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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system (RAS) is one of the body's most powerful regulators of arterial pressure and body fluid volumes. Although the acute effects of angiotensin II (AngII), the primary active component of the RAS, on arterial pressure are mediated primarily by peripheral vasoconstriction, its chronic BP effects are closely intertwined with volume homeostasis, particularly with intrarenal actions that influence pressure natriuresis. AngII shifts pressure natriuresis toward higher BP primarily by increasing tubular reabsorption rather than decreasing GFR. In fact, activation of the RAS can serve as an important means of preventing decreases in GFR during volume depletion or circulatory depression. However, with prolonged excess AngII formation, particularly in association with hypertension or overperfusion of the kidney, AngII can contribute to glomerular injury and a gradual loss of nephron function through its hemodynamic actions. The multiple effects of AngII to increase tubular reabsorption provide a powerful mechanism to protect against volume depletion and low BP. However, when AngII levels are inappropriately elevated, this necessitates increased arterial pressure to maintain sodium and water balance. Blockade of the RAS has proved to be a powerful therapeutic tool for lowering BP and improving kidney function in disorders such as hypertension, congestive heart failure, and chronic renal disease.
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PMID:Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney. 1020 80

Angiotensin II increased the inositol phosphates production (EC50 = 3.4+/-0.7 nM) in Chinese hamster ovary (CHO) cells expressing the cloned human angiotensin AT1 receptor (CHO-AT1 cells). Coincubation with angiotensin AT1 receptor antagonists produced parallel rightward shifts of the concentration-response curve without affecting the maximal response. The potency order is 2-ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-benz imidazoline-7-carboxylic acid (candesartan) > 2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]i midazole-5-carboxylic acid (EXP3174) > 2-n-butyl-4-spirocyclopentane-1-[(2'-(1H-tetrazol-5-yl)biphe nyl-4-yl)methyl]2-imidazolin-5-one (irbesartan)> of 2-n-butyl-4-chloro-5-hydroxymethyl-1-(2'-(1H-tetrazol-5-yl)bipheny l-4-yl)methyl]imidazole (losartan). Additionally, preincubation with these antagonists depressed the maximal response, i.e., 95%, 70%, 30% of the control response for candesartan, EXP3174 and irbesartan and not detectable for losartan. Increasing the antagonist concentration or prolonging the preincubation time did not affect this depression. Furthermore, these values remained constant for candesartan and EXP3174, when the angiotensin II incubation time varied between 1 and 5 min. Our data indicate that antagonist-receptor complexes are divided into a fast reversible/surmountable population and a tight binding/insurmountable population at the very onset of the incubation with angiotensin II.
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PMID:Insurmountable angiotensin AT1 receptor antagonists: the role of tight antagonist binding. 1039

Idiopathic edema is a syndrome of real or perceived excessive weight gain. This article reviews what is known about the possible causes, evaluation, and treatment. Although the cause is unknown but often thought to be due to secondary hyperaldosteronism, primary abnormalities of the hypothalamus, thyroid, dopaminergic release or renal dopaminergic metabolism, vascular basement membrane, or capillary sphincter control could perhaps contribute in some patients. The diagnosis requires careful attention to possible abnormalities of the liver, heart, kidneys, gastrointestinal tract, thyroid, and pancreas. The history must include an evaluation for risks of bulimia and purging; diuretic and laxative screening should be performed. Specific records of daily weights, urinary outputs, and menstral cycle dates are useful. Treatment may include dietary counseling to provide weight control and a constant carbohydrate intake, treatments for depression, compression stockings, spironolactone, amiloride, angiotensin II inhibitors, or sympathomimetic agents, depending on the severity and timing of the patient's symptoms. Unfortunately, idiopathic edema may be a multifactorial disorder that has not been completely delineated. Further research into possible causative mechanisms is required before a more useful algorithm for evaluation and treatment is available.
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PMID:Idiopathic edema. 1046 50

