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)

The selective biphenylimidazole and tetrahydroimidazopyridine antagonists exemplified by losartan (DuP 753) and PD 123319 have been shown to bind selectively to angiotensin AT1 and AT2 receptor subtypes, respectively. To characterize which subtypes of angiotensin II receptors are expressed in mammalian portal vein smooth muscle, we performed, using both membrane and strip preparations, [3H]angiotensin II binding experiments and then contraction experiments to investigate the functional relevance of these binding sites. Specific binding of [3H]angiotensin II was of high affinity, saturable and reversible. Specific binding of [3H]angiotensin II was completely displaced by angiotensin II and the peptide antagonist [Sar1,Ile8]angiotensin II. The inhibition of [3H]angiotensin II binding by losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl)- methyl]imidazole, potassium salt) and DuP 532 (2-n-propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-yl)biph enyl-4-yl)- methyl]imidazole-5-carboxylic acid) was biphasic and LIGAND curve-fitting analysis revealed two populations of specific binding sites. One subpopulation represented 75% of the total binding and showed high affinity for angiotensin II, losartan and DuP 532, but low affinity for the peptide angiotensin AT2 receptor antagonist CGP 42112A (N-alpha-nicotinoyl-Tyr-Lys-[N-alpha-CBZ-Arg]-His-Pro-Ile-OH) and thus appeared identical to the cloned angiotensin AT1 receptor subtype. The remaining 25% of the sites showed nearly 1000-fold lower affinity for losartan, 6500-fold lower affinity for DuP 532 and high affinity for PD 123319 (S-1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-diphenylacetyl- 4,5,6,7-tetrahydro-1H-imidazo-[4,5-c] pyridine-6-carboxylic acid, difluoroacetate monohydrate) and CGP 42112A, with values of Ki in the same range (nM) as those found for losartan and DuP 532 at angiotensin AT1 binding sites. These sites appear to be angiotensin AT2 receptors. Only the angiotensin AT1 receptor subtype interacted with G-proteins, as indicated by the 80% inhibition of [3H]angiotensin II binding in the presence of guanosine 5'-O-(3-thiophosphate) or fluoroaluminates. Although the angiotensin II-induced contraction was completely inhibited by losartan with a pA2 value of 8.8, PD 123319 reduced the angiotensin II-induced contraction by 20-25%, indicating that both angiotensin AT1 and AT2 receptor subtypes are functional in portal vein smooth muscle.
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PMID:Angiotensin II receptor subtypes and contractile responses in portal vein smooth muscle. 755 78

Angiotensin II (Ang II) has been reported to modulate cGMP formation in various types of cells. To acquire direct information on the intracellular transduction involved in this mechanism, we tested the effects of Ang II on vascular tone and on cGMP content of in vitro isolated carotid arteries from 12-week-old Wistar-Kyoto rats. Segments of carotid artery 20 mm long (n = 8 for each group) maintained at a transmural pressure of 100 mm Hg were immersed in a bath (38 degrees C) containing oxygenated Tyrode's solution. At the end of each experiment, the vessel diameter was measured, and the wall cGMP content was determined by enzyme immunoassay. Under basal conditions, mean diameter was 968 +/- 19 microns, and mean cGMP carotid artery content was 38.9 +/- 3.5 fmol/mg tissue. Incubation for 20 minutes with Ang II (10(-5) mol/L) significantly increased cGMP wall content, twofold above the basal content (P < .01), and constricted the vessel (60 +/- 2.2% of the control diameter, P < .001). After preincubation with a nonselective antagonist of Ang II receptors, saralasin ([Sar1,Val5,Ala8]Ang II, 5 x 10(-5) mol/L), or with a specific antagonist of Ang II AT1 receptor subtype, losartan (5 x 10(-5) mol/L), carotid diameter and cGMP content were no longer affected by Ang II. Exposure of carotid arteries to a specific antagonist of Ang II AT2 receptor, PD 123319 (10(-7) mol/L), modified neither Ang II-induced diameter decrease nor cGMP content increase. Constriction of the vessel with KCl (26 +/- 3%, P < .001) did not modify the basal cGMP wall content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II increases cGMP content via endothelial angiotensin II AT1 subtype receptors in the rat carotid artery. 758 39

