Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The angiotensin II antagonistic activity of SB 203220, [E-alpha-[[2-butyl-1-(4-carboxy-1-naphthalenyl)methyl]-1H- imidazol-5-yl]-methylene]-2-thiophene-propanic acid], was examined in several in vitro and in vivo assays. SB 203220 displaced [125I]angiotensin II binding from a variety of tissues including the cloned human AT1 receptor (IC(50)5-15 nM). SB 203220 (10 microM) did not interact with AT2, endothelin (ETA and ETB) or calcitonin gene-related peptide receptors. [3H]SB 203220 bound with high affinity to the AT1 receptor (Kd = 4.9 nM), but dissociated from the receptor at a much slower rate when compared to [3H]SK&F 108566. SB 203220 antagonized intracellular Ca2+ mobilization induced by angiotensin II in rat vascular smooth muscle cells and exhibited a selective and partially insurmountable antagonism of angiotensin II-induced contraction in isolated rabbit aorta. In the aorta, SB 203220 produced a concentration-dependent parallel shift in the concentration-response curve to angiotensin II [EC30 = 5.94 +/- 1.6 10(-11) M] and depressed the maximal contractile response to angiotensin II by approximately 35%. The antagonistic effect of SB 203220 in rabbit aorta was slowly reversible compared to SK&F 108566. SB 203220 displayed no agonist activity and had no effect on the contractile responses to KCl, endothelin-1 or norepinephrine. In rats, SB 203220 at 10 mg/kg i.v. inhibited angiotensin II-induced aldosterone release. Intraduodenal or oral administration of SB 203220 (1-10 mg/kg) to conscious rats and dogs inhibited the pressor responses to exogenous angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Pharmacology of a potent long-acting imidazole-5-acrylic acid angiotensin AT1 receptor antagonist. 749 22

Endothelin-1 (ET-1) and angiotensin II (AII) are potent vasoconstrictor hormones which regulate tissue perfusion and blood pressure. We pharmacologically characterized endothelin and angiotensin receptors mediating contractions of human mammary resistance arteries in myographs for isometric tension recording. ET-1 caused potent contractions. The concentration response curve was shifted to the right by ETA antagonist FR 139317, but a high sensitivity, low efficacy component remained. After incubation with ETB agonist sarafotoxin (S6c) this component of the concentration response curve resistant to FR 139317 disappeared. The ETA/ETB-receptor antagonist bosentan shifted the entire concentration response curve to the right. AI and AII caused marked contractions. The effects of AI were reduced by the ACE inhibitor benazeprilat, while those of AII were prevented by valsartan, an AT1 antagonist. In summary, in human resistance arteries, contractions to ET-1 are mediated by ETA- and ETB-receptors while those to AII are exclusively mediated by AT1-receptors.
 ...
PMID:Characterization of contractile endothelin and angiotensin receptors in human resistance arteries: evidence for two endothelin and one angiotensin receptor. 798 May 30

This study investigates the cellular localization and regulation of endothelin-1 (ET-1) and angiotensin II (Ang II) receptors and the effects of ET-1 and Ang II on [Ca2+]i in cardiac hypertrophy due to volume overload in the rat. Radioligand binding assays and [Ca2+]i measurements by fura 2 methodology were performed on isolated ventricular cardiomyocytes and fibroblasts from the heart of rats with a 4-week aortocaval shunt. In the hypertrophied myocardium, ET-1 and Ang II concentrations were unchanged in ventricles. Ventricular ET-1 receptors had a cell-specific distribution: > 90% of ET receptors in cardiomyocytes are of the ETA subtype, whereas fibroblasts had a nearly equal proportion of the ETA and ETB subtypes. ET-1 receptor densities, affinities, and ET-1-induced [Ca2+]i were not significantly different from control in both ventricular cell types from hypertrophied myocardium. Ang II specific binding was very low on isolated ventricular cardiomyocytes, suggesting few receptors in control conditions. However, [Ca2+]i responses induced by Ang II at concentrations > 10(-8) mol/L were detectable and were significantly higher in hypertrophied cardiomyocytes. Ang II receptor density (exclusively AT1) on fibroblasts was significantly reduced (42,970 +/- 3330 versus 73,870 +/- 7940 sites per cell for control cells, P < .01), but AT1 receptor affinity was unchanged after volume overload. The maximum increase in [Ca2+]i evoked by 10(-6) to 10(-4) mol/L Ang II was significantly lower in fibroblasts from overloaded hearts. In conclusion, ET-1 receptor proportion is cell specific, with cardiomyocytes possessing predominantly the ETA subtype and fibroblasts possessing both ETA and ETB receptors. Plasma and cardiac ET-1 concentrations and ET-1 receptor regulation on both ventricular cell types are not altered in cardiac volume overload, suggesting that cardiac ET-1 may not play a significant role in this model. Cardiac hypertrophy induced a significant downregulation of AT1 receptors on fibroblasts, whereas total binding and [Ca2+]i sensitivity to Ang II were significantly enhanced in hypertrophied cardiomyocytes. This suggests that cardiac Ang II may be involved in the pathophysiology of the cardiac hypertrophy of volume overload.
 ...
PMID:Endothelin-1 and angiotensin II receptors in cells from rat hypertrophied heart. Receptor regulation and intracellular Ca2+ modulation. 857 74

