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)

1. Conscious, Long Evans rats (n = 10), chronically instrumented for the measurement of regional haemodynamics, were studied on 3 consecutive experimental days to assess responses to angiotensin II (AII) (125 pmol kg-1, i.v.) and noradrenaline (1 nmol kg-1, i.v.) in the absence and presence of the AT2-receptor antagonist, PD 123319 (10 mg kg-1, i.v.) (day 1), the AT1-receptor antagonist, EXP 3174 (1 mg kg-1, i.v.) (day 2), and PD 123319 (10 mg kg-1, i.v.) given 24 h after EXP 3174 (day 3). 2. In naive rats (day 1), PD 123319 did not antagonize the haemodynamic effects of AII or noradrenaline. EXP 3174 (day 2) caused a marked, prolonged blockade of the haemodynamic effects of AII but not those of noradrenaline. Twenty four h after administration of EXP 3174 (day 3) there was still significant attenuation of the haemodynamic effects of AII. However, administration of PD 123319 at this time caused a further inhibition (lasting 1 h) of the effects of AII but not those of noradrenaline. 3. An identical 3 day protocol was used in a separate group of rats (n = 6) in which the AT2-receptor antagonist, PD 123177, was given instead of PD 123319, and the results were essentially the same, i.e., PD 123177 significantly attenuated the haemodynamic effects of AII but only when given 24 h after EXP 3174.4. In a separate group of rats (n = 4), a low dose of EXP 3174 (60 pg kg-' i.v.) was given to naive rats in order to simulate the degree of inhibition of the effects of All seen after administration of AT2-receptor antagonists in animals pretreated with EXP 3174. This low dose of EXP 3174 did not produce a sustained inhibition of the effects of All and the time course of recovery of All responses was similar to that seen with PD 123319 or PD 123177 given after the high dose of EXP 3174.5. The apparent inhibition of the effects of AII by the AT2-receptor antagonists, PD 123319 and PD 123177, when these were administered 24 h after the AT,-receptor antagonist, EXP 3174, may have been due to the functional activation of AT2-receptors and/or loss of AT2-receptor antagonist selectivity,and/or the displacement of nonspecifically bound EXP 3174 by AT2-receptor antagonists. While the latter explanation seems the most likely, these results raise the possibility that nonpeptide, All-receptor antagonists that act at both AT,- and AT2-receptors may have therapeutic advantages over selective AT,-receptor antagonists.
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PMID:Inhibition of the haemodynamic effects of angiotensin II in conscious rats by AT2-receptor antagonists given after the AT1-receptor antagonist, EXP 3174. 147 80

1. Regional haemodynamic responses to the homologous peptides, pituitary adenylate cyclase-activating peptide (1-27) (PACAP27) and vasoactive intestinal polypeptide (VIP) were assessed by giving 20 min infusions (1.5-15 nmol kg-1 h-1) in conscious, chronically-instrumented, Long Evans rats. 2. PACAP27 caused dose-dependent depressor and tachycardic effects associated with renal, mesenteric and hindquarters vasodilatations, although only in the latter vascular bed was there a sustained increase in flow. 3. VIP caused dose-dependent depressor and tachycardic effects that were not significantly different from those caused by equimolar doses of PACAP27. However, the hindquarters vasodilator effects of VIP (at 7.5 and 15 nmol kg-1 h-1) were greater than those of PACAP27 (at the same doses), and accompanied by reductions in renal and mesenteric flows and conductances. 4. In the presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 11 mumol kg-1 h-1), there was significant inhibition of the hindquarters vasodilator effects of PACAP27 and VIP (at 7.5 and 15 nmol kg-1 h-1). Under these circumstances the renal and mesenteric vasoconstrictor effects of VIP were abolished. 5. The beta 2-adrenoceptor antagonist, ICI 118551 (670 nmol kg-1 bolus, 335 nmol kg-1 h-1 infusion), reduced the matched hindquarters vasodilator responses to PACAP27 (15 nmol kg-1 h-1) and VIP (7.5 nmol kg-1 h-1), and also abolished the renal vasoconstrictor effects of VIP. 6. The AT1-receptor antagonist, losartan potassium (20 mumol kg-1), had no significant effect on the haemodynamic response to PACAP27 (15 nmol kg-1 h-1), but augmented the hypotensive action of VIP (7.5 nmol kg-1 h-1). This influence of losartan was associated with conversion of the renal and mesenteric vasoconstrictor effect of VIP to vasodilatation. 7. Our findings show that similar changes in mean systemic arterial blood pressure in response to PACAP27 and VIP conceal substantial differences in their regional haemodynamic actions. Although the hindquarters vasodilator effects of both peptides involve NO- and Beta2-adrenoceptor-mediated mechanisms,it appears that activation of the renin-angiotensin system contributes significantly to the haemodynamic effects of VIP, but not to those of PACAP27.
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PMID:Regional haemodynamic responses to pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide in conscious rats. 791 21

