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

Angiotensin II (ANG II) is the primary mediator of the renin-angiotensin system, which has an important functional role in cardiovascular homeostasis. The angiotensin receptor and its functional correlates have been redefined by the cloning of angiotensin receptors and the discovery and widespread study of specific nonpeptide ANG II-receptor antagonists losartan (AT1 selective) and PD123177 (AT2 selective). With these antagonists, it has been possible to extend the concept of ANG II-receptor heterogeneity to virtually every tissue and species. The losartan-sensitive sites have been shown to mediate all of the major ANG II-induced biologic effects, including vasoconstriction, aldosterone and catecholamine release, and central, ANG II-induced drinking behavior. The function of the AT2 site is not fully understood, but it may be involved in neuronal ion channel modulation and in fibroblast collagen metabolism. The presence of AT2 sites in fetal tissues and in discrete locations in the brain has encouraged continued research. Losartan, which represents the first of a new class of therapeutic agents, is currently undergoing clinical trials. A growing number of other AT1-selective ANG II-receptor antagonists are under development, including L-158,809, SKF 108566, and GR117285. Rat AT1-receptor subtypes have been cloned and sequenced (AT1A and AT1B). Human ANG II receptors have also been cloned and shown to have high affinity for losartan. A number of atypical angiotensin-binding sites have been identified from mycoplasma, amphibians, and mouse neuroblastoma, which are not sensitive to either losartan or PD123177.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II receptors and functional correlates. 129 Jun 17

On the basis of biochemical and autoradiographic studies it has been shown that the inferior olivary nucleus (ION) contains predominantly angiotensin II (Ang II) receptors of the subtype 2 (AT2). In the present investigation we used microiontophoretic techniques to test the effect of Ang II on the spontaneous firing rate of rat neurones in the ION in vivo. Ang II excited the majority of histologically identified ION neurones. Furthermore, the antagonism of this angiotensin-induced excitation by selective angiotensin receptor blockers of subtype 1 and 2 (AT1 and AT2) was examined. The excitation could be blocked by low doses of the AT2-antagonists PD 123177 and CGP 42112A, whereas the AT1-antagonist DuP 753 was ineffective even at high doses. On a few occasions, however, ejection of the AT1-antagonist resulted in a potentiation of angiotensin-induced excitation. The results suggest that Ang II has an excitatory effect on a considerable number of ION neurones and that this effect is mediated by AT2-receptors.
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PMID:Effects of angiotensin II and its selective antagonists on inferior olivary neurones. 133 23

[125I]EXP985 is the first nonpeptide radioligand with high specific activity for the AT1 angiotensin receptor. The biochemical and pharmacological profiles of this ligand were determined using either ligand-receptor binding techniques in rat adrenal cortical microsomes or cellular Ca2+ mobilization in rat smooth muscle cells. Specific binding with 0.1 nM [125I]EXP985 increased slowly with time reaching an equilibrium at 60 min of incubation (22 degrees C). Scatchard analysis of the inhibition/binding data revealed a single class of binding sites having a Kd of 1.49 +/- 0.06 nM and a Bmax of 3.6 +/- 0.1 pmol/mg protein. These sites were saturable and the ligand-receptor complex dissociated with a t1/2 of 58 min. The binding was inhibited by Ang peptides with the following order of potency and IC50 (nM): Ang II (3.7) > Ang III (69) > Ang I (3650), and by the nonpeptide AT1 receptor antagonist, losartan, with an IC50 of 3.2 nM. PD123177, an AT2 selective antagonist, showed minimal inhibitory effect. Specific binding of [125I]EXP985 was found on rat aortic smooth cells. Ang II-induced Ca2+ mobilization in these cells was blocked by EXP985 in a noncompetitive manner. These data show that [125I]EXP985 (or its unlabeled) is a potent and highly specific radioligand or noncompetitive antagonist which represents a novel tool to further our understanding of the biochemistry of AT1 receptors.
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PMID:[125I]EXP985: a highly potent and specific nonpeptide radioligand antagonist for the AT1 angiotensin receptor. 144 40

To better understand the action of angiotensin II (ANG II) and angiotensin receptor antagonists (ARA) in human kidney, ANG II receptors were characterized by in vitro autoradiography in fetal and adult human renal tissue using 125I-[Sar1-Ile8]ANG II (125I-ANG II), a potent ANG II antagonist. Binding was inhibited with the ARAs DuP 753 and PD 123177, respectively. In adult kidneys (n = 5), binding of 125I-ANG II showed the following characteristics: arterial vessels had dissociation constant (Kd) = 387.6 +/- 29.1 (SD) pM and maximal binding (Bmax) = 41.4 +/- 3.6 fmol/mg tissue equivalent (TE); glomeruli had Kd = 885.7 +/- 217.1 pM and Bmax = 35.5 +/- 8.1 fmol/mg TE; and outer medulla had Kd = 142.1 +/- 52.5 pM and Bmax = 7.7 +/- 2.3 fmol/mg TE. PD 123177 effectively displaced 125I-ANG II only in large preglomerular vessels [half-maximal inhibitory concentration (IC50) = 0.22 +/- 0.1 nM, type 2 receptor (AT2)], whereas DuP 753 displaced only the labeled ligand in glomeruli (IC50 = 0.28 +/- 0.11 nM) and outer medulla (IC50 = 0.39 +/- 0.11 nM, AT1). In fetal kidneys (n = 4), a diffuse 125I-ANG II binding was demonstrated in the medulla (Kd = 36.6 +/- 7.1 pM; Bmax = 25 +/- 3.8 fmol/mg TE) and in the cortex (Kd = 19.5 +/- 8 pM; Bmax = 7.2 +/- 2.2 fmol/mg TE). Both cortical (IC50 = 0.039 +/- 0.019 nM) and medullary binding (IC50 = 0.076 +/- 0.039 nM) could only be displaced by PD 123177.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Autoradiographic characterization of angiotensin receptor subtypes in fetal and adult human kidney. 153 89