In rabbit, ventricular myocytes loaded with indo-1/AM, angiotensin II (0.1 nM-0.1 microM) exerted a positive inotropic effect with a significant increase in the amplitude of Ca2+ transients. For a given increase in cell shortening, the increase in Ca2+ transients induced by angiotensin II was less than that induced by elevation of extracellular Ca2+ concentration ([Ca2+]0) or isoprenaline, an indication that both the increase in mobilization of intracellular Ca2+ ions and myofibrillar sensitivity to Ca2+ ions contribute to the positive inotropic effect of angiotensin II. The effects of angiotensin II on Ca2+ transients and cell shortening were inhibited by the AT1 receptor antagonist losartan. A Na+ -H+ exchange inhibitor EIPA [5-(N-ethyl-N-isopropyl)amiloride] at 1 and 3 microM did not affect the Ca2+ transients and cell shortening, but it inhibited the angiotensin-II-induced responses in a concentration-dependent manner more effectively than the responses to elevation of [Ca2+]0, indicating that EIPA elicited a selective inhibitory action on the effects of angiotensin II. The observation that EIPA at 10 microM abolished the positive inotropic effect of angiotensin II without a significant depression of the inotropic response to elevation of [Ca2+]0 supports the selective action of EIPA at the high concentration on the response to angiotensin II. A novel selective Na+ -Ca2+ exchange (reverse mode) inhibitor KB-R7943, 2-[2-[4-(-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulphonate, at 0.3 and 1 microM inhibited also the responses to angiotensin II more effectively than the response to elevation of [Ca2+]0; however, over the same concentration range it suppressed significantly the amplitude of Ca2+ transients and cell shortening. Combination of EIPA (3 microM) and KB-R7943 (0.3 microM), each of which attenuated partially the angiotensin-II-induced responses, abolished the positive inotropic effect and the increase in Ca2+ transients induced by angiotensin II with much less depressant effect on the responses to elevation of [Ca2+]0. Thus, these ion exchange inhibitors exerted selective actions on the respective targets. The results with these selective inhibitors indicate that the activation of Na+ -H+ exchanger and subsequent modulation of the activity of Na+ -Ca2+ exchanger may be responsible for the increase in [Ca2+]i and the myofilament Ca2+ sensitization induced by stimulation of AT1 receptors by angiotensin II in rabbit ventricular myocytes.
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PMID:Influence of a Na+-H+ exchange inhibitor ethylisopropylamiloride, a Na+-Ca2+ exchange inhibitor KB-R7943 and their combination on the increases in contractility and Ca2+ transient induced by angiotensin II in isolated adult rabbit ventricular myocytes. 1059 97

Losartan, a selective angiotensin II (AII) type I receptor antagonist, may protect against myocardial stunning and arrhythmia in ischemia and reperfusion. To examine the cellular basis for these protective actions, we studied effects of losartan and AII on contractile and electrical activity of ventricular myocytes exposed to simulated ischemia and reperfusion. Ionic currents were measured with voltage-clamp techniques and contractions were measured with a video edge detector. After 10 min of superfusion with Tyrode's solution at 37 degrees C, cells were exposed to simulated ischemia (hypoxia, acidosis, hyperkalemia, hypercapnia, lactate accumulation, and substrate deprivation) for 30 min followed by 25 min of reperfusion with normal Tyrode's solution. During ischemia, drug-treated cells were exposed to either 0.1 microM AII, 10 microM losartan, or both simultaneously. In reperfusion, contractions were depressed to 42% of preischemic levels in untreated cells. Losartan treatment significantly improved contractile recovery to 84% (P <. 05) of preischemic levels. AII-treated cells showed contractile recovery similar to untreated cells (40%), whereas cells treated with losartan plus AII recovered to 101% of preischemic levels. Cells exposed to losartan or losartan plus AII also exhibited reduced incidence of transient inward current (I(TI)) (20%, P <.05; 36%) relative to untreated cells (60%). However, I(TI) incidence was not altered by treatment with AII alone (57%). Treatment with exogenous agonist did not potentiate contractile depression or I(TI) incidence, and losartan exerted protective effects in the presence and absence of AII. Thus, losartan may have effects that are independent of AII receptor blockade.
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PMID:Losartan improves recovery of contraction and inhibits transient inward current in a cellular model of cardiac ischemia and reperfusion. 1104 8