Volume expansion has been shown to increase plasma atrial natriuretic peptide (ANP) levels, but the precise role of paracrine and autocrine factors in stretch-induced cardiac hormone release is not clear. In the present study, we report the effects of endothelin (ET) and angiotensin receptor (AT receptor) antagonists on baseline and atrial stretch-induced immunoreactive ANP (IR-ANP) and immunoreactive N-terminal ANP (IR-NT-ANP) release in vivo by using BQ-123 (ETA receptor antagonist), bosentan (ETA and ETB receptor antagonist), and losartan (AT1 receptor antagonist). Intravenous administration of BQ-123 had no significant effect on baseline hemodynamics in conscious rats, whereas bosentan (10 mg/kg) and losartan (10 mg/kg) decreased slightly (4 to 7 mm Hg, P < .05 to .001) the mean arterial pressure. Both the ETA receptor antagonist BQ-123 and ETA/ETB receptor antagonist bosentan decreased plasma ANP and NT-ANP responses to volume load (P < .05 to .001), whereas the AT1 receptor antagonist losartan had no significant effect on this response. The relative increase in plasma IR-ANP corresponding to a 3 mm Hg increase in right atrial pressure was 2.7-fold in the vehicle-treated group. BQ-123 (0.3 and 1.0 mg/kg) decreased this response 2.5- and 2.1-fold (P < .05); bosentan (3 and 10 mg/kg), 1.7-fold (P < .001) and 1.9-fold (P < .05); and bosentan (10 mg/kg)+losartan (10 mg/kg), 1.6-fold (P < .001). The responses in plasma IR-NT-ANP decreased simultaneously. These results indicate that combined inhibition of ETA/B and AT1 receptors almost completely blocks ANP response to acute volume load. Therefore, our study shows that endogenous paracrine and/or autocrine factors liberated in response to atrial wall stretch rather than myocyte stretch itself are responsible for the activation of ANP peptide secretion in response to acute volume load. Our results also show that ETA receptors are more important in the regulation of mechanical stretch-induced changes in cardiac hormone secretion than AT1 receptors.
 ...
PMID:Combined inhibition of endothelin and angiotensin II receptors blocks volume load-induced cardiac hormone release. 897 30

