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This study investigated the effect of intracerebroventricular administration of the angiotensin AT1 receptor antagonist losartan on the natriuresis, pressor effect, and arginine vasopressin (AVP) secretion caused by intracerebroventricular infusion of either ANG II, hypertonic saline, or carbachol. Losartan (1 mg/h) or artificial cerebrospinal fluid (CSF) was infused into the lateral ventricle before, during, and after infusions of either ANG II at 10 microg/h for 1 h, 0.75 mol/l NaCl at 50 microl/min for 20 min, or carbachol at 1.66 microg/min for 15 min. Intracerebroventricular infusions of ANG II, 0.75 mol/l NaCl, or carbachol caused increases in renal Na+ and K+ excretion, arterial pressure, and plasma AVP levels. Increases in arterial pressure, Na+ excretion, and plasma AVP concentration ([AVP]) in response to intracerebroventricular ANG II or intracerebroventricular 0.75 mol/l NaCl were either abolished or attenuated by intracerebroventricular infusion of losartan but not by intracerebroventricular infusion of artificial CSF or intravenous losartan. Intracerebroventricular losartan did not reduce the increase in plasma [AVP] or arterial pressure in response to intracerebroventricular carbachol, but it did attenuate the natriuretic response to intracerebroventricular carbachol. We conclude that an intracerebroventricular dose of losartan (1 mg/h) that inhibits responses to intracerebroventricular ANG II also inhibits vasopressin secretion, natriuresis, and the pressor response to intracerebroventricular hypertonic saline. These results suggest that common neural pathways are involved in the responses induced by intracerebroventricular administration of ANG II and intracerebroventricular hypertonic NaCl. We propose that intracerebroventricular infusion of hypertonic saline activates angiotensinergic pathways in the central nervous system subserving the regulation of fluid and electrolyte balance and arterial pressure in sheep.
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PMID:Central losartan blocks natriuretic, vasopressin, and pressor responses to central hypertonic NaCl in sheep. 968 92

This study was performed to determine whether the stimulatory effect of plasma angiotensin II (ANG II) on arginine vasopressin (AVP) and oxytocin (OT) secretion in humans is mediated by AT1 subtype receptors. For this purpose, the effects of the AT1 receptor antagonist losartan (50 mg orally) or a placebo on the AVP and OT responses to ANG II (intravenous infusion for 60 minutes of successively increasing doses of 4, 8, and 16 ng/kg min; each dose for 20 minutes) administration were evaluated in seven normal men. In additional experiments, the same subjects were tested with losartan (50 mg orally) alone or placebo alone. Neither losartan nor placebo given alone modified the basal levels of AVP and OT. ANG II infusion induced significant increments in both serum AVP and OT levels (mean peaks were 1.55 and 1.41 times higher than baseline, respectively). Both hormonal responses to ANG II were completely abolished by pretreatment with losartan. These data provide evidence of AT1 receptor involvement in mediation of the ANG II-stimulating effect on AVP and OT secretion.
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PMID:Arginine vasopressin and oxytocin responses to angiotensin II are mediated by AT1 receptor subtype in normal men. 971 80

1. A set-up for computerized acquisition and evaluation of haemodynamic data was constructed. Blood flow (BF) in the superior mesenteric and femoral artery of urethane-anaesthetized rats was measured with the ultrasonic transit time shift technique. The signals for arterial blood pressure and BF were fed into a personal computer via an analogue-digital converter. Mean arterial blood pressure, heart rate and vascular conductance (CV) were calculated on-line. For subsequent analysis of the data, algorithms were programmed to filter the data, and to determine average and peak values for each parameter. 2. Systemic hypertension induced by phenylephrine (3-300 nmol kg-1), angiotensin II (0.1-3.0 nmol kg-1) and arginine vasopressin (0.03-1.0 nmol kg-1) was accompanied by constriction of the mesenteric artery. In contrast, the femoral artery responded to phenylephrine with constriction, to angiotensin II with dilatation and to arginine vasopressin with dilation followed by constriction. The haemodynamic effects of endothelin-1 (0.03-3.0 nmol kg-1) were generally biphasic, the initial hypotension being associated with dilatation, and the delayed hypertension being accompanied by constriction of both the mesenteric and femoral arterial bed. 3. Terbutaline (3-1.0 nmol kg-1) and calcitonin gene-related peptide (0.03-1 nmol kg-1) caused systemic hypotension along with mesenteric and femoral vasodilatation. 4. Telmisartan (1 mg kg-1), an angiotensin AT1 receptor antagonist, dilated the mesenteric artery, but had no effect on femoral VC. In contrast, the alpha 1-adrenoceptor antagonist prazosin (0.1 mg kg-1), dilated the femoral artery without altering mesenteric VC. Similarly, the beta-adrenoceptor antagonist propranolol (1 mg kg-1) had no effect on mesenteric VC, but constricted the femoral arterial bed. 5. These data demonstrate that the haemodynamic effects of exogenously administered drugs can widely differ between the mesenteric and femoral arterial beds of urethane-anaesthetized rats. Furthermore, vascular tone of these two arterial beds in maintained by different vasoconstrictor systems. While the femoral artery is mainly under adrenergic control, the renin-angiotensin axis is predominant in the mesenteric arterial bed. In addition, this study also demonstrates that computerized analysis enables quick and accurate estimation of haemodynamic drug effects, and is superior to 'by hand' evaluation of peak changes in the functional diameter of the vascular bed under study.
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PMID:Differential regulation of mesenteric and femoral blood flow in the rat as revealed by computerized data acquisition and evaluation. 972 24