In previous studies, we found that central administration of the AT1-receptor antagonist, EXP 3174, and the AT2-receptor antagonist, PD 123319, blocked the cardiovascular response to centrally-injected angiotensin II (AII), although another AT2-receptor antagonist (PD 123177) was ineffective. In the present study, we examined the effects of these three compounds on the pressor and dipsogenic response to centrally-injected AII in conscious, male Long Evans rats, and the effect of EXP 3174 and PD 123319 on drinking in response to water-deprivation in Brattleboro rats. In Long Evans rats, AII-induced water intake and pressor effects were inhibited by EXP 3174 and PD 123319 (although with different time courses). In contrast, PD 123177 had little effect on the pressor response to i.c.v. AII, but enhanced its dipsogenic action. Following 8 h water deprivation in Brattleboro rats, neither EXP 3174 nor PD 123319 inhibited drinking when water was returned. These data indicate that EXP 3174 and PD 123319 inhibit thirst evoked by centrally injected AII, but not that caused by extracellular dehydration. In addition, since the putative AT2-receptor antagonists PD 123319 and PD 123177 have the opposite effects on i.c.v. AII-induced water intake, these results cannot be easily reconciled with a simple model of thirst in which AT2-receptors are involved in a final common pathway for drinking.
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PMID:Effects of angiotensin II AT1- or AT2-receptor antagonists on drinking evoked by angiotensin II or water deprivation in rats. 792 26

In conscious, chronically instrumented, male Long-Evans rats, we showed previously that central administration (intracerebroventricular) of the AT1-receptor antagonist EXP-3174 (1 microgram) caused a rapid-onset marked, but transient, blockade of the regional hemodynamic responses to intracerebroventricular angiotensin II (ANG II). In contrast, the AT2-receptor antagonist PD-123319 (80 micrograms) caused a slow-onset, but marked and persistent, antagonism of the effects of intracerebroventricular ANG II. In the present study we attempted to mimic the actions of PD-123319 by giving a supramaximal dose of EXP-3174 (10 micrograms), and we also assessed the effects of PD-123177 (80 micrograms), an AT2-receptor antagonist that differs from PD-123319 only by a dimethyl group. The higher dose of EXP-3174 did not exert prolonged antagonistic effects against responses to intracerebroventricular ANG II, and PD-123177 was without inhibitory effects in this model. The results indicate important functional differences between putative AT2-receptor antagonists, when assessed in vivo, that are not apparent from binding studies.
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PMID:Differential blockade of central effects of angiotensin II by AT2-receptor antagonists. 834 37

