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)

L-158,809 (5,7-dimethyl-2-ethyl-3-[[2'-(1H-tetrazol-5yl)[1,1']-bi- phenyl-4-yl]-methyl]-3H-imidazo[4,5-b]pyridine) is a potent, competitive and specific antagonist of AT1 subtype of angiotensin II (AII) receptors in in vitro radioligand binding and functional isolated tissue assays. The present study was carried out to characterize the in vivo pharmacology of this potent AII receptor antagonist. In conscious, normotensive and anesthetized pithed rats, L-158,809 inhibits AII (0.1 microgram/kg i.v.) elevations in blood pressure without altering pressor responses to methoxamine or arginine vasopressin. In conscious rats, the relative potencies (ED50) were 29 micrograms/kg i.v. and 23 micrograms/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. In similar experiments using rhesus monkeys, the potencies of L-158,809 were 10 micrograms/kg i.v. and approximately 100 micrograms/kg p.o. In these rats and monkeys, L-158,809 was 10 to 100 times more potent than DuP-753 (losartan) and approximately 3 times more potent than the metabolite, EXP3174. AII-induced elevation of plasma aldosterone in rats was also inhibited by L-158,809. Unlike angiotensin converting enzyme inhibitors, L-158,809 did not potentiate the hypotensive responses to i.v. bradykinin. L-158,809 was antihypertensive in high renin hypertensive rats (aortic coarction) and volume-depleted rhesus monkeys. The maximum hypotensive responses with acute doses of L-158,809 were equal to those with an angiotensin converting enzyme inhibitor in these renin-dependent animal models. From these in vivo data, L-158,809 is a selective AII receptor antagonist with high potency, good p.o. absorption, long duration and antihypertensive efficacy equal to angiotensin converting enzyme inhibition after single doses.
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PMID:In vivo pharmacology of L-158,809, a new highly potent and selective nonpeptide angiotensin II receptor antagonist. 162 93

Responses to angiotensin II, bradykinin and arginine vasopressin were compared in helical strips of canine pulmonary arteries and veins. Angiotensin II contracted the artery but relaxed the vein strip. The artery contraction was augmented by indomethacin and aspirin and was abolished by losartan. The vein relaxation was not affected by endothelium denudation but was abolished by the cyclooxygenase inhibitors, a prostaglandin I2 synthase inhibitor and losartan. The bradykinin-induced artery relaxation was inhibited by endothelium denudation, NG-nitro-L-arginine (L-NA) or indomethacin and abolished by their combined treatment. The vein relaxation produced by bradykinin was endothelium-independent and was abolished by indomethacin. Vasopressin produced a slight relaxation in the arteries, which was abolished by endothelium denudation and L-NA. The vein relaxation produced by vasopressin was abolished by endothelium denudation and combined treatment with L-NA and indomethacin. It may be concluded that (1) activation of angiotensin AT1 receptor subtype in smooth muscle produces contraction and also relaxation due to prostaglandin I2 release; the former predominates over the latter in the artery, whereas only the latter is operative in the vein, (2) the bradykinin-induced relaxation is due to nitric oxide (NO) from the endothelium and prostaglandin I2 from subendothelial tissues in the artery and solely to prostaglandin I2 in the veins, and (3) the vasopressin-induced relaxation is mediated by endothelial NO in the artery, and NO and prostaglandin I2 in the vein.
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PMID:Comparison of responses of canine pulmonary artery and vein to angiotensin II, bradykinin and vasopressin. 749 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

The purpose of this study was to determine whether central angiotensin II (ANG II) participates in mediating selected sympathetic nervous system and neuroendocrine adjustments to heat stress in conscious freely moving rats. Mean arterial pressure (MAP), heart rate (HR), splanchnic sympathetic nerve activity (SpNA), plasma arginine vasopressin (AVP) concentration, and colonic temperature were measured before and during whole body heating (42 degrees C ambient temperature). Heating was stopped when a colonic temperature of 41 degrees C was attained. On consecutive days, rats received an intracerebroventricular (icv) injection of saline (0.9%) or 25 micrograms of the ANG II AT1-selective receptor antagonist losartan 20 min before the start of heating. Neither treatment influenced control levels of any parameter. The increase above baseline for MAP at the end of heating was attenuated by > 50% in the losartan, compared with the saline trial (P < 0.05), while HR remained unchanged from control values for both trials. Pretreatment with losartan icv eliminated the increase in SpNA observed during the heating period in the saline trial. Furthermore, the magnitude of change in plasma AVP during heating was significantly elevated in rats after icv administration of saline compared with losartan. These findings indicate that central ANG II receptor antagonism significantly attenuates the heating-induced elevations in MAP, sympathetic neural activity to visceral regions, and plasma AVP and suggest that the central nervous system actions of endogenous ANG II are required for full expression of the sympathoexcitatory, pressor, and neuroendocrine responses associated with nonexertional heat stress in the conscious rat.
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PMID:Modulation of autonomic nervous system adjustments to heat stress by central ANG II receptor antagonism. 802 55

