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)

Ornithine decarboxylase (ODC,EC 4.1.1.7), a rate-limiting enzyme in polyamine biosynthesis, is known to be induced by a beta-adrenoceptor agonist, isoproterenol (ISO). ODC activity and cardiac polyamine content are considered to be correlated with ISO-induced cardiac hypertrophy in rat hearts. To determine whether ISO-induced cardiac ODC activity is mediated through the renin-angiotensin system, especially at the AT1-receptor, we used a nonpeptide AT1 receptor antagonist, losartan, in this study. Losartan (10 mg/kg) suppressed both heart ODC and polyamine contents in ISO-treated rats. Although metoprolol (a selective beta-adrenoceptor antagonist) totally suppressed ODC activity, these results suggest that ISO-stimulated cardiac ODC activity may be regulated through beta 2-adrenoceptors coupled with AT1 receptors in rats.
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PMID:Effect of losartan, an AT1 selective angiotensin II receptor antagonist, on isoproterenol-induced cardiac ornithine decarboxylase activity. 762 Aug 35

Antihypertensive drug therapy can lower blood pressure and prolong life, but many hypertensive patients continue to develop further risk factors and to die prematurely of heart disease. Antihypertensive drugs can also interfere with the patient's quality of life, and many are not compatible with the concomitant medical conditions of the patient and the medications taken to treat them. For these reasons, the antihypertensive therapy selected should meet the specific and complete needs of each patient, not just treat the high blood pressure. An analysis of the drugs that inhibit the renin-angiotensin system suggests that several of these drugs have a more favorable therapeutic profile than other classes of hypotensive agents. The newly developed receptor-site-specific blockers are expected to be tolerated better by hypertensive patients and, consequently, to enhance their quality of life. The first of the new class of nonpeptide blockers of the AT1 receptor, losartan--which has no partial agonist activity--is likely to have the advantages of the angiotensin-converting enzyme inhibitors without their adverse effects, notably cough. In selected patients, the AT1-receptor blockers could become the drugs of first choice for the management of hypertension.
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PMID:Antihypertensive therapy targeted to the needs of the patient: focus on the renin-angiotensin system; older and newer agents. 763 60

The renin-angiotensin system is critical for regulating extracellular fluid volume and blood pressure. Angiotensin II, the active peptide hormone produced by the renin enzymatic cascade, sustains vascular volume and blood pressure by constricting vessels, stimulating adrenal aldosterone secretion, increasing renal tubular sodium absorption, activating the sympathetic nervous system, and increasing cardiac contractility. These actions are a disability in the pathophysiologic states of hypertension and congestive heart failure (CHF), however, since reactive increases in renal renin and angiotensin II stimulate sympathetic activity and renal sodium retention, leading consequently to circulatory volume over-load. The actions of angiotensin II are mediated by its interactions with specific cell-surface angiotensin II receptors, namely, AT1 and AT2; most cardiovascular actions of angiotensin II come from its interaction with the AT1 receptor. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers antagonize the actions of the renin-angiotensin axis, neutralizing its effects on hypertension and heart failure. Losartan is the first oral, nonpeptide, selective AT1-receptor blocker to be approved. Clinical trials show it to be effective and well tolerated as therapy for hypertension and CHF. Data obtained thus far suggest ACE inhibitors and AT1-receptor blockers have similar efficacy for treating these conditions, but the receptor blockers appear to produce fewer adverse effects. Whether the sustained increase in angiotensin II concentrations after AT1-receptor antagonism produces deleterious effects is not known. The concern is that these high levels may stimulate unblocked AT2 receptor; the effect of that stimulation may not be important, however.
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PMID:Angiotensin receptors: physiology and pharmacology. 763 61