1. Male (350-450 g) Long Evans rats were chronically instrumented to permit regional haemodynamics to be monitored in the conscious state. In the first experiment, either saline (0.4 ml h-1) or dexamethasone (3 mg kg-1, 125 micrograms kg-1 h-1) was infused continuously for 24 h, before co-infusion of lipopolysaccharide of (LPS, 150 micrograms kg-1 h-1) for 24 h. Dexamethasone prevented the delayed (5-24 h) fall in mean arterial blood pressure (MAP) and the renal and hindquarters vasodilatation seen with LPS infusion alone, but not the initial (about 2 h) fall in MAP or renal vasodilatation. However, at this dose, dexamethasone itself caused a significant rise in MAP and regional vasoconstrictions. 2. In the second experiment, dexamethasone at a lower dose (12.5 micrograms kg-1 h-1) had only slight pressor and vasoconstrictor effects. However, in its presence, infusion of LPS caused a substantial and progressive rise in MAP (maximum at 8 h, +32 +/- 3 mmHg) together with persistent mesenteric and hindquarters vasoconstriction and a transient renal vasodilatation. 3. In the third experiment, the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 h-1), blocked the slight pressor and regional vasoconstrictor effects of the lower dose of dexamethasone. Furthermore, in the presence of dexamethasone and SB 209670, infusion of LPS caused marked, but transient hypotension (nadir at 5 h, -24 +/- 2 mmHg) and renal and mesenteric vasodilatation. 4. At the end of all experimental protocols, sequential administration of the AT1-receptor antagonist, losartan, followed by the V1-receptor antagonist, (+)-(CH2)5-O-Me-Tyr, vasopressin, caused effects indicating a variable involvement of angiotensin and vasopressin in the maintenance of cardiovascular status. 5. Collectively, the results indicate that, in the conscious rat, dexamethasone interacts with vasoconstrictor and vasodilator mechanisms, and hence its influence on the haemodynamic responses to LPS cannot be attributed, simply, to inhibition of the activity of inducible nitric oxide synthase and/or cyclo-oxygenase-2.
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PMID:Effects of dexamethasone and SB 209670 on the regional haemodynamic responses to lipopolysaccharide in conscious rats. 873 87

The aim of this study was to compare the effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II (AII) AT1-receptor blockade, and dihydropyridine calcium antagonism on hypertrophy and on vascular albumin permeability in kidney, heart, and mesenteric artery in a model combining genetic hypertension and diabetes mellitus. Diabetes mellitus was induced by streptozotocin in 8-week-old spontaneously hypertensive rats. The animals were randomized to receive no treatment, the angiotensin converting enzyme inhibitor ramipril, the AII AT1-receptor blocker valsartan, or the dihydropyridine calcium antagonist lacidipine for 3 weeks. Vascular albumin permeability was measured as the tissue content of intravenously injected Evans blue dye (EB) in kidney, heart, and mesenteric artery and the tissue/plasma EB ratio was calculated. Systolic blood pressure was reduced by all three antihypertensive regimens. Glycemic control was similar in all diabetic groups. Kidney hypertrophy was not affected by any of the antihypertensive drugs. Hypertrophy of the mesenteric artery was enhanced by lacidipine but was not affected by ramipril or valsartan. Relative heart weight was also increased by lacidipine. Vascular albumin permeability, expressed as EB content in micrograms/gram dry weight or as tissue/plasma EB ratio, was higher in the kidneys of lacidipine-treated rats than in any other group of diabetic rats. There was a positive correlation between kidney weight/body weight and kidney/plasma EB ratio in the diabetic rats. These findings indicate that the dihydropyridine calcium antagonist lacidipine is associated with an unfavorable effect on vascular hypertrophy and on vascular albumin permeability in the kidneys in rats with hypertension and diabetes mellitus. Furthermore, there seems to be a coupling in the diabetic kidney between hypertrophy and increased vascular albumin permeability.
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PMID:Vascular hypertrophy and albumin permeability in a rat model combining hypertension and diabetes mellitus. Effects of calcium antagonism, angiotensin converting enzyme inhibition, and angiotensin II-AT1-receptor blockade. 887 46

