Monophasic and biphasic effects of angiotensin II and III on norepinephrine uptake and release in rat adrenal medulla.

Angiotensin II and III have hypertensive effects. They induce vascular smooth muscle constriction, increase sodium reabsorption by renal tubules, stimulate the anteroventral third ventricle area, increase vasopressin and aldosterone secretions, and modify catecholamine metabolism. In this work, angiotensin II and III effects on norepinephrine uptake and release in rat adrenal medulla were investigated. Both angiotensins decreased total and neuronal norepinephrine uptake. Angiotensin II showed a biphasic effect only on evoked neuronal norepinephrine release (an earlier decrease followed by a later increase), while increasing the spontaneous norepinephrine release only after 12 min. On the other hand, angiotensin III showed a biphasic effect on evoked and spontaneous neuronal norepinephrine release. Both angiotensins altered norepinephrine distribution into intracellular stores, concentrating the amine into the granular pool and decreasing the cytosolic store. The results suggest a physiological biphasic effect of angiotensin II as well as angiotensin III that may be involved in the modulation of sympathetic activity in the rat adrenal medulla.     

Angiotensin II potentiates responses of the rabbit basilar artery to adrenergic nerve stimulation

Angiotensin II has little contractile effect on the isolated rabbit basilar artery; however, it markedly potentiates contractile responses to adrenergic nerve stimulation. This is not a post-synaptic effect of angiotensin, as responses to exogenous norepinephrine are not altered. Angiotensin increases stimulation-evoked release of norepinephrine, and this effect probably accounts for the increased response to adrenergic nerve stimulation. Since sympathetic stimulation may protect the cerebral circulation from hypertensive damage, increased responsiveness to adrenergic nerve activity produced by angiotensin may have a beneficial effect.     

Modulation of delayed rectifier potassium current by angiotensin II in CATH.a cells

Angiotensin II (Ang II) modulates, via Ang II type 1 (AT(1)) receptors, the activity of brain catecholaminergic neurons. Here we utilized catecholaminergic CATH.a cells to define the effects of Ang II on delayed rectifier K(+) current (I(Kv)), one of the factors that determines changes in neuronal activation. Receptor binding analyses demonstrated the presence of AT(1) receptors in CATH.a cells. Whole cell voltage clamp experiments in these cells revealed that Ang II (100nM) produced a significant inhibition of I(Kv), that was abolished by the AT(1) receptor blocker, losartan (1 microM), or by inhibition of phospholipase C (PLC) with U73122 (10 microM). Furthermore, this action of Ang II was completely abolished by co-inhibition of protein kinase C (PKC) and calcium/calmodulin protein kinase II (CaMKII). These results demonstrate that Ang II produces an inhibition of I(Kv) in CATH.a cells, via an intracellular pathway that includes PLC, PKC, and CaMKII.     

Angiotensin II potentiates adrenergic and muscarinic modulation of guinea pig intracardiac neurons

The intrinsic cardiac plexus represents a major peripheral integration site for neuronal, hormonal, and locally produced neuromodulators controlling efferent neuronal output to the heart. This study examined the interdependence of norepinephrine, muscarinic agonists, and ANG II, to modulate intrinsic cardiac neuronal activity. Intracellular voltage recordings from whole-mount preparations of the guinea pig cardiac plexus were used to determine changes in active and passive electrical properties of individual intrinsic cardiac neurons. Application of either adrenergic or muscarinic agonists induced changes in neuronal resting membrane potentials, decreased afterhyperpolarization duration of single action potentials, and increased neuronal excitability. Adrenergic responses were inhibited by removal of extracellular calcium ions, while muscarinic responses were inhibited by application of TEA. The adrenergic responses were heterogeneous, responding to a variety of receptor-specific agonists (phenylephrine, clonidine, dobutamine, and terbutaline), although α-receptor agonists produced the most frequent responses. Application of ANG II alone produced a significant increase in excitability, while application of ANG II in combination with either adrenergic or muscarinic agonists produced a much larger potentiation of excitability. The ANG II-induced modulation of firing was blocked by the angiotensin type 2 (AT(2)) receptor inhibitor PD 123319 and was mimicked by the AT(2) receptor agonist CGP-42112A. AT(1) receptor blockade with telmasartin did not alter neuronal responses to ANG II. These data demonstrate that ANG II potentiates both muscarinically and adrenergically mediated activation of intrinsic cardiac neurons, doing so primarily via AT(2) receptor-dependent mechanisms. These neurohumoral interactions may be fundamental to regulation of neuronal excitability within the intrinsic cardiac nervous system.     