Angiotensin II (Ang II) has diverse physiological actions that lead, for instance, to increases in extracellular volume and peripheral vascular resistance and blood pressure, and it has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated AT1 and AT2. Most effects of Ang II are mediated by AT1 receptors. Much less is known about the physiological role of AT2 receptors. Recent evidence suggests involvement of AT2 receptors in development, cell differentiation, apoptosis, and regeneration in various tissues. AT1 and AT2 receptors have been shown to exert counteracting effects on cellular growth and differentiation, vascular tone, and the release of arginine vasopressin. In each condition, the AT2 receptor appears to down-modulate actions mediated by the AT1 receptor, resulting in decreased cellular proliferation, decreased levels of serum arginine vasopressin levels, or decreased vasoconstrictor responses. In addition, in neuronal cell lines, the AT2 receptor exerts antiproliferative actions and promotes neurite outgrowth, an effect accompanied by significant changes in the expression pattern of growth/differentiation-related genes.
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PMID:Physiological and pharmacological implications of AT1 versus AT2 receptors. 973 62

Because dopamine influences arginine vasopressin (AVP) release, the present studies were designed to ascertain the dopamine receptor subtype that potentiates angiotensin II-induced AVP secretion in cultured hypothalamo-neurohypophysial explants. Dopamine (a nonselective D1/D2 agonist), apomorphine (a D2 >> D1 agonist), and SKF-38393 (a selective D1 agonist) dose dependently increased AVP secretion. Maximal AVP release was observed with 5 microM dopamine, 307 +/- 66% . explant-1 . h-1, 1 microM SKF-38393, 369 +/- 41% . explant-1 . h-1, and 0.1 microM apomorphine, 374 +/- 67% . explant-1 . h-1. Selective D1 antagonism with 1 microM SCH-23390 blocked AVP secretion to values no different from basal. Domperidone (D2 antagonist), phenoxybenzamine (nonselective adrenergic antagonist), and prazosin (alpha1-antagonist) failed to prevent release. D1 antagonism also prevented AVP secretion to 1 microM angiotensin II [angiotensin II, 422 +/- 87% . explant-1 . h-1 vs. angiotensin II plus SCH-23390, 169 +/- 28% . explant-1 . h-1 (P < 0.05)], but D2 and alpha1-adrenergic blockade did not. In contrast, AT1 receptor inhibition with 0.5 microM losartan blocked angiotensin II- but not dopamine-induced AVP release. AT2 antagonism had no effect. Although subthreshold doses of the agonists did not increase AVP secretion (0. 05 microM dopamine, 133 +/- 44% . explant-1 . h-1; 0.01 microM SKF-38393, 116 +/- 26% . explant-1 . h-1;and 0.001 microM angiotensin II, 104 +/- 29% . explant-1 . h-1 ), the combination of dopamine and angiotensin II provoked a significant rise in AVP [420 +/- 83% . explant-1 . h-1 (P < 0.01)]. Similar results were observed with SKF-38393 and angiotensin II, and the AVP response was blocked to basal levels by either D1 or AT1 antagonism. These findings support a role for D1 receptor activation to increase AVP release and mediate angiotensin II-induced AVP release within the hypothalamo-neurohypophysial system. The data also suggest that the combined subthreshold stimulation of receptors that use distinct intracellular pathways can prompt substantial AVP release.
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PMID:Dopaminergic control of angiotensin II-induced vasopressin secretion in vitro. 975 89

Angiotensin II (Ang II) has diverse physiological actions leading, for example, to increases in extracellular volume, peripheral vascular resistance and blood pressure, and has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated as AT1 and AT2. Most effects of Ang II are mediated by AT1 receptors. Much less is known about the physiological role of AT2 receptors. Recent evidence suggests involvement of AT2 receptors in development, cell differentiation, apoptosis and regeneration in various tissues. AT1 and AT2 receptors have been shown to exert counteracting effects on cellular growth and differentiation, vascular tone and the release of arginine vasopressin (AVP). In each condition the AT2 receptor appears to down-modulate actions mediated by the AT1 receptor, resulting in decreased cellular proliferation, decreased levels of serum AVP levels or decreased vasoconstrictor responses. In addition, in neuronal cell lines, the AT2 receptor reportedly exerts antiproliferative effects and promotes neurite outgrowth, an effect accompanied by significant changes in the gene expression pattern of growth- and differentiation-related genes.
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PMID:Angiotensin II receptor pharmacology and AT1-receptor blockers. 1007 16