Angiotensin II receptor number was higher in superior cervical ganglia of 2-week-old when compared to 8-week-old rats. In both young and adult rats, specific binding of [125I][Sar1]angiotensin II was displaced competitively by the AT1-receptor antagonist DuP 753 but not by the AT2-receptor competitor PD 123177. In ganglia from adult rats, DuP 753 competed with an IC50 of 113 nM. The stable guanine nucleotide GTP gamma S inhibited binding of [125I][Sar1]angiotensin II in young and adult rats by approximately 50% with IC50 values of 105 and 120 nM, respectively, suggesting that the angiotensin receptor is G-protein linked. Angiotensin II at a dose of 1 microM stimulated inositol phosphate formation 58% over control values in superior cervical ganglia from 8-week-old rats. This effect was totally blocked by 10 microM DuP 753 but not by 10 microM PD 123177. Our findings demonstrate that rat superior cervical ganglia contain AT1-type angiotensin receptors that are probably G-protein linked, and their stimulation results in increased inositol phospholipid metabolism.
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PMID:Angiotensin II AT1 receptors in rat superior cervical ganglia: characterization and stimulation of phosphoinositide hydrolysis. 166 60

Quantitative autoradiography was used to characterize angiotensin AT1 and AT2 receptors, in the rat aorta at three developmental ages; embryonic day 18 (E18), and postnatal weeks 2 and 8. The expression of angiotensin receptors was higher in the aorta of E18 and 2-week-old rat. A major proportion of the angiotensin receptors expressed in the aorta at these two ages was AT2 (84 and 81% respectively). Conversely, in the aorta of 8-week-old rats, AT1 was the predominant angiotensin receptor subtype (71%). In 8-week-old rats, the AT2 subtype was also present (28%). In pre- and postnatal rats, [125I]Sar1-angiotensin II binding to AT1 receptors was sensitive to GTP gamma S whereas binding to AT2 receptors was not. AT2 receptors may serve an important role during stages of rapid growth of the aorta, and also have a significant function in the adult vasculature.
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PMID:Changes in expression of angiotensin receptor subtypes in the rat aorta during development. 193 Jan 81

The displacement of [125I]Sar1, Ile8 angiotensin II binding by the receptor subtype selective angiotensin II antagonists, DuP-753 and WL-19 (PD121981) was used to define the relative proportion of angiotensin subtype AT1 and subtype AT2 receptors, respectively in various tissues (aorta, heart, adrenal cortex, kidney cortex and brain) of the rat, rabbit and monkey. The relative abundance of these receptor subtypes varied greatly not only among different tissues of the same species but also within the same tissue of different species. The relative affinity of the DuP-753 and WL-19 for the angiotensin receptor subtypes did not vary markedly suggesting that the two angiotensin receptor subtypes in these tissues and species are similar.
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PMID:Angiotensin receptor subtypes in rat, rabbit and monkey tissues: relative distribution and species dependency. 194 52

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

The effects of four nonpeptide angiotensin receptor antagonists, i.e., losartan (AT1) PD123177 (AT2), and 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl)- methyl]biphenyl-carboxylic acid (BIBS 39; AT1 and AT2), and 2-n-butyl-1-[4-(6-carboxy-2,5-di-chlorbenzoylamino)-benzyl]-6-N- (methylaminocarbonyl)-n-pentylamino-benzimidazole (BIBS 222; AT1 and AT2) on cardiovascular responses to angiotensin II (AII) were investigated in propranolol-pretreated pithed rats. AII (0.01-10 nmol/kg intravenously, i.v.) induced a dose-dependent increase in diastolic blood pressure (DBP), the rate of increase in left ventricular pressure (LVdP/dtmax), cardiac output (CO), and total peripheral resistance (TPR) without changing LV end-diastolic pressure (LVEDP) or heart rate (HR). Losartan 3 and 10 mg/kg i.v. caused dose-dependent parallel rightward shifts of the dose-response curves (DBP and LVdP/dtmax) without altering the maximal responses to AII. PD123177 (100 mg/kg i.v.) did not influence the dose-response curves for AII significantly. BIBS 39 (1, 3, and 10 mg/kg i.v.) and BIBS 222 (1, 3, and 10 mg/kg, i.v.) shifted the dose-response curves (DBP and LVdP/dtmax) for AII to the right. Although these two compounds (BIBS 39 1, 3, and 10 mg/kg and BIBS 222 1 and 3 mg/kg) did not alter the maximal increase in DBP to angiotensin AII, they decreased the maximal increase in LVdP/dtmax by approximately 35%. BIBS 39 (3 and 10 mg/kg) significantly reduced the increase in CO caused by AII and therefore mean arterial pressure (MAP), whereas the AII-induced increase in TPR remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of various angiotensin receptor antagonists on cardiovascular responses to angiotensin II in pithed rats. 752 74


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