This study was designed to examine the possible involvement of prostaglandins and nitric oxide (NO) in the renin stimulatory effect of angiotensin II (AngII) antagonists. To this end, plasma renin activities (PRAs) and renal renin mRNA levels were assayed in rats that were treated with the Ang-converting enzyme inhibitor ramipril or with the AngII AT1-receptor antagonist losartan. Ramipril and losartan increased PRA values from 7.5 +/- 1.6 to 86 +/- 6 and 78 +/- 22 ng of AngI per h per ml and renin mRNA levels from 112 +/- 9% to 391 +/- 20% and 317 +/- 10%, respectively. Inhibition of prostaglandin formation with indomethacin did not influence basal or ramipril-affected PRA. Basal renin mRNA levels also were unchanged by indomethacin, while increases in renin mRNA levels after ramipril treatment were slightly reduced by indomethacin. Inhibition of NO synthase by nitro-L-arginine methyl ester (L-NAME) reduced PRA values to 3.2 +/- 0.9, 34 +/- 13, and 12.1 +/- 2.7 ng of AngI per h per ml in control, ramipril-treated, and losartan-treated animals, respectively. Renin mRNA levels were reduced to 77 +/- 14% under basal conditions and ramipril- and losartan-induced increases in renin mRNA levels were completely blunted after addition of L-NAME. The AngII antagonists, furthermore, induced an upstream recruitment of renin-expressing cells in the renal afferent arterioles, which was also blunted by L-NAME. These findings suggest that renin mRNA levels are tonically increased by NO and that the action of NO is counteracted by AngII.
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PMID:Tonic stimulation of renin gene expression by nitric oxide is counteracted by tonic inhibition through angiotensin II. 764 29

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

The role of the brain renin-angiotensin system (RAS) in heart failure was examined by administering intracerebroventricular (ICV) infusions of the angiotensin II (ANG II) type 1 (AT1)-receptor antagonist losartan (0.1 followed by 0.5 mg.kg-1.3 h-1) to six concious sheep before (nonpaced) and after induction of heart failure by rapid left ventricular pacing (paced). In both nonpaced and paced states, ICV losartan abolished drinking, induced a significant diuresis (P < 0.05) and anti-natriuresis (P < 0.05), and increased plasma renin activity (P < 0.05) and ANG II (P < 0.01) and aldosterone levels (0.1 > P > 0.05). Plasma arginine vasopressin was suppressed by ICV losartan only in the paced state (P < 0.05). Hemodynamics were not altered by ICV losartan in the nonpaced animals. In the paced state, however, significant reductions in left ventricular systolic, mean arterial, and left atrial pressures were observed (decrements of 13 +/- 7, 12 +/- 5, and 3.4 +/- 0.7 mmHg, respectively, all P < 0.05). In conclusion, ANG II within the brain participates in the regulation of thirst and body electrolyte and fluid homeostasis in normal and heart-failed sheep and appears to play a role in regulating resting hemodynamic status in this model of heart failure.
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PMID:Central angiotensin II AT1-receptor antagonism in normal and heart-failed sheep. 765 6

This study aimed to investigate the inter-relation between the angiotensin II (ANG II) AT1 receptor and renin gene expression in rat kidneys. To this end, renin mRNA levels and mRNA levels for AT1a and AT1b were assayed by RNase protection in the kidneys of normal rats, in animals treated with the AT1 antagonist losartan and in rats bearing 0.2-mm left renal artery clips for 2 days. In normal rats, we found a negative correlation between renin mRNA levels and AT1a receptor mRNA levels. Losartan led to a fourfold increase in renin mRNA levels without changing AT1 receptor mRNA levels. Unilateral renal artery clipping increased renin mRNA levels fourfold in the clipped kidney and suppressed renin mRNA levels in the contralateral kidneys. AT1 receptor mRNA levels were not changed in the contralateral intact kidneys, but were significantly decreased by 15-25% in the clipped kidneys. Renin mRNA levels were inversely correlated to AT1a mRNA levels in the clipped, but not in the contralateral, kidneys. Our findings suggest that the systemic activity of the renin angiotensin system has no regulatory influence on renal AT1 receptor gene expression. Renin mRNA levels in normal and in clipped kidneys appear to be negatively determined by the level of AT1a receptor gene expression. Thus modulation of AT1a receptor gene expression could be a pathway for indirect modulation of renin gene expression by ANG II. This conclusion is in agreement with the observation that AT1 receptor antagonists are powerful stimulators of the renin system.
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PMID:Renin gene and angiotensin II AT1 receptor gene expression in the kidneys of normal and of two-kidney/one-clip rats. 767 36

We report a simple method using copy RNA (cRNA) internal standards for quantitative Northern hybridization. This was accomplished by synthesis of a full-length or "half"-length cRNA and mixing these RNA internal standards with samples to be tested for the abundance of a given mRNA. Both full-length and truncated cRNAs are detected in Northern analysis by the nucleic acid detection probe (which can be labeled with 32P or biotin), and the known amount of the truncated cRNA is compared to the homologous mRNA present in the specimen being examined. We demonstrate the usefulness of this method by measuring the expression of renin in rat kidney with ureteral obstruction and angiotensin II receptor (AT1-R) mRNA in kidneys from spontaneously hypertensive rats. It was found that this method of preparing cRNA internal standards successfully controlled for variables (such as differences in loading, transfer and hybridization efficiency) that often frustrate efforts to use Northern analysis as a quantitative tool and enabled direct estimation of absolute mRNA amount present in samples. This technique may have wide applicability and permit a more quantitative use of Northern analysis.
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PMID:Internal cRNA standards for quantitative northern analysis. 768 49

The effects of EXP3174 (0.03-0.3 mg/kg), the active metabolite of the angiotensin II (AII) receptor antagonist losartan, on systemic and coronary hemodynamics as well as on regional myocardial blood flow (radioactive microspheres) were evaluated in anesthetized, open-chest dogs with or without preactivated renin-angiotensin system (RAS) (furosemide treatment). These effects were compared with those of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat (0.1-1 mg/kg). In dogs without preactivated RAS, EXP3174 or enalaprilat did not exert marked hemodynamic effects other did not exert marked hemodynamic effects other than a significant decrease in mean arterial blood pressure (MAP) at the highest doses. In dogs with preactivated RAS, EXP3174 induced a marked, dose-dependent decrease in MAP (maximum decrease -23 +/- 7%), associated with a significant decrease in total peripheral resistance (TPR), whereas cardiac output (CO), heart rate (HR), and left ventricular dP/dt remained unchanged. At the coronary level, EXP3174 induced a decrease in mean coronary resistance that paralleled that of AP. Similar systemic and coronary hemodynamic effects were obtained with enalaprilat administered at doses three times higher. However, regional myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural) or its transmural distribution (endo/epi ratios) was not affected by EXP3174 or enalaprilat. Thus, these results indicate that blockade of the AT1 receptor of AII by EXP3174 induces hemodynamic modifications similar to those evoked by the ACE inhibitor enalaprilat. The lack of effect of EXP3174 or enalaprilat on regional myocardial blood flow (RMBF) suggests, however, that the RAS does not play a role in regulation of myocardial tissue perfusion.
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PMID:Systemic and coronary effects of the angiotensin II receptor antagonist EXP3174 in dogs. 769 96

The efficacy of SR 47436 (BMS-186295), 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)- biphenyl-4-yl)methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, a non-peptide angiotensin AT1 receptor antagonist, was characterized in various conscious hypertensive rat models. In spontaneously hypertensive rats, single intravenous or oral doses of SR 47436 induced mild to modest antihypertensive effects. No tolerance of the antihypertensive effect was observed when the oral treatment was extended to 15 days. SR 47436 was highly effective to lower blood pressure in high renin-dependent hypertensive models such as two-kidney, one-clip renal hypertensive rats and renal artery-ligated hypertensive rats. In this last model, intravenous or oral administration of the angiotensin II antagonist produced a dose-dependent decrease in blood pressure. When injected after the maximal effective dose, enalapril did not induce any further decrease in blood pressure. Furthermore, the antihypertensive effect elicited after a single oral dose (10 mg/kg) was long-lasting (at least 24 h). The simultaneous blunting effect of the angiotensin II-induced blood pressure increase indicated clearly that the antihypertensive effect was due to the blockade of vascular angiotensin AT1 receptors. As expected, the angiotensin AT1 receptor antagonist did not show any efficacy in deoxycorticosterone acetate hypertensive rats, with a suppressed renin-angiotensin system. In genetic and renal hypertensive rats, the antihypertensive effect induced after acute dosing of SR 47436 was similar to that observed after losartan and enalapril. A reflex tachycardia accompanied the antihypertensive effect only after intravenous treatment with either SR 47436 or losartan. These results show that this angiotensin II antagonist, SR 47436, is an effective and long-lasting antihypertensive agent in rats.
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PMID:Efficacy of SR 47436 (BMS-186295), a non-peptide angiotensin AT1 receptor antagonist in hypertensive rat models. 769 70


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