The effect of temperature on adrenergic receptors of alveolar type II cells of a heterothermic marsupial

Fat-tailed dunnarts, Sminthopsis crassicaudata, survive dramatic changes in body temperature during torpor without experiencing surfactant dysfunction. Adrenergic factors regulate surfactant secretion through beta(2)-adrenergic receptors on alveolar type II cells. Temperature has no effect on the secretory response of dunnart type II cells to adrenergic stimulation. We hypothesise that during torpor, dunnart type II cells up-regulate the number of adrenergic receptors present on type II cells to enable stimulation at lower concentrations of agonist. Here, we isolated type II cells from warm-active (35 degrees C) and torpid (15 degrees C) dunnarts and examined the effects of an in vitro temperature change on the number and activity of adrenergic receptors. Torpor did not affect the beta-adrenergic receptor number. However, we observed a significant decrease in adrenergic receptor number when cells from warm-active animals were incubated at 15 degrees C and when cells from torpid animals were incubated at 37 degrees C. cAMP production was significantly higher in type II cells from torpid dunnarts than warm-active dunnarts and this may contribute, in part, to the temperature insensitivity we have previously observed in the adrenergic regulation of surfactant secretion.     

Role of angiotensin II in renal hemodynamic functions during the initial stages of acute ureteral obstruction

This investigation examines the role of Angiotensin II in renal hemodynamic functions during acute unilateral ureteral obstruction (UUO) in a dog model. An electro magnetic flow probe was utilized to assess renal blood flow while the arteriovenous extraction technique of technetium 99m DTPA was utilized for the assessment of changes in filtration fraction and glomerular filtration rate. The effects of Angiotensin II receptor blockade on renal hemodynamic functions during acute UUO was evaluated in six dogs and compared to acute ureteral obstruction without receptor blockade in seven dogs. Angiotensin II blockade with (Sar1, Thr8)-Angiotensin II during UUO led to a striking increase in renal blood flow that was significantly different in comparison to normalized values from UUO alone (+delta 63 +/- 17 vs. +delta 22 +/- 6% at 30 min; p less than 0.05). There were, however, no significant differences in the magnitude of the decrease in filtration fraction and glomerular filtration rate in comparison to UUO alone. This investigation demonstrates that Angiotensin II has an inhibitory effect on the initial increase in renal blood flow with acute UUO. The possibility of successful pharmacologic intervention in the setting of UUO can be examined using animal models similar to the one described here. Pharmacologic treatment in the setting of acute UUO in patients might permit better preservation of renal function.     

Brain Angiotensin II: New Developments, Unanswered Questions and Therapeutic Opportunities