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A1 receptor stimulation which results in an upregulation of protein kinase C (PKC). Subsequent sustained ischemia then causes renewed stimulation of adenosine A1 receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection. If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P < 0.01). This protection could be blocked by the AT1 receptor blocker losartan (10 microM), but not by the AT2 receptor blocker PD 123319 (10 microM). Polymyxin B (50 microM), a PKC inhibitor, also blocked the protective effect of AII. These observations demonstrated that activation of PKC by AT1 receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the 30 min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort AII's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PKC during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT1 or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.
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PMID:Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. 760 6

Cardiovascular responses after the central blockade of the brain angiotensin system with peptide or nonpeptide angiotensin II analogs in conscious, freely moving hypertensive Dahl salt-sensitive (DS/JR) rats were measured. Four-week-old animals were maintained on an 8% salt diet until experimentation at 7 weeks of age. At the time of experimentation, mean arterial pressures were 176 +/- 6 mm Hg. The i.c.v. administration of 20 micrograms of the peptide analog sarcosine1, threonine8-angiotensin II (sarthran) resulted in a significant bradycardic response (approximately 17% decrease in H.R. peaking at 8 min after injection) without a significant change in blood pressure. Central administration of the AT1 antagonist losartan (10 micrograms) or of the AT2 antagonist PD 123319 (10 micrograms) was without effect. The peptide and nonpeptide analogs differed in their ability to inhibit central angiotensin II (10 ng)-induced pressor and dipsogenic responses. PD 123319 (10 micrograms) had no effect on the pressor and dipsogenic responses, whereas losartan (10 micrograms) and sarthran (20 micrograms) inhibited both responses for 85 +/- 17 and 29 +/- 3 min, respectively. The effect of preblocking either the AT1 or the AT2 receptors on the sarthran-induced bradycardia was also determined. Preblocking with either losartan (10 micrograms) or PD 123319 (10 micrograms) inhibited the bradycardic response by approximately 45%, which suggests that both receptor subtypes are involved in the central cardiovascular responses in the DS/JR rat and that, because it was attenuated by pure antagonists, the response to sarthran may be mediated by its agonist actions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cardiovascular effects after the intracerebroventricular administration of peptide and nonpeptide angiotensin antagonists in Dahl salt-sensitive rats. 763 38

Cardiovascular responses to intracerebroventricular angiotensin II (ANG II) were measured in conscious rats, chronically instrumented for the measurement of regional hemodynamics, over 4 consecutive days in the absence and presence of either the AT2 receptor antagonist, PD 123319 (experiment 1), or the AT1 receptor antagonist, EXP-3174 (experiment 2). Intracerebroventricular ANG II had pressor and bradycardic effects, which were associated with marked mesenteric and hindquarters vasoconstriction, and a small transient renal vasoconstriction. Both PD 123319 and EXP-3174, given intracerebroventricularly, abolished the cardiovascular response to intracerebroventricular ANG II, although the profiles of activity of the compounds were different. PD 123319 caused a slowly developing, but remarkably prolonged (1-2 days) inhibition of the effects of ANG II, whereas EXP-3174 caused an immediate inhibition of the effects of ANG II, although responses to ANG II had returned to control levels by the following day. These data suggest that the hemodynamic effects of ANG II may involve concurrent, and interdependent, activation of AT1 and AT2 receptors or that PD 123319 undergoes a unique biotransformation in the brain to some product(s) with AT1 receptor antagonist activity.
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PMID:Central administration of PD 123319 or EXP-3174 inhibits effects of angiotensin II. 767 56