The prognosis for patients with congestive heart failure (CHF) has been improved as a result of the use of angiotensin converting enzyme inhibitors and beta-adrenergic receptor blockers. The success of these therapies underscores the pathogenic role of neurohormonal activation in CHF. Clinical and experimental evidence supports a pathophysiologic role for pro-inflammatory cytokines and nitric oxide (NO) in the effects of angiotensin II and norepinephrine in CHF. Potential mechanism(s) responsible for the effects of these immunomodulators can be explained on the basis of established principles of myocardial excitation contraction coupling (E-C). A novel hypothesis is proposed that cytokines and NO-mediated alterations in E-C coupling contribute to the reversible myocardial depression and beta-adrenergic desensitization observed in a diverse group of clinical conditions that activate host inflammatory responses, including CHF. Basic studies into cytokine signaling pathways in cardiac myocytes have the potential to provide important new insights relevant to the design of new management strategies for the treatment of congestive heart failure patients.
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PMID:Interactions between cytokines and neurohormonal systems in the failing heart. 1130 30

Alterations of the central nervous system may be important for imbalance of cardiovascular and fluid regulation in heart failure. The central renin-angiotensin and atrial natriuretic peptide (ANP) systems act as mutual antagonists. The effects of angiotensin converting enzyme (ACE) inhibition (quinapril, 6 mg/kg/day) and angiotensin II type 1 (AT1) receptor blockade (losartan, 10 mg/kg/day) on ANP levels in 18 selected, microdissected brain nuclei were determined in sham-operated rats and rats with left ventricular dysfunction 8 weeks after myocardial infarction (MI). Plasma ANP tended to increase in MI rats and was further increased by quinapril. ANP was decreased in 12 brain areas of MI rats. ANP concentration was also significantly decreased by quinapril in six brain nuclei including subfornical organ and organum vasculosum laminae terminalis (areas lacking blood-brain barrier), and by losartan in 16 brain nuclei outside and within the blood-brain barrier in sham operated rats. However, both quinapril and losartan prevented a further reduction of central ANP as a result of myocardial infarction. These data suggest that there are effects on central ANP that result from chronic left ventricular dysfunction as well as an ACE-inhibitor and AT1-antagonist. Mechanisms and consequences of central ANP depression remain unclear. They could, however, support systemic vasoconstriction and sodium and fluid retention.
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PMID:Chronic effects of ACE-inhibition (quinapril) and angiotensin-II-type-1 receptor blockade (losartan) on atrial natriuretic peptide in brain nuclei of rats with experimental myocardial infarction. 1140 19

We showed recently that post-frusemide (furosemide) natriuresis was associated with a major depression of medullary circulation. In the present study, prior to administration of frusemide the tubular transport of NaCl was modified by loading the animals with 5% saline to elucidate a possible interrelation between the tubular and vascular effects of the drug. Moreover, a possible involvement of the renin-angiotensin system was examined by pharmacological blockade using captopril, an inhibitor of angiotensin converting enzyme (1 mg x kg(-1), I.V.), or losartan, a selective inhibitor of angiotensin AT1 receptor (10 mg x kg(-1), I.V.). The effects of frusemide (0.25 mg x kg(-1) I.V., then the same dose given over 1 h) on renal medullary and cortical circulation (using laser-Doppler flowmetry) and renal excretion of sodium (U(Na)V), water and total solutes were measured in anaesthetised rats. With no pre-treatment, frusemide decreased the medullary flow (36.6 +/- 6.0%) significantly more than the cortical flow (10.1 +/- 1.0%; P < 0.001). The difference between the medulla and cortex was not significant in rats which showed high U(Na)V after hypertonic saline loading (2.0 +/- 0.4 vs. 0.4 +/- 0.1 micromol x min(-1) in non-loaded rats): 21.1 +/- 3.9% and 15.8 +/- 1.5%, respectively. At very high U(Na)V (9.5 +/- 1.1 micromol x min(-1)) the post-frusemide decrease in blood flow tended to be smaller in the medulla (7.6 +/- 7.7%) than in the cortex (16.2 +/- 2.6%). The fall in medullary blood flow was attenuated by pre-treatment with captopril (22.0 +/- 3.3%) and abolished by pre-treatment with losartan (2.8 +/- 11.8%). The decrease in cortical blood flow was not changed by hypertonic saline or angiotensin II blockers. The abolition of the post-frusemide depression of medullary blood flow by previous salt loading confirms the proposed link between tubular transport status and vasoconstriction. A similar modification of the response by blockade of the renin-angiotensin system suggests that the system is involved in the mechanism of medullary vasoconstriction.
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PMID:Renal vascular effects of frusemide in the rat: influence of salt loading and the role of angiotensin II. 1157 89