1. Angiotensin II (AII) and the endothelins (ET) are known to be potent trophic stimuli in various cells including cardiomyocytes. In order to characterize further these effects we studied, in neonatal rat ventricular cardiomyocytes, the effects of several endothelin-receptor antagonists and the AT1-receptor antagonist losartan on AII- and endothelin-induced inositol phosphate (IP)-formation (assessed as accumulation of total [3H]-IPs in myo-[3H]-inositol prelabelled cells) and increase in rate of protein synthesis (assessed as [3H]-phenylalanine incorporation). 2. Endothelin (10 pM-1 microM) concentration-dependently increased IP-formation (max. increase at 100 nM ET-1: 130 +/- 14% above basal, n = 25) and [3H]-phenylalanine incorporation (max. increase at 1 microM: 52 +/- 4% above basal, n = 16) with an order of potency: ET-1 > > ET-3. Both effects were antagonized by the ETA/ETB-receptor antagonist bosentan and the ETA-receptor antagonist BQ-123, but not affected by the ETB-receptor antagonist IRL 1038 and the AT1-receptor antagonist losartan. 3. Pretreatment of the cells with 500 ng ml-1 pertussis toxin (PTX) overnight that completely inactivated PTX-sensitive G-proteins did not attenuate but rather enhance ET-1-induced IP-formation. On the other hand, in PTX-pretreated cardiomyocytes ET-1-induced [3H]-phenylalanine incorporation was decreased by 39 +/- 5% (n = 5). 4. All (1 nM-1 microM) concentration-dependently increased IP-formation (max. increase at 1 microM: 42 +/- 7% above basal, n = 16) and [3H]-phenylalanine incorporation (max. increase at 1 microM: 29 +/- 2%, n = 9). These effects were antagonized by losartan, but they were also antagonized by bosentan and BQ-123. 5. In well-defined cultures of cardiomyocytes (not contaminated with non-myocyte cells) All failed to increase [3H]-phenylalanine incorporation: addition of non-myocyte cells to the cardiomyocytes restored All-induced increase in [3H]-phenylalanine incorporation. 6. We conclude that, in rat neonatal ventricular cardiomyocytes, (a) the ET-1-induced increase in rate of protein synthesis (through ETA-receptor stimulation) involves at least two signalling pathways: one via a PTX-insensitive G-protein coupled to IP-formation, and the other one via a PTX-sensitive G-protein, and (b) the trophic effects of All are brought about via local ET-1 secretion upon AT1-receptor stimulation in neonatal rat ventricular non-myocyte cells.
 ...
PMID:Trophic effect of angiotensin II in neonatal rat cardiomyocytes: role of endothelin-1 and non-myocyte cells. 914 95

We measured the activity of mitogen-activated protein (MAP) kinases, enzymes believed to be involved in the pathway for cell proliferation, in rat aortic strips with or without endothelium, and examined effects of angiotensin receptor antagonists, endothelin receptor antagonists and nitric oxide (NO)-related agents. Endothelium removal produced an activation of MAP kinase activity in the strips, whereas the enzyme activity was not affected in the adventitia. The MAP kinase activation was inhibited by either the angiotensin AT1 receptor antagonist losartan or the endothelin ETA receptor antagonist BQ 123. The combination of both antagonists caused an additive inhibition. The angiotensin AT2 receptor antagonist PD 123,319 and the endothelin ETB receptor antagonist BQ 788 did not affect the MAP kinase activation. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) caused an activation of MAP kinase in the endothelium-intact aorta and the MAP kinase activation was inhibited by losartan or BQ123. The NO releaser nitroprusside inhibited the MAP kinase activation induced by endothelium removal or angiotensin II. These results suggest that even in isolated arteries, NO of endothelial origin tonically exert MAP kinase-inhibiting effects and endogenous angiotensin II and endothelins in the media are tonically released to cause MAP kinase-stimulating effects in medial smooth muscle.
 ...
PMID:Evidence that angiotensin II, endothelins and nitric oxide regulate mitogen-activated protein kinase activity in rat aorta. 965 1

The endothelial nitric oxide synthase (eNOS) is activated in response to stimulation of endothelial cells by a number of vasoactive substances including, bradykinin (BK), angiotensin II (Ang II), endothelin-1 (ET-1) and ATP. In the present study we have used in vitro activity assays of purified eNOS and in vitro binding assays with glutathione S-transferase fusion proteins to show that the capacity to bind and inhibit eNOS is a common feature of membrane-proximal regions of intracellular domain 4 of the BK B2, the Ang II AT1 and the ET-1 ETB receptors, but not of the ATP P2Y2 receptor. Phosphorylation of serine or tyrosine residues in the eNOS-interacting region of the B2 receptor results in a loss of eNOS inhibition due to a decrease in the binding affinity of the receptor domain for the eNOS enzyme. Furthermore, the B2 receptor is transiently phosphorylated on tyrosine residues in cultured endothelial cells in response to BK stimulation. Phosphorylation occurs during the time in which eNOS transiently dissociates from the receptor accompanied by a transient increase in nitric oxide production. Taken together, these data support the hypotheses that eNOS is regulated in endothelial cells by reversible and inhibitory interactions with G-protein-coupled receptors and that these interactions can be modulated by receptor phosphorylation.
 ...
PMID:Endothelial nitric oxide synthase interactions with G-protein-coupled receptors. 1051 Feb 97