We have characterized a specific binding site for angiotensin IV in bovine adrenal cortex membranes. Pseudo-equilibrium studies at 37 degrees C for 2 h have shown that this binding site recognizes angiotensin IV with a high affinity (Kd = 0.24 +/- 0.03 nM). The binding site is saturable and relatively abundant (maximal binding capacity around 0.5 pmol/mg protein). Non-equilibrium kinetic analyses at 37 degrees C revealed a calculated kinetic Kd of 47 pM. The binding site is pharmacologically distinct from the classic angiotensin receptors AT1 or AT2. Competitive binding studies with bovine adrenal cortex membranes demonstrated the following rank order of effectiveness: angiotensin IV (Val-Tyr-Ile-His-Pro-Phe) = angiotensin II-(3-7) (Val-Tyr-Ile-His-Pro) > angiotensin III (Arg-Val-Tyr-Ile-His-Pro-Phe) > or = angiotensin II-(4-7) (Tyr-Ile-His-Pro) > angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) > angiotensin II-(1-6) (Asp-Arg-Val-Tyr-Ile-His) > angiotensin II-(4-8) (Tyr-Ile-His-Pro-Phe) > > > angiotensin II-(3-6) (Val-Tyr-Ile-His), angiotensin II-(4-6) (Tyr-Ile-His), L-158,809 (5,7-dimethyl-2-ethyl-3-[(2'(1-H-tetrazol-5-yl)[1,1'-biphenyl]-4-y l) methyl]-3-H-imidazo[4,5-beta]pyridine H2O) and PD 123319 (1-[4-(dimethylamino)3-methylphenyl]methyl-5-(diphenylacetyl)4,5,6 ,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid). The divalent cations Mg2+ and Ca2+ were shown to diminish the binding of 125I-angiotensioffn IV to bovine adrenal cortex membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A specific binding site recognizing a fragment of angiotensin II in bovine adrenal cortex membranes. 769 12

We have previously shown that the human adrenocortical H295R cell line expresses the type 1 angiotensin II receptor (AT1-R) and that expression of this receptor is downregulated at the level of mRNA by forskolin or dibutyryl-cAMP as well as by angiotensin II (Ang II). In this study we examine the effects of K+ on both AT1-R mRNA and receptors, as monitored through 125I-Ang II binding in the presence of PD 123319. After treatment with a maximal stimulatory steroidogenic dose of K+ (14 mmol/L), H295R cells showed an increase in cytosolic free Ca2+ from 113 to 212 nmol/L. Unlike the effects of Ang II, this increase could be abolished by pretreatment with the Ca2+ channel antagonist nifedipine (1 mumol/L). AT1-R mRNA levels also fell in response to elevated extracellular K+ in a dose-dependent (Kd, 9 mmol/L; maximal fall in message at 12 mmol/L) and time-dependent (maximum 50% at 12 hours) manner. The change in AT1-R mRNA level was less rapid than that in response to activation of phosphoinositidase C by Ang II or adenylyl cyclase by forskolin or by dibutyryl-cAMP. Unlike the action of Ang II but similar to the action of forskolin or dibutyryl-cAMP, the action of K+ was sustained. Changes in mRNA level in response to treatment with K+, Ang II, or dibutyryl-cAMP were also paralleled by changes in 125I-Ang II binding in each case.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Potassium negatively regulates angiotensin II type 1 receptor expression in human adrenocortical H295R cells. 776 52