1. Male, Long Evans rats were instrumented chronically with pulsed Doppler probes and intravascular catheters to allow assessment of regional haemodynamic changes during i.v. infusion of lipopolysaccharide (LPS, 150 micrograms kg-1 h-1). 2. In the presence of the AT1-receptor antagonists, losartan (10 mg kg-1 + 10 kg-1 h-1), the initial (1-2 h) hypotensive and renal, mesenteric and hindquarters vasodilator responses to LPS were enhanced significantly. Thereafter these effects waned, but between 8-23 h after the onset of LPS infusion, a further fall in mean atrial blood pressure (MAP) and increases in renal and hindquarters flows and conductances occurred. All these changes were significantly greater than seen with losartan or LPS alone, and exceeded the sum of their effects. 3. In the presence of captopril (2 mg kg-1 + 2 mg kg-1 h-1), the initial hypotensive and renal vasodilator responses to LPS were enhanced, but less so than in the presence of losartan. However, the effects of LPS in the presence of losartan and captopril together were not different from those in the presence of losartan alone. These observations indicate that the ability of captopril to inhibit the degradation of bradykinin had no additional influence, and the differences between the effect of captopril and losartan on the initial effects of LPS were probably due to more effective suppression of the action of angiotensin II by losartan. 4. In the absence of LPS, co-infusion of losartan and the non-selective endothelin antagonist, SB 209670 (600 micrograms kg-1 + 600 micrograms kg-1 h-1), caused a substantial, progressive hypotension (-25 +/- 2 mmHg at 24 h) accompanied by increases in renal, mesenteric and hindquarters vascular conductances (31 +/- 13, 44 +/- 9 and 45 +/- 12%, respectively), indicating an involvement of angiotensin II and endothelin in the maintenance of normal cardiovascular status in conscious, Long Evans rats. 5. In the presence of losartan and SB 209670, the initial, LPS-induced fall in MAP (-42 +/- 2 mmHg) was not different from that in the presence of losartan (-39 +/- 4 mmHg), and the increases in renal, in mesenteric, and in hindquarters vascular conductances were similar in the two conditions. However, there was no recovery in MAP, and there were persistent renal, mesenteric and hindquarter vasodilatations. 6. In all experiments involving LPS, administration of the V1- receptor antagonist, d(CH2)5-O-Me-Tyr-AVP (10 micrograms kg-1), 23 h after the start of LPS infusion caused additional hypotension and mesenteric vasodilatation, particularly. This effect was most marked in animals pretreated with losartan and SB 209670. 7. The results indicate that the initial (1-2 h) depressor and dilator effects of LPS infusion in conscious Long Evans rats are opposed by the actions of angiotensins II, rather than endothelin. However, between 2-8 h after the onset of LPS infusion the involvement of endothelin develops and that of angiotensin II fades. By 24 h after the start of infusion of LPS, the pressor and vasoconstrictor actions of endothelin wane, and a role of vasopressin is apparent. At no stage is there clear evidence for an involvement of bradykinin in the haemodynamic sequelae of endotoxaemia in this model.
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PMID:Temporal differences between the involvement of angiotensin II and endothelin in the cardiovascular responses to endotoxaemia in conscious rats. 898 10

We explored the putative inhibitory effects of losartan, a potent nonpeptide, AT1 receptor antagonist, against thromboxane A2 (TxA2)/prostanoid (TP) receptor-mediated transcapillary shift of plasma fluid and proteins. The effects of the TP receptor agonist U-46619 (1.25 or 10 microg/kg intravenously) on hematocrit (Hct), albumin extravasation (AE), and mean arterial pressure (MAP) were evaluated in anesthetized Sprague-Dawley rats. U-46619 dose-dependently increased Hct (by 4.5% +/- 0.7% and 7.5% +/- 1.0% at the low and high dose, respectively; both P < .05 v vehicle-infused group) and decreased MAP (by 7.9% +/- 4.1% and 16.8% +/- 5.7% at the low and high dose, respectively; P = NS and P < .05 v vehicle-infused group, respectively). In these experiments, using a quantitative Evans blue technique, we showed that U-46619 dose-dependently increased AE in kidney, lung, spleen, and testis (by approximately 31%, 172%, 52%, and 57% at the highest dose) but not in adipose tissue, brain, liver, mesentery, and skeletal muscle. In the heart, AE was maximally increased by the low dose of U-46619. The U-46619 (10 microg/kg)-induced increases in Hct and AE and decreases in MAP were blocked by pretreatment with the TP receptor antagonist SQ 29,548 (2.5 mg/kg intravenously + 2.5 mg/kg/h) and the high dose of losartan (40 mg/kg intravenously). The low dose of losartan (10 mg/kg intravenously) did not significantly alter the responses to U-46619 except for the AE, which was reduced in some but not all tissues. Furthermore, the U-46619-induced changes in Hct (+6.3% +/- 1.7%), MAP (-13.9% +/- 8.4%) and AE were not affected in rats pretreated with the converting-enzyme inhibitor enalapril. Thus, selective activation of TP receptors by U-46619 induced plasma fluid and protein exudation; these responses were specifically attenuated by the relatively high dose of losartan, suggesting that this compound acts as a TP receptor antagonist in this experimental model.
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PMID:Losartan prevents thromboxane A2/prostanoid (TP) receptor mediated increase in microvascular permeability in the rat. 932 14

Using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new model of human non-insulin-dependent diabetes mellitus (NIDDM), we examined the role of local angiotensin II in cardiovascular and renal complications of NIDDM. OLETF rats were orally given cilazapril (an angiotensin-converting enzyme inhibitor, 1 or 10 mg/kg), E4177 (an angiotensin AT1 receptor antagonist, 10 mg/kg), or vehicle for 26 or 40 weeks (from the age of 20 to 46 or 60 weeks). Cardiac mRNAs were measured by Northern blot analysis, and the thickening of the coronary arterial wall and the degree of perivascular fibrosis were determined by an image analyzer. Cilazapril or E4177 did not significantly affect body weight or plasma glucose and insulin levels of OLETF rats, indicating the minor effects on diabetes itself. However, both drugs significantly and similarly prevented coronary microvascular remodeling (the increase in wall thickening and perivascular fibrosis in coronary arterioles and small coronary arteries) in OLETF rats, and they were associated with the suppression of cardiac transforming growth factor-beta1 expression. Both drugs suppressed not only the increase in left ventricular weight but also the downregulation of cardiac alpha-myosin heavy chain expression in OLETF rats. Glomerulosclerosis and glomerular hypertrophy in OLETF rats were improved by cilazapril and E4177 to a comparable extent. These results, taken together with the fact that OLETF rats show normal plasma renin levels, support that the AT1 receptor is involved in the pathogenesis of cardiac and renal complications in NIDDM.
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PMID:Angiotensin blockade improves cardiac and renal complications of type II diabetic rats. 936 55

In order to evaluate the role played by vasopressin on pressor responses elicited by stimulation of the periaqueductal gray (PAG) area by excitatory amino acids we carried out in vivo studies in genetically vasopressin deficient rats (Brattleboro). Microinjections of 1-glutamic acid (glutamate, 0.6 to 60 nmol/rat) or N-methyl-d-aspartic acid (NMDA, 0.07 to 7 nmol/rat) into the PAG area of freely moving Brattleboro rats induced increases of arterial blood pressure values significantly lower than those obtained in Long Evans rats (control) (glutamate in Brattleboro rats: from +2+/-1 mmHg to 16+/-3 mmHg; glutamate in Long Evans rats: from +16+/-2 mmHg to +36+/-4 mmHg; NMDA in Brattleboro rats: from +5+/-2 mmHg to +34 +/-8 mmHg; NMDA in Long Evans rats: from +18+/-7 mmHg to 80+/-9 mmHg; n=5). Similarly, in anaesthetized Brattleboro rats (urethane 1.2 g/kg i.p.) pressor responses to NMDA microinjections (0.7 nmol/rat) into the PAG area were significantly lower than in Long Evans rats (controls) (+15+/-3 mmHg vs +24+/-4 mmHg). In Long Evans rats NMDA injection also reversed blood pressure decrease induced by ganglionic blocker, hexamethonium and/or losartan (3 mg/kg i.v.), an AT1 receptor antagonist. In Brattleboro rats, NMDA injection did not reverse blood pressure decreases induced by hexamethonium (5 mg/kg i.v.). Moreover, hexamethonium induced blood pressure decrease was not reversed by acetylcholine injection (137 nmol/rat) into the PAG area of anaesthetized Long Evans rats, but if injected before hexamethonium, acetylcholine was able to increase blood pressure (+25+/-3 mmHg). Our results document: i) the importance of the PAG area in the control of cardiovascular system; ii) the involvement of excitatory amino acids in the neural control of vasopressin release; iii) the close relationship between glutamate and vasopressin in the central blood pressure regulation.
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PMID:Role of vasopressin on excitatory amino acids mediated pressor responses in the periaqueductal gray area. 965 Aug 3


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