Endothelin (ET) antagonists do not decrease blood pressure in normal rats. Since angiotensin II (AII) and ET both induce smooth muscle cell contraction through the same transduction pathways we designed experiments to assess whether blockade of the renin angiotensin system would unmask a vasodilatory response to ET receptor antagonists in rats. For this purpose, we tested the effect on arterial blood pressure of the mixed ETA-ETB receptor antagonist bosentan or of the ETA antagonist BQ-123 in the absence or the presence of the AII receptor antagonist losartan. In control conditions bosentan did not affect arterial blood pressure. In contrast, in losartan-pretreated rats, bosentan induced a marked, dose-dependent decrease in arterial pressure (% change after bosentan 10 mg/kg: control -3 +/- 3, losartan -32 +/- 6; cilazapril -28 +/- 3). Similarly, BQ-123 decreased blood pressure in losartan-pretreated but not in control rats. Bosentan also increased the hypotensive effect of losartan in conscious, normotensive rats. The hypotensive effect of the combination of bosentan and losartan was not associated with any changes in cardiac output or heart rate, and thus was entirely due to a decrease in total peripheral resistance. We conclude that blockade of angiotensin II, AT1 receptors unmasks a vasodilator response to ET antagonists. This suggests that endogenous ET plays an active role in the maintenance of arterial blood pressure in rats which can be unmasked by a concomitant inhibition of the renin angiotensin system.
 ...
PMID:Angiotensin II receptor blockade unmasks a depressor response to endothelin antagonists in rats. 1079 56

1. The renal medulla plays an important role in regulating body sodium and fluid balance and blood pressure homeostasis through its unique structural relationships and interactions between renomedullary interstitial cells (RMIC), renal tubules and medullary vasculature. 2. Several endocrine and/or paracrine factors, including angiotensin (Ang)II, endothelin (ET), bradykinin (BK), atrial natriuretic peptide (ANP) and vasopressin (AVP), are implicated in the regulation of renal medullary function and blood pressure by acting on RMIC, tubules and medullary blood vessels. 3. Renomedullary interstitial cells express multiple vasoactive peptide receptors (AT1, ETA, ETB, BK B2, NPRA and NPRB and V1a) in culture and in tissue. 4. In cultured RMIC, AngII, ET, BK, ANP and AVP act on their respective receptors to induce various cellular responses, including contraction, prostaglandin synthesis, cell proliferation and/or extracellular matrix synthesis. 5. Infusion of vasoactive peptides or their antagonists systemically or directly into the medullary interstitium modulates medullary blood flow, sodium excretion and urine osmolarity. 6. Overall, expression of multiple vasoactive peptide receptors in RMIC, which respond to various vasoactive peptides and paracrine factors in vitro and in vivo, supports the hypothesis that RMIC may be an important paracrine target of various vasoactive peptides in the regulation of renal medullary function and long-term blood pressure homeostasis.
 ...
PMID:Renomedullary interstitial cells: a target for endocrine and paracrine actions of vasoactive peptides in the renal medulla. 1087

We assessed the role of angiotensin (Ang) II type 1 receptor (AT1) and endothelin type A and B (ETA & ETB) receptor in cardiovascular hypertrophy associated with angiotensin II-induced hypertension (200 ng/kg.min s.c. for 10 or 17 days). Antagonism of AT1 receptors was obtained by oral administration of losartan (10 or 30 mg/kg.day) and blockade of ETA and ETB receptors was obtained by oral administration of bosentan (30 mg/kg.day). Losartan and bosentan were administered 24 h before and during the 10 days of angiotensin II (prevention) or they were given after the development of hypertension i.e. from day 10 to 17 of angiotensin II (treatment). Tail-cuff pressure (TCP) was measured before and at the end of the period of administration of antagonists. At the end of experiments, cross sectional area (CSA, mm2) of the carotid was measured after perfusion and fixation at 100 mmHg and heart weight index (HWI, mg/g body weight) was determined. Results are mean +/- SEM. [table: see text] In addition to its blood pressure lowering effect, both doses of losartan prevented and reversed the cardiovascular hypertrophy induced by angiotensin II. Similarly, bosentan prevented and reversed the effect of angiotensin II on cardiovascular structure independently of arterial pressure. These results indicate that the effect of angiotensin II on blood pressure, heart and carotid structure is exclusively mediated by AT1 receptors. The influence of bosentan suggests that endothelin plays an important role in local action of angiotensin II independently of blood pressure level.
 ...
PMID:[Cardiac and vascular hypertrophy in hypertension due to angiotensin II. Effect of losartan and bosentan]. 1098 42


1 2 3 Next >>