1. The effects of the nonpeptide angiotensin II receptor (AT) antagonists losartan and PD 123319 on actions of angiotensin II in the rat caudal artery and rat vas deferens preparations were investigated. 2. Angiotensin II (1.0 microM) increased perfusion pressure in isolated segments of the rat caudal artery. This increase in perfusion pressure was prevented by the AT1-antagonist, losartan (0.1 microM) but was not affected by the AT2-antagonist, PD 123319 (0.1 microM). 3. Angiotensin II (0.1-3.0 microM) produced a concentration-dependent enhancement of the stimulation-induced (S-I) efflux of [3H]-noradrenaline from isolated segments of rat caudal artery in which the noradrenergic transmitter stores had been labelled with [3H]-noradrenaline. The maximum enhancement of S-I efflux was approximately 60% with 1.0 microM angiotensin II. 4. Losartan (0.01 and 0.1 microM) reduced the enhancement of S-I efflux produced by 1.0 microM angiotensin II in the caudal artery. 5. PD 123319 (0.01 microM) did not affect the enhancement of S-I efflux produced by angiotensin II (1.0 microM) in the caudal artery. However, in a higher concentration (0.1 microM), PD 123319 reduced the enhancement of S-I efflux produced by 1.0 microM angiotensin II. 6. Angiotensin II produced concentration-dependent enhancement of the purinergic twitch responses (1 pulse/60 s) in the rat vas deferens. 7. Losartan (0.03 microM) and PD 123319 (0.03 microM) each reduced the angiotensin II-induced enhancement of the twitch responses in the rat vas deferens. 8. These findings indicate that the enhancement of sympathetic neuroeffector transmission in both the caudal artery and vas deferens of the rat involves angiotensin receptor subtype(s) sensitive to both losartan and PD 123319. In contrast, the direct vasoconstrictor effect of angiotensin II in the rat caudal artery involves activation of a receptor subtype sensitive only to losartan.
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PMID:Evidence for the involvement of different receptor subtypes in the pre- and postjunctional actions of angiotensin II at rat sympathetic neuroeffector sites. 778 Jun 40

The effect of peripherally administered angiotensin II (AII) on blood flow to choroid plexuses was examined in pentobarbital-anesthetized rats. The indicator fractionation method with 123I- or 125I-N-isopropyl-p-iodoamphetamine as the marker was employed to measure blood flow. Basal blood flow to choroid plexus of the lateral cerebral ventricle (LVCP) (3.19 +/- 0.23 ml g-1 min-1) was lower than that to choroid plexuses of the third (3VCP) and fourth (4VCP) ventricles (3.90 +/- 0.38 and 3.95 +/- 0.36 ml g-1 min-1, respectively). The effect of AII on choroidal blood flow varied depending on peptide dose and anatomical location of the choroidal tissue. AII infused intravenously at rates of 30 and 50 ng kg-1 min-1 decreased blood flow to both LVCP and 4VCP by 12-20%. Both lower (10 ng kg-1 min-1) and higher (100 and 300 ng kg-1 min-1) AII doses did not alter blood flow to LVCP and 4VCP. Blood flow to the 3VCP was not affected by any dose of the peptide used. In comparison, blood flow to cerebral cortex increased by 33% during intravenous AII infusion at a rate of 300 ng kg-1 min-1. The choroidal blood flow-lowering effect of moderate AII doses was abolished by both AT1 (losartan) and AT2 (PD 123319) receptor subtype antagonists (3 mg kg-1 i.v.). To determine whether the hemodynamic changes observed in choroid plexuses with moderate AII doses influence CSF formation, the ventriculocisternal perfusion was performed in rats (under the experimental conditions described) with Blue Dextran 2000 as the indicator.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of angiotensin II in the regulation of blood flow to choroid plexuses and cerebrospinal fluid formation in the rat. 779 32

The effect of central administration of angiotensin II (AII) on cerebrospinal fluid (CSF) formation was studied in pentobarbital-anesthetized, artificially-ventilated rats. CSF production was measured by the ventriculocisternal perfusion method with Blue Dextran 2000 as the indicator. Baseline value of CSF production was 3.35 +/- 0.08 microliters/min. Intracerebroventricular (i.c.v.) infusion of AII at rates of 0.5 and 5 pg/min significantly lowered (P < 0.01) CSF formation by 23% and 16%, respectively. In comparison, high peptide doses (50 and 500 pg/min) did not alter this parameter. The inhibitory effect of low AII doses on CSF formation was blocked by the i.c.v. AT1 receptor subtype antagonists, losartan and SK&F 108566 (2.4 and 2.7 ng/min, respectively), but not by the AT2 receptor subtype-specific agent, PD 123319 (3.8 ng/min). Peptide AII antagonists, [Sar1,Ile8]AII (5 ng/min), which binds to both AT1 and AT2 receptors, had a similar effect to those of AT1-specific blockers. It is concluded that AII, by controlling CSF formation, may influence the water and electrolyte balance in the brain.
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PMID:AT1 receptor subtype mediates the inhibitory effect of central angiotensin II on cerebrospinal fluid formation in the rat. 783 1


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