We have previously shown that AT1 and AT2 angiotensin II (Ang II) receptors mediate the release of arginine vasopressin (AVP) to central injections of Ang II. In this study we have tested the hypothesis that Ang II, acting at AT1 and AT2 receptors in the brain, is involved in mediating osmotically stimulated AVP release. Adult Sprague-Dawley rats were fitted with intraventricular (i.v.t.) cannulas and catheters in the carotid artery and the femoral vein. Intraventricular injections of Ang II receptor antagonists specific to different subtypes of the receptor (AT1 and AT2) were given before a 30 min infusion of hypertonic (2.5 M) saline. Arterial blood samples were collected 5 min before and at two time points after (+15 min and +30 min) beginning the saline infusion. We found that both losartan (AT1 specific) and CGP42112A (AT2 specific) significantly reduced osmotically induced release of AVP. PD123319 (AT2 specific) had no effect of osmotically stimulated AVP release. A combined treatment of losartan + PD123319 was no more effective than losartan in blocking the AVP response. Since losartan was the most rapid and effective antagonist of osmotically stimulated AVP release, we conclude that AT1 receptors are directly involved in the response. However, but since CGP42112A was also an effective antagonist and since, AT2 receptors are located at sites distant from the hypothalamus, such as the locus ceruleus, they may also contribute to this response. We conclude that brain Ang II receptors are involved in osmotically stimulated AVP release.
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PMID:Involvement of angiotensin receptor subtypes in osmotically induced release of vasopressin. 818 Jul 89

Renal vasoconstrictor responses to the adenosine A1 agonist N6-cyclopentyladenosine (CPA) were compared in the in situ autoperfused rat kidney to responses evoked by angiotensin II (ANG II), endothelin-1 (ET-1), arginine vasopressin (AVP), carbocyclic thromboxane A2 (CTxA2), phenylephrine (PE), and 5-hydroxytryptamine (5-HT). On the basis of their ED50 values (dose of agonist, in mass units, that produced 50% of maximal response to that agonist), the order of vasoconstrictor potency was ANG II > or = AVP > ET-1 > CPA > 5-HT > or = PE > CTxA2. Dose-response curves to CPA were shallower and maximal responses were weaker than those produced by the other agonists. Maximal responses, the log ED50, and the slope of the dose-response curve to CPA were markedly potentiated in the presence of the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Selective antagonism of A1 receptors increased renal blood flow and markedly attenuated CPA-induced renal vasoconstriction in the absence or presence of L-NAME but had no effect on the maximal responses to ANG II. Conversely, AT1 receptor antagonism attenuated renal vasoconstriction produced by ANG II but had little effect on the produced by CPA. These results suggest that endogenous NO modulates renal vasoconstriction produced by A1 receptor stimulation and provide evidence against an interaction between renovascular adenosine A1 and angiotensin AT1 receptors.
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PMID:Interactions of adenosine A1 receptor-mediated renal vasoconstriction with endogenous nitric oxide and ANG II. 823 45

It is well established that neurons in the dorsal medulla, including the area postrema and the medial nucleus tractus solitarius (mNTS), are involved in the central actions of circulating peptides such as angiotensin II (ANG II) and arginine vasopressin (AVP). This report describes a preparation that permits the identification and maintenance of area postrema/mNTS neurons in culture in which the cellular and potentially subcellular responses to neurotransmitters and neuropeptides on area postrema/mNTS cells can be investigated. Following 15-21 days in culture, the effects of ANG II and AVP on changes in intracellular Ca2+ concentration ([Ca2+]i) were examined. Both ANG II and AVP resulted in a rapid and transient increase in [Ca2+]i reaching maximum in 15 s and returning towards baseline values within 180 s. The ANG II-mediated increase in [Ca2+]i was almost completely abolished by the selective angiotensin AT1 receptor subtype antagonist, losartan (DuP 753). These results suggest that ANG II and AVP modulate area postrema/mNTS neuronal activity by increasing intracellular Ca2+.
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PMID:Increases in cytosolic Ca2+ in rat area postrema/mNTS neurons produced by angiotensin II and arginine-vasopressin. 850 70