Perindopril erbumine is a once-daily angiotensin-converting enzyme (ACE) inhibitor that effectively lowers systolic and diastolic blood pressure (BP) in patients with mild-to-moderate hypertension. Converted from the prodrug ester perindopril, the active diacid perindoprilat is distributed rapidly and extensively, primarily to tissues with high ACE activity. Its ability to lower BP is comparable to or better than that of other antihypertensive agents, both of its own class and other classes, and its trough-peak ratio is consistently between 75% and 100%, translating into 24 hours of true efficacy per dose. First-dose hypotension caused by an initial acute BP depression occurs less frequently with perindopril than with other ACE inhibitors, an advantage in volume-contracted patients and those whose BP is angiotensin II dependent, such as patients with congestive heart failure. A missed-dose study showed that most of the antihypertensive effect of perindopril remains for 24 to 48 hours after dosing, a characteristic that confers protection to patients who miss a dose. Perindopril improves the distensibility and compliance of large and small arteries, which are compromised in hypertension, and can effect vascular remodeling by a mechanism independent of BP lowering. The clinical implications of these effects are being investigated in large trials. Perindopril is well tolerated in the elderly, and combination therapy with a diuretic was shown to yield significant additional BP reduction. Perindoprilat is cleared renally; dosage should be adjusted in patients with renal impairment.
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PMID:Dosage considerations with perindopril for systemic hypertension. 1159 56

The renal medulla is sensitive to hypoxia, and a depression of medullary circulation, e.g. in response to angiotensin II (Ang II), could endanger the function of this zone. Earlier data on Ang II effects on medullary vasculature were contradictory. The effects of Ang II on total renal blood flow (RBF), and cortical and medullary blood flow (CBF and MBF: by laser-Doppler flux) were studied in anaesthetised rats. Ang II infusion (30 ng kg(-1) min(-1) i.v.) decreased RBF 27 +/- 2 % (mean +/- S.E.M.), whereas MBF increased 12 +/- 2 % (both P < 0.001). Non-selective blockade of Ang II receptors with saralasin (3 microg kg(-1) min(-1) i.v.) increased RBF 12 +/- 2 % and decreased MBF 8 +/- 2 % (P < 0.001). Blockade of AT(1) receptors with losartan (10 mg kg(-1)) increased CBF 10 +/- 2 % (P < 0.002) and did not change MBF. Losartan given during Ang II infusion significantly increased RBF (53 +/- 7 %) and decreased MBF (27 +/- 7 %). Blockade of AT(2) receptors with PD 123319 (50 microg kg(-1) min(-1) i.v.) did not change CBF or MBF. Intramedullary infusion of PD 123319 (10 microg min(-1)) superimposed on intravenous Ang II infusion did not change RBF, but slightly decreased MBF (4 +/- 2 %, P < 0.05). We conclude that in anaesthetised surgically prepared rats, exogenous or endogenous Ang II may not depress medullary circulation. In contrast to the usual vasoconstriction in the cortex, vasodilatation was observed, possibly related to secondary activation of vasodilator paracrine agents rather than to a direct action via AT(2) receptors.
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PMID:Differential effect of angiotensin II on blood circulation in the renal medulla and cortex of anaesthetised rats. 1177 24


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