1. There are two Angiotensin II systems in the brain. The discovery of brain Angiotensin II receptors located in neurons inside the blood brain barrier confirmed the existence of an endogenous brain Angiotensin II system, responding to Angiotensin II generated in and/or transported into the brain. In addition, Angiotensin II receptors in circumventricular organs and in cerebrovascular endothelial cells respond to circulating Angiotensin II of peripheral origin. Thus, the brain responds to both circulating and tissue Angiotensin II, and the two systems are integrated. 2. The neuroanatomical location of Angiotensin II receptors and the regulation of the receptor number are most important to determine the level of activation of the brain Angiotensin II systems. 3. Classical, well-defined actions of Angiotensin II in the brain include the regulation of hormone formation and release, the control of the central and peripheral sympathoadrenal systems, and the regulation of water and sodium intake. As a consequence of changes in the hormone, sympathetic and electrolyte systems, feed back mechanisms in turn modulate the activity of the brain Angiotensin II systems. It is reasonable to hypothesize that brain Angiotensin II is involved in the regulation of multiple additional functions in the brain, including brain development, neuronal migration, process of sensory information, cognition, regulation of emotional responses, and cerebral blood flow. 4. Many of the classical and of the hypothetical functions of brain Angiotensin II are mediated by stimulation of Angiotensin II AT₁ receptors. 5. Brain AT₂ receptors are highly expressed during development. In the adult, AT₂ receptors are restricted to areas predominantly involved in the process of sensory information. However, the role of AT₂ receptors remains to be clarified. 6. Subcutaneous or oral administration of a selective and potent non-peptidic AT₁ receptor antagonist with very low affinity for AT₂ receptors and good bioavailability blocked AT₁ receptors not only outside but also inside the blood brain barrier. The blockade of the complete brain Angiotensin II AT₁ system allowed us to further clarify some of the central actions of the peptide and suggested some new potential therapeutic avenues for this class of compounds. 7. Pretreatment with peripherally administered AT₁ antagonists completely prevented the hormonal and sympathoadrenal response to isolation stress. A similar pretreatment prevented the development of stress-induced gastric ulcers. These findings strongly suggest that blockade of brain AT₁ receptors could be considered as a novel therapeutic approach in the treatment of stress-related disorders. 8. Peripheral administration of AT₁ receptor antagonists strongly affected brain circulation and normalized some of the profound alterations in cerebrovascular structure and function characteristic of chronic genetic hypertension. AT₁ receptor antagonists were capable of reversing the pathological cerebrovascular remodeling in hypertension and the shift to the right in the cerebral autoregulation, normalizing cerebrovascular compliance. In addition, AT₁ receptor antagonists normalized the expression of cerebrovascular nitric oxide synthase isoenzymes and reversed the inflammatory reaction characteristic of cerebral vessels in hypertension. As a consequence of the normalization of cerebrovascular compliance and the prevention of inflammation, there was, in genetically hypertensive rats a decreased vulnerability to brain ischemia. After pretreatment with AT₁ antagonists, there was a protection of cerebrovascular flow during experimental stroke, decreased neuronal death, and a substantial reduction in the size of infarct after occlusion of the middle cerebral artery. At least part of the protective effect of AT₁ receptor antagonists was related to the inhibition of the Angiotensin II system, and not to the normalization of blood pressure. These results indicate that treatment with AT₁ receptor antagonists appears to be a major therapeutic avenue for the prevention of ischemia and inflammatory diseases of the brain. 9. Thus, orally administered AT₁ receptor antagonists may be considered as novel therapeutic compounds for the treatment of diseases of the central nervous system when stress, inflammation and ischemia play major roles. 10. Many questions remain. How is brain Angiotensin II formed, metabolized, and distributed? What is the role of brain AT₂ receptors? What are the molecular mechanisms involved in the cerebrovascular remodeling and inflammation which are promoted by AT₁ receptor stimulation? How does Angiotensin II regulate the stress response at higher brain centers? Does the degree of activity of the brain Angiotensin II system predict vulnerability to stress and brain ischemia? We look forward to further studies in this exiting and expanding field.     

The effect of angiotensin II on electrolyte excretion by the renal tubules.

In vivo studies were done on mongrel dogs to determine the effect of angiotensin II on renal electrolyte excretion. Angiotensin II was infused directly into the left renal artery at a rate of 1 ng/kg/min. Angiotensin produced consistent reductions in the excretion of Na+, K+, and Cl- in the left kidney. These reductions could not be attributed to decreases in GFR or RPF. Electrolyte excretion by the right kidney was constant. These data are consistent with the hypothesis that angiotensin II may function as an intrarenal, antinatriuretic hormone.     

Effects of angiotensin II on adipose conversion and expression of genes of the renin-angiotensin system in human preadipocytes.

A complete functional renin-angiotensin system exists in human adipose tissue, but its regulation and the effects of angiotensin II on cells from this tissue are only beginning to be understood. In this study, we examined the effects of angiotensin II on changes in lipid accumulation, specific glycerol-3-phosphate dehydrogenase activity, and the expression of five genes of the renin-angiotensin system during the adipose conversion of human primary cultured preadipocytes. Angiotensin II leads to a distinct reduction in insulin-induced differentiation, but only has a marginal effect on the adipose conversion of cells stimulated with insulin, cortisol, and isobutyl methyl xanthine. During differentiation, angiotensinogen mRNA levels rise, renin mRNA levels decline, whereas renin-binding protein and angiotensin-converting enzyme levels are unaffected. Angiotensin II downregulates angiotensinogen and renin gene expression, but it does not affect renin-binding protein and angiotensin-converting enzyme levels. Angiotensin II thus prevents the development of adipocytes in contact with high insulin levels, while not inhibiting differentiation, which is further stimulated. Therefore, angiotensin II could be a protective factor against uncontrolled expansion of adipose tissue. Further studies are needed to find out whether the effects of angiotensin II on the renin-angiotensin system are direct feedback loops or secondary to changes in the differentiation program.     

Angiotensin II regulation of neuromodulation: downstream signaling mechanism from activation of mitogen-activated protein kinase

Angiotensin II (Ang II) stimulates expression of tyrosine hydroxylase and norepinephrine transporter genes in brain neurons; however, the signal-transduction mechanism is not clearly defined. This study was conducted to determine the involvement of the mitogen-activated protein (MAP) kinase signaling pathway in Ang II stimulation of these genes. MAP kinase was localized in the perinuclear region of the neuronal soma. Ang II caused activation of MAP kinase and its subsequent translocation from the cytoplasmic to nuclear compartment, both effects being mediated by AT1 receptor subtype. Ang II also stimulated SRE- and AP1-binding activities and fos gene expression and its translocation in a MAP kinase-dependent process. These observations are the first demonstration of a downstream signaling pathway involving MAP kinase in Ang II-mediated neuromodulation in noradrenergic neurons.     