Central serotonin (5-HT) and angiotensin (ANG II) stimulate arginine vasopressin (AVP), oxytocin (OT), and adrenocorticotropin (ACTH) secretion and increase blood pressure. Studies were conducted in conscious rats to determine whether neuroendocrine activation by 5-HT requires a brain angiotensinergic intermediate pathway. In the first study, ANG II formation was inhibited by the angiotensin-converting enzyme inhibitor enalapril before injection of the 5-HT releaser/uptake inhibitor d-fenfluramine. Fenfluramine (2 mg/kg ip) stimulated AVP, OT, corticosterone, and prolactin (PRL) secretion (P<0.01). Enalapril (60 mg/l in drinking water for 4 days and 10 mg/kg ip 2 h before the rats were killed) inhibited only the AVP response (P<0.01) to d-fenfluramine. In the second study, the effect of intracerebroventricular injection of the 5-HT2A/2C antagonist LY-53857 (10 microgram), or the ANG II AT1 antagonist DuP-753 (10 microgram), on intracerebroventricular 5-HT (10 microgram)-stimulated AVP, OT, ACTH, PRL, renin secretion, mean arterial pressure (MAP) and heart rate (HR) was tested. LY-53857 inhibited the AVP, OT, and ACTH responses to 5-HT (P<0.01), whereas DuP-753 inhibited only the AVP response (P<0.01). Intraventricular injection of 5-HT increased MAP and decreased HR. The MAP response was not affected by LY-53857 or DuP-753, and at no time did MAP decline below starting levels. The decreased HR was inhibited by LY-53857 but not by DuP-753. These results demonstrate that 5-HT-induced AVP secretion is mediated selectively via brain angiotensinergic mechanisms by way of the AT1 receptor.
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PMID:Neuroendocrine and cardiovascular effects of serotonin: selective role of brain angiotensin on vasopressin. 863

The present study was conducted to develop a standardized ganglionic blockade protocol to assess neurogenic pressor activity in conscious rats. Rats were instrumented with arterial and venous catheters for measurement of arterial pressure and heart rate and for administration of three different ganglionic blockers (trimethaphan, hexamethonium, and chlorisondamine). To investigate the role of the pressor hormones angiotensin II (AII) and arginine vasopressin (AVP) in modulating the cardiovascular responses to ganglionic blockade, we also administered ganglionic blockers to rats pretreated with AVP and AII receptor antagonists. The peak depressor responses to trimethaphan (20 mg/kg; -45 +/- 2 mm Hg), hexamethonium (20 mg/kg; -44 +/- 2 mm Hg), and chlorisondamine (2.5 mg/kg; -47 +/- 3 mm Hg) were not different from each other. With trimethaphan, there was a significantly enhanced peak depressor response after blockade of AT1/V1 receptors (-45 +/- 2 vs -59 +/- 2 mm Hg). No significant differences were observed for hexamethonium or chlorisondamine after hormonal blockade (-44 +/- 2 vs. -46 +/- 3 and -47 +/- 3 vs -48 +/- 4 mm Hg, respectively). These observations suggest that, for hexamethonium and chlorisondamine, the peak depressor response to ganglionic blockade is a consistent measure of neurogenic pressor activity in the conscious rat. This response is not influenced by circulating AII or AVP. On the other hand, trimethaphan should be used carefully due to its complex interactions with other systems, particularly under conditions in which AVP or AII may be altered.
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PMID:Use of ganglionic blockers to assess neurogenic pressor activity in conscious rats. 864 81

Angiotensin II (ANG II) and arginine vasopressin (AVP) act on area postrema (AP) neurons to modulate the baroreflex. Because activation of AP neurons by either ANG II or AVP increases intracellular free Ca2+ concentrations ([Ca2+]i), the goal of this study was to analyze the factors affecting the [Ca2+]i responses to ANG II and AVP. Neurons were recovered from 14- to 16-day old rats and studied after 8-14 days in culture by use of the microscopic digital image analysis for fura 2-loaded cells. The effects of ANG II (100 nM) and AVP (100 nM) on [Ca2+]i were determined in normal (2 mM) and low (< 10 nM) extracellular Ca2+ concentrations. In 143 of 240 neurons, ANG II increased [Ca2+]i 4.65-fold after 20 s, and a similar response was observed in the absence of extracellular Ca2+ (3.65-fold after 20 s). After 60 s of observation, steady-state levels of increased [Ca2+]i were still present under both conditions. Pretreatment with AT1 antagonist or pertussis toxin abolished the response to ANG II. AVP also increased [Ca2+]i (3.6-fold at peak, 20 s) in normal and low extracellular Ca2+. Pretreatment with AVP V1 antagonist or pertussis toxin abolished the response to AVP. This study indicates that ANG II-induced increases in [Ca2+]i are independent of extracellular Ca2+ concentrations and involve the activation of AT1 receptors and a pertussis toxin-sensitive G protein. Although AVP affects a fewer number of AP neurons, the mechanisms of activation are also independent of extracellular Ca2+ concentration and are mediated by a pertussis toxin-sensitive G protein.
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PMID:Subcellular mechanisms of angiotensin II and arginine vasopressin activation of area postrema neurons. 876 Feb 1


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