykinin accumulation. Angiotensin II receptor antagonists may provide more effective blockade of the renin-angiotensin-aldosterone system without causing bradykinin accumulation and thus associated side effects. The potential benefits of treating heart failure patients with an angiotensin II receptor antagonist instead of or in addition to an ACE-inhibitor are discussed.
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PMID:Theoretical basis for the use of angiotensin II antagonists in the treatment of heart failure. 763 6

The pressure-natriuresis curve of transgenic rats harboring an extra mouse renin gene [TGR(mRen-2)27] is shifted rightward compared with controls; however, whether intrarenal angiotensin II effects are responsible for the rightward shift is unknown. To clarify this issue we infused the converting enzyme inhibitor captopril or the angiotensin II receptor blocker CV 11974 into transgenic and normotensive Sprague-Dawley Hannover control rats. We eliminated any other neural or endocrine regulatory differences between transgenic and control rats by renal denervation and infusion of vasopressin, aldosterone, corticosterone, and norepinephrine in sufficient quantities to occupy all receptors. Sodium excretion increased from 3.4 +/- 1.2 to 10.1 +/- 0.5 mumol/min per gram kidney weight in transgenic rats when renal perfusion pressure was increased from 158 to 201 mm Hg. Captopril (4 mg/kg) and CV 11974 (0.1 mg/kg) shifted the pressure-natriuresis curve of transgenic rats leftward, so that sodium excretion was threefold higher at similar renal perfusion pressures (150 to 160 mm Hg). Similarly, fractional sodium and water excretion curves were shifted leftward, so that values for transgenic and control rats were no longer different. Over the pressure range, renal blood flow in transgenic rats ranged from 3.1 +/- 0.7 to 4.4 +/- 0.5 mL/min per gram kidney weight and increased (P < .05) with both captopril and CV 11974 to ranges from 4.8 +/- 0.9 to 6.8 +/- 0.6 or from 4.5 +/- 0.7 to 6.9 +/- 1.0 mL/min per gram kidney weight, respectively. Glomerular filtration rate in transgenic rats, on the other hand, was not increased. Transgenic kidneys showed severe hypertension-induced nephrosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of captopril and angiotensin II receptor blockade on pressure natriuresis in transgenic TGR(mRen-2)27 rats. 764 84

The octapeptide angiotensin II mediates the physiological actions of the renin-angiotensin system through activation of several angiotensin II receptor subtypes; in particular the AT1. In many tissues, the presence of multiple angiotensin II receptor subtypes, together with a low number of receptors, makes it difficult to study biological responses to physiological concentrations (10(-11)-10(-9) M) of angiotensin II. Also, cultured cells show diminished angiotensin II receptor binding with respect to time in culture and passage number. To address these problems, we expressed the recombinant AT1A receptor in CHO-K1 cells. The stably transfected receptor was characterized using radioligand binding studies and functional coupling to cytosolic free calcium. Radioligand binding of [125I] angiotensin II to the angiotensin II receptor was specific, saturable, reversible and modulated by guanine nucleotides. Like the endogenous AT1A receptor, reported in a variety of tissues, the specific, noncompetitive, nonpeptide AII receptor antagonist, EXP3174, blocked binding of [125I] angiotensin II to the transfected receptor. Scatchard analysis demonstrated that the transfected receptor had a dissociation constant of 1.9 nM with a density of 3.4 pmol/mg protein. An important feature of many of the responses to angiotensin II is the rapid desensitization that occurs following agonist occupancy and the development of tachyphylaxis. In AT1A receptor transfected CHO-K1 cells, angiotensin II (10(-9) M) stimulated a rapid increase in cytosolic free calcium that was completely desensitized within 50 sec following receptor occupancy. Agonist induced desensitization was unaffected when receptor internalization was blocked by pretreatment with concanavalin A or incubation at 4 degrees C, and no changes in AT1A receptor affinity or number were observed. Receptor desensitization was also unaffected by inhibition or activation of protein kinase C. Thus, we have established a permanent, high-level transfectant of the AT1A receptor in CHO-K1 cells and have shown that these receptors rapidly desensitize following exposure to physiological concentrations of agonist. The mechanism of rapid desensitization is not related to receptor sequestration, internalization or controlled by PKC phosphorylation. This provides an excellent model for studying AII actions mediated through a specific receptor subtype, at subnanomolar concentrations.
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PMID:Stable expression of a functional rat angiotensin II (AT1A) receptor in CHO-K1 cells: rapid desensitization by angiotensin II. 765 82

Changes in the mRNA and protein expression of renin-secreting cells in the juxtaglomerular apparatus (JGA) were examined in the rat following administration of ZENECA ZD8731, an angiotensin II receptor antagonist. Doses of 0 or 90 mg/kg were administered daily by gavage for 26 wk. JGA hypertrophy was apparent in histological sections. Immunohistochemistry demonstrated an increase in the number of renin-containing cells in both the afferent arterioles and the interlobular arteries. Similarly, renin mRNA expression, demonstrated by in situ hybridization, had extended to more proximal segments of the afferent arterioles and was also present in efferent arterioles and interlobular arteries. In conclusion, JGA hypertrophy occurred as a result of antagonism of the angiotensin II receptor. Associated with JGA hypertrophy was increased expression of both renin and renin mRNA, indicative of stimulated renin synthesis caused by an exaggerated pharmacological response of renin-secreting cells to the loss of feedback inhibition by angiotensin II.
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PMID:The effects of ZENECA ZD8731, an angiotensin II antagonist, on renin expression by juxtaglomerular cells in the rat: comparison of protein and mRNA expression as detected by immunohistochemistry and in situ hybridization. 765 50


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