α1-Adrenergic Receptor-Mediated Downregulation of Angiotensin II Receptors in Neuronal Cultures

Previous evidence has suggested that brain catecholamine levels are important in the regulation of central angiotensin II receptors. In the present study, the effects of norepinephrine and 3,4-dihydroxyphenylethylamine (dopamine) on angiotensin II receptor regulation in neuronal cultures from rat hypothalamus and brainstem have been examined. Both catecholamines elicit significant decreases in [125I]angiotensin II-specific binding to neuronal cultures prepared from normotensive rats, effects that are dose dependent and that are maximal within 4-8 h of preincubation. Saturation and Scatchard analyses revealed that the norepinephrine-induced decrease in the binding is due to a decrease in the number of angiotensin II receptors in neuronal cultures, with little effect on the receptor affinity. Norepinephrine has no significant actions on [125I]angiotensin II binding in cultures prepared from spontaneously hypertensive rats. The downregulation of angiotensin II receptors by norepinephrine or dopamine is blocked by alpha 1-adrenergic and not by other adrenergic antagonists, a result suggesting that this effect is initiated at the cell surface involving alpha 1-adrenergic receptors. This is further supported by our data indicating a parallel downregulation of specific alpha 1-adrenergic receptors elicited by norepinephrine. In summary, these results show that norepinephrine and dopamine are able to alter the regulation of neuronal angiotensin II receptors by acting at alpha 1-adrenergic receptors, which is a novel finding.     

L-type calcium channel β subunit modulates angiotensin II responses in cardiomyocytes

Angiotensin II regulation of L-type calcium currents in cardiac muscle is controversial and the underlying signaling events are not completely understood. Moreover, the possible role of auxiliary subunit composition of the channels in Angiotensin II modulation of L-type calcium channels has not yet been explored. In this work we study the role of Ca_vβ subunits and the intracellular signaling responsible for L-type calcium current modulation by Angiotensin II. In cardiomyocytes, Angiotensin II exposure induces rapid inhibition of L-type current with a magnitude that is correlated with the rate of current inactivation. Semi-quantitative PCR of cardiomyocytes at different days of culture reveals changes in the Ca_vβ subunits expression pattern that are correlated with the rate of current inactivation and with Angiotensin II effect. Over-expression of individual b subunits in heterologous systems reveals that the magnitude of Angiotensin II inhibition is dependent on the Ca_vβ subunit isoform, with _Cavβ1bcontaining channels being more strongly regulated. _Cavβ2acontaining channels were insensitive to modulation and this effect was partially due to the N-terminal palmitoylation sites of this subunit. Moreover, PLC or diacylglycerol lipase inhibition prevents the Angiotensin II effect on L-type calcium channels, while PKC inhibition with chelerythrine does not, suggesting a role of arachidonic acid in this process. Finally, we show that in intact cardiomyocytes the magnitude of calcium transients on spontaneous beating cells is modulated by Angiotensin II in a Ca_vβ subunit-dependent manner. These data demonstrate that Ca_vβ subunits alter the magnitude of inhibition of L-type current by Angiotensin II.     

Angiotensin II type 1 receptor regulation and differential trophic effects on rat cardiac myofibroblasts after acute myocardial infarction

Fibroblast growth in the scar and surviving tissue is a key element of the remodeling post myocardial infarction. The regulation of fibroblast growth after acute myocardial infarction remains to be determined. Recently, Angiotensin II has been demonstrated to be a mitogen for neonatal cardiac fibroblasts. In this study adult rat cardiac fibroblasts were isolated from different regions of the infarcted rat heart and Angiotensin II effects examined. Adult Wistar-rats were sham operated or left coronary artery ligated. After 4 days, hearts were removed and fibroblasts from sham operated, infarct- and non-infarct regions of the left ventricle isolated. Radioligand binding studies were performed and cell number, cell area, total protein, and AT(1) receptor mRNA after stimulation determined. Radioligand binding studies demonstrated that myofibroblasts expressed a single class of high affinity Angiotensin II AT(1) receptors. Myofibroblasts from the infarct area revealed a lower maximal binding capacity, compared to sham operated myocardium. Conversely, myofibroblasts from the non-infarct area had a higher expression of Angiotensin II AT(1) receptor mRNA compared to sham operated myofibroblasts. Angiotensