Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In hypertensive heart disease, after myocardial infarction or in congestive heart failure, myocardial fibrosis presenting as a diffuse perivascular and interstitial accumulation of fibrillar collagens within the normal connective tissue structures of the myocardium is associated with an activated renin-angiotensin system (RAS). This reactive fibrosis occurs in the overloaded left ventricle and the nonoverloaded right ventricle irrespective of myocyte necrosis or the development of myocyte hypertrophy. Therefore, it appears that hemodynamic factors or the load of the ventricle are not primarily responsible for the adverse fibrous tissue response in the myocardium, and humoral factors may play a key role in regulating the myocardial collagen matrix. The neurohumoral response in hypertensive heart disease, after myocardial infarction with overall deterioration of left ventricular function or congestive heart failure leads to an activation of either the cardiac or the circulating RAS, which closely interacts with the bradykinin-prostaglandin system. To ascertain whether the RAS modulates collagen fibroblasts that express mRNAs for types I and III collagens (the major fibrillar collagens in the heart) and matrix metalloproteinase 1 (MMP1; the key enzyme for collagen degradation), collagen synthesis was measured by [3H]proline incorporation normalized to total protein synthesis and MMP1 activity was determined by degradation of [14C]collagen in cultured fibroblasts after 24-hour incubation with various concentrations of angiotensin II or PGE2 (10(-11)-10(-3) M) under serum-free conditions. In addition, effects of angiotensin II were evaluated in the presence or absence of either type 1 (ICI D8731) or type 2 (PD 123177) angiotensin II (AT1 or PGE2 (10(-11)-10(-3) M) under serum-free conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of angiotensin II and prostaglandin E2 in regulating cardiac fibroblast collagen turnover. 749 21

Thyroid dysfunction produces marked cardiovascular responses; the renin-angiotensin system (RAS) is important in control of the cardiovascular system. We have measured changes in the plasma RAS and in angiotensin II (AT) receptors in experimentally hyperthyroid, euthyroid, or hypothyroid rats. Hyperthyroidism activated the plasma RAS, increasing plasma angiotensinogen by 85% after 7-day triiodothyronine (T3) treatment, plasma renin activity (PRA) by 47% and concentration by 52%, and plasma AT by 1.250%. Hypothyroidism reduced plasma angiotensinogen by 71%, PRA by 73%, and plasma AT by 81% without altering plasma renin concentration (PRC). Plasma aldosterone was reduced by 39% in hyperthyroid rats and by 95% in hypothyroid rats. AT receptors were characterized in heart, liver, adrenal gland, and kidney. Cardiac, liver, and kidney AT receptor densities increased in hyperthyroidism by 73, 113, and 75%, respectively; adrenal gland receptor density decreased by 39%. Similar results were observed in hypothyroidism except that adrenal gland receptor density was markedly increased by 205%. AT receptor subtypes were characterized in ventricular homogenates by the selective antagonist losartan. Hyperthyroidism markedly increased AT2-subtype density by 204% in left ventricle, and by 304% in right ventricle and decreased AT1-subtype density by 38% and 31% in left and right ventricles, respectively. AT2-subtype density increased by 168% in hypothyroid rats; AT1-subtype density was unchanged. Thyroid dysfunction causes significant changes in the RAS and in AT receptor density, especially of the AT2 subtype. Although a physiological function has not yet been reported for AT2 receptors, our results suggest that selective AT2-receptor antagonists may prove therapeutically useful in treatment of cardiovascular disease in thyroid dysfunction.
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PMID:Renin-angiotensin system in thyroid dysfunction in rats. 750 37

We describe the pharmacologic properties of SC-52458, 5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-[2-(1H-tetrazol - 5-ylphenyl)]pyridine, a novel nonpeptide angiotensin II (AII) receptor antagonist. SC-52458 was a potent inhibitor of [125I]AII binding to AT1 receptors in rat adrenal cortex and uterine smooth muscle membranes (IC50 values of 2.8 and 6.9 nM, respectively). Contraction of rabbit aortic rings by AII was antagonized by SC-52458 in a competitive and reversible manner (pA2 of 8.18). SC-52458 had no effect on the activity of angiotensin converting enzyme (ACE) or renin in vitro. In normotensive rats, administration of SC-52458, either intravenously (i.v.) or by gavage, inhibited the pressor response to AII. Daily treatment with SC-52458 at 20, 30, and 50 mg/kg by gavage for 4 days decreased blood pressure (BP) in conscious, spontaneously hypertensive rats (SHR). Further studies in renal-artery ligated rats and sodium-deficient dogs demonstrated that oral administration of SC-52458 decreased BP and that this activity was correlated with significant plasma levels of the compound. SC-52458 is an orally active, competitive AT1-receptor antagonist with antihypertensive properties.
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PMID:Pharmacology of SC-52458, an orally active, nonpeptide angiotensin AT1 receptor antagonist. 750 65

Angiotensin-II (AII), a component of the renin-angiotensin system, is the major factor that regulates the formation of aldosterone in the adrenal cortex zona glomerulosa (ZG). The activity of this system is increased by an increase in potassium intake or a decrease in sodium intake. Using immunoblotting analysis, we determined whether these ions affect the expression of type 1 AII receptors (AT1) and compared the results thus obtained with the AT1 receptor mRNA levels. We also studied the interrelation among AII, AT1 receptors, cytochrome P450 aldosterone synthase (P450c18), and plasma aldosterone levels in rats fed a normal diet or a low sodium or high potassium diet with or without captopril, an inhibitor of angiotensin-converting enzyme, for 7 days. The effects of ions on the level of ACTH receptor mRNA were also analyzed. We found that a low sodium intake increased plasma aldosterone levels from 5.5 to 236 ng/dl and led to 2.3- and 3.7-fold increases in the levels of adrenal ZG AT1 receptor protein and AT1 receptor mRNA, whereas a 11.8-fold increase was found in the level of P450c18 mRNA. Captopril almost completely reversed these effects. We have shown that a high potassium intake increased plasma aldosterone levels to 25.9 ng/dl and also led to 1.84- and 1.95-fold increases in the level of ZG AT1 receptor protein and AT1 receptor mRNA, whereas the ZG P450c18 mRNA level was increased 3.5-fold. The plasma aldosterone level of animals fed a high diet of potassium and captopril was still higher than that in control animals at 16.6 ng/dl, and the levels of ZG AT1 receptor and P450c18 mRNAs were only slightly less than those of the high potassium groups, indicating that captopril did not efficiently block aldosterone formation under these conditions. ACTH receptor mRNA levels remain unaffected by either low sodium or high potassium intake. Collectively, these results indicate that the increased aldosterone secretion induced by low sodium or high potassium intake involves concomitant increases in AT1 receptor and P450c18 mRNAs, which are effectively translated into their respective proteins, and that the expression of both proteins is mediated in part by AII.
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PMID:Both low sodium and high potassium intake increase the level of adrenal angiotensin-II receptor type 1, but not that of adrenocorticotropin receptor. 750 36

The renin-angiotensin system (RAS) has been proposed to play a major role in causing the heart to hypertrophy during pressure overload. We examined whether blockade of this system by the angiotensin-converting enzyme (ACE) inhibitors enalapril (0.5 to 20 mg/kg p.o.) or ramipril (1.0 mg/kg p.o.) or the angiotensin receptor (AT1) antagonist losartan (3.0 mg/kg p.o.) could prevent pressure overload-induced hypertrophy. Pressure overload was produced by abdominal aortic constriction in rats. Cardiac hypertrophy was assessed by an increase in the ratio of left ventricular (LV) weight to body weight and total protein content of the left ventricle. Treatment with enalapril or ramipril, initiated 3 weeks after aortic banding and continued for 3 more weeks, failed to prevent the progression or cause regression of cardiac hypertrophy. Treatment for 6 weeks with ramipril initiated immediately after aortic banding also failed to prevent cardiac hypertrophy. Losartan treatment initiated 3 weeks after aortic banding and continued for 3 more weeks resulted in a slight but significant reduction in the extent of cardiac hypertrophy (45.6% hypertrophy in controls and 35.6% hypertrophy in losartan-treated animals, p < 0.05, n = 11 and 10, respectively). Surgical removal of bands 3 weeks after placement reduced cardiac hypertrophy to a greater extent than that observed in losartan-treated animals. These results suggest that angiotensin may not play a major role in causing pressure overload-induced hypertrophy or in maintaining such hypertrophy.
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PMID:Role of angiotensin in pressure overload-induced hypertrophy in rats: effects of angiotensin-converting enzyme inhibitors, an AT1 receptor antagonist, and surgical reversal. 751 60

The renin angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. For this reason, attempts to specifically block this system have been a pharmacological goal for over 25 years. Blockade of the renin system has been attempted at 3 pivotal sites: the rate limiting angiotensinogen-renin step, conversion of angiotensin I to angiotensin II, and the active receptor sites for the terminal products of angiotensin II and aldosterone. Converting enzyme inhibitors have been successfully studied and utilised in clinical cardiovascular disorders, but questions persist regarding the specificity of their action. Thus, other more specific approaches remain under evaluation. Inhibition of the action of renin on angiotensinogen was demonstrated with early inhibitory peptides and in experimental studies with specific antibodies. Most currently available renin inhibitors are nonpeptides, which nonetheless require intravenous administration. An oral renin inhibitor with clinical effects has been evaluated in early human trials. Like renin inhibitors and converting enzyme inhibitors, specific angiotensin antagonists were studied early in the course of renin system pharmacological blockade. Early angiotensin antagonists were limited, due to the requirement for intravenous administration and because of their short half-lives. They also had the potential for mixed agonist/antagonist physiological and pharmacological effects, which could result in a pressor, rather than a depressor, response. The angiotensin receptor antagonists have the appeal of blocking the specific receptor at its target tissue site, analogous to other well described systems. Newer angiotensin antagonists do not have the limitations of the precursor peptides. Losartan (DUP753) is a specific angiotensin II AT1 receptor antagonist. It is orally effective without agonist activity, and has high receptor binding characteristics. Early studies indicate that it is a specific probe of the renin system, and is providing newer insights into the role of the renin system in cardiovascular disorders. Emerging clinical studies indicate that it is effective for blood pressure reduction and as a vasodilator. Aldosterone antagonists such as spironolactone have been available for decades. Spironolactone is being used in an ongoing trial to assess the impact of combined converting enzyme and aldosterone inhibition. Newer aldosterone antagonists could add to targeted blockade of aldosterone without the adverse effects of the precursor compound, and the potential for combined specific renin system blockade.
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PMID:The clinical potential of renin inhibitors and angiotensin antagonists. 751 58

Recent studies have revealed that angiotensin II (Ang II) interacts with two pharmacologically different types of seven-transmembrane domain receptors, hence named Ang II type 1 and type 2 (AT1 and AT2) receptors. cDNAs for the AT1 receptor have been cloned, and the existence of two receptor subtypes, AT1A and AT1B, has been revealed in rat and mouse. This study presents a new approach for the specific quantification of AT1A and AT1B receptor mRNAs by reverse transcription and polymerase chain reaction amplification in the presence of an AT1 receptor mutant cRNA as internal standard. Absolute quantities of mRNA are then determined by extrapolation using the standard curve generated with the internal standard. Moreover, addition of this internal standard to each tube controls for both reverse transcription and polymerase chain reaction amplification in each sample. In male Wistar rats, the highest absolute AT1A receptor mRNA levels were found in liver and kidney and those for AT1B receptor mRNA in the pituitary. Expressed as a percentage of total AT1A+AT1B receptor mRNA content, AT1A receptor mRNA content was 100% in liver, 85% in lung, 73% in kidney, 65% in aorta, 48% in adrenals, and 15% in the hypophysis. Since this approach can determine absolute AT1A and AT1B receptor mRNA quantities in different organs, it allows the study of the regulation of their expression under different pathophysiological conditions. After sodium depletion, known to induce hyperactivity of the renin-angiotensin system, adrenal AT1A and AT1B receptor mRNA levels were increased by 60% and 110%, respectively. In contrast, in renovascular hypertension (two-kidney, one clip), also associated with elevated circulating plasma renin activity, adrenal AT1B receptor mRNA levels decreased by 50%, whereas there was no change in those of AT1A. Therefore, the differential distribution and regulation of these two receptor subtypes suggest that each of them might be involved in the mediation of different biological effects of Ang II.
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PMID:Tissular expression and regulation of type 1 angiotensin II receptor subtypes by quantitative reverse transcriptase-polymerase chain reaction analysis. 752 76

Since dietary salt loading enhances nitric oxide (NO) generation in the kidney, we investigated the hypothesis that changes in salt intake have specific effects on vascular resistance in the kidney mediated by the L-arginine-NO pathway. We contrasted changes in renal and hindquarter vascular resistances (RVR and HQVR) in anesthetized rats during intravenous infusions of graded doses of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME). Groups (N = 8 to 10) of rats were maintained on a high salt (HS) or low salt (LS) diet for two weeks. Compared to those on LS, rats on HS had a greater increase in mean arterial pressure (delta MAP; +32 +/- 4 vs. +22 +/- 3%; P = 0.05) and RVR (+160 +/- 17 vs. +83 +/- 10%; P < 0.005) and a greater fall in renal blood flow (delta RBF; -47 +/- 3 vs. -32 +/- 4%; P < 0.01); changes in HQVR were similar in the two groups. The enhanced RVR response to L-NAME in HS rats could not be ascribed to the higher renal perfusion pressure (RPP) since it persisted in rats whose RPP was controlled by adjustment of a suprarenal aortic clamp. Changes in RVR with an NO donor (SIN-1) were similar in HS and LS rats. L-NAME reduced plasma renin activity in both HS and LS rats. After inhibition of ACE with captopril, or of angiotensin II type I (AT1) receptor with losartan, the increase in RVR with L-NAME remained greater in HS than LS rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal vasoconstriction during inhibition of NO synthase: effects of dietary salt. 752 72

We examined the pharmacological properties of U-97018, a novel nonpeptide angiotensin II (AII) receptor antagonist, in various in vitro and in vivo studies. U-97018 selectively displaced 125I-AII specific binding in the membrane fraction derived from the rat mesenteric artery and adrenal cortex (AT1 subtype) with IC50 of 1.3 +/- 0.2 and 7.7 +/- 1.3 nM, respectively, without altering the AII binding of the rat adrenal medulla (AT2 subtype). In rat adrenal cortical cells, U-97018 inhibited 1 nM AII-induced aldosterone secretion with an IC50 of 0.48 nM; it shifted concentration-secretion response curve for AII to the right and inhibited the maximal response to AII, yielding a pKB of 9.8. Similarly, U-97018 showed insurmountable antagonism with a pKB of 10.6 against the AII-induced contraction in the isolated rabbit aorta. U-97018 had no direct effect on the activities of renin and angiotensin converting enzyme in vitro. In pithed rats, U-97018 inhibited the AII-induced pressor response with an ED50 of 0.28 mg/kg, i.v. without any partial agonistic activity. In anesthetized rats and dogs, intraduodenal administration of U-97018 at a dose of 1 mg/kg inhibited the AII-induced pressor response by about 60%. In spontaneously hypertensive rats, U-97018 at 10 mg/kg p.o. produced antihypertensive effects which lasted for 24 hr after administration. Thus, U-97018 is an orally active, insurmountable AII receptor antagonist without any agonistic activity.
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PMID:Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, U-97018. 756 67

During the past decade, experimental and clinical evidence has indicated an important role for the renin-angiotensin system in the progressive destruction of nephrons in a wide variety of chronic renal diseases. Studies have indicated that in the subtotally nephrectomized rat model of progressive glomerulosclerosis, in experimental diabetes mellitus, in the chronic phase of puromycin aminonucleoside-induced nephrotic syndrome and in Heymann's nephritis, angiotensin-converting enzyme (ACE) inhibitors dramatically preserve both nephron structure and function. Clinical studies have similarly noted that chronic administration of ACE inhibitors inhibits progression of renal failure in type I diabetes and type II diabetes as well as primary glomerulopathies, sickle cell nephropathy, systemic lupus erythematosis, chronic pyelonephritis and adult polycystic kidney disease. Current evidence suggests that the beneficial effect of ACE inhibitors is primarily due to inhibition of angiotensin II production, and there is strong suggestive evidence for increases in local intrarenal activation of the renin-angiotensin system in these conditions. In obstructive uropathy, activation of the renin-angiotensin system has also been shown to be an important aspect of the early functional changes and may be of importance in the subsequent generation of interstitial fibrosis. In the obstructed kidney, renin and angiotensinogen production increase and type I angiotensin receptors decrease. Inhibitors of angiotensin II production and angiotensin II action partially reverse the vasoconstriction and the reduced renal blood flow, and abolish the changes in expression of AT1 MRNA induced by obstruction. Studies suggest that the angiotensin-mediated increases in tubulointerstitial fibrosis may be mediated by increased production of transforming growth factor-beta.
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PMID:Angiotensin II-mediated renal injury. 756 81


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