With increasing case reports, it has been indicated that some cases with adrenocorticotropic hormone (ACTH)-independent macronodular adrenal hyperplasia (AIMAH) show abnormal responses in cortisol to various stimulation tests. Here we report a case of AIMAH that showed an aberrant response to angiotensin II via AT1 receptor in cortisol hypersecretion. A 53-yr-old man was admitted to our division seeking further examinations for the possible diagnosis of Cushing's syndrome. He had hypertension, diabetes mellitus, and physical stigmata, such as moon face and central obesity. His plasma ACTH level was undetectable, and plasma cortisol level was high. Plasma cortisol showed no normal diurnal rhythm and was not suppressed after the administration of 8 mg of dexamethasone. Abdominal computed tomography demonstrated nodular enlargement of bilateral adrenal glands. He was diagnosed with Cushing's syndrome owing to AIMAH. An injection of arginine vasopressin (AVP) increased plasma cortisol and aldosterone levels, whereas ACTH remained undetectable. After 4 h in an upright position, plasma cortisol and aldosterone levels were increased. Pretreatment with candesartan, angiotensin II receptor AT1 antagonist, blocked the increase in plasma cortisol level. These results suggested a possibility of adrenal hypersensitivity to angiotensin II and AVP in cortisol secretion. Bilateral laparoscopic adrenalectomy was performed. The histological findings of the specimen were compatible with AIMAH. In summary, we have made the first report on a case of AIMAH with possible hypersensitivity to angiotensin II.
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PMID:Case of adrenocorticotropic hormone-independent macronodular adrenal hyperplasia with possible adrenal hypersensitivity to angiotensin II. 1157 27

Our previous studies have shown that central administration of angiotensin (ANG II) causes arginine vasopressin (AVP) release in the fetus at 70-90% gestation. This is evidence that the hypothalamic-neurohypophysial system is relatively mature before birth. However, few data exist regarding central ANG receptor mechanisms-mediated AVP response during fetal life. To determine roles of brain ANG receptor subtypes in this response, AT1 and AT2 receptor antagonists, losartan and PD123319, were investigated in the brain in chronically prepared ovine fetuses at the last third of gestation. Application of losartan intracerebroventricularly (i.c.v.) at 0.5 mg/kg suppressed central ANG II-stimulated plasma AVP release. Losartan at 5 mg/kg (i.c.v.) demonstrated a significant enhancement of AVP increase to i.c.v. ANG II. Associated with the increase of plasma vasopressin levels, c-fos expression in the hypothalamic neurons was significantly different between the low and high doses of losartan. The low dose losartan markedly reduced the dual immunoreactivity for FOS and AVP in the supraoptic nuclei and paraventricular nuclei after i.c.v. ANG II, whereas the high dose losartan together with ANG II, significantly increased the co-localization of positive FOS in the AVP-containing neurons than that induced by i.c.v. ANG II alone. Central ANG II induced fetal plasma vasopressin increase was not altered by PD123319. The data suggest that losartan in the fetal brain has remarkably different effects based on the doses administrated on central ANG II-related neuroendocrine effects at the late gestation, and that the AT1 mechanism is critical in the regulation of fetal body fluid homeostasis related to plasma AVP levels.
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PMID:Effects of i.c.v. losartan on the angiotensin II-mediated vasopressin release and hypothalamic fos expression in near-term ovine fetuses. 1667 37

Our objectives were to compare the levels of circulating electrolytes, hormones, and renal function during 20 days of dehydration in camels versus the level in non-dehydrated camels and to record the effect of blocking angiotensin II AT1 receptors with losartan during dehydration. Dehydration induced significant increments in serum sodium, creatinine, urea, a substantial fall in body weight, and a doubling in plasma arginine vasopressin (AVP) levels. Plasma aldosterone, however, was unaltered compared with time-matched controls. Losartan significantly enhanced the effect of dehydration to reduce body weight and increase serum levels of creatinine and urea, whilst also impairing the rise in plasma AVP and reducing aldosterone levels. We conclude that dehydration in the camel induces substantial increments in serum sodium, creatinine, urea and AVP levels; that aldosterone levels are altered little by dehydration; that blockade of angiotensin II type 1 receptors enhances the dehydration-induced fall in body weight and increase in serum creatinine and urea levels whilst reducing aldosterone and attenuating the rise in plasma AVP.
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PMID:Responses to dehydration in the one-humped camel and effects of blocking the renin-angiotensin system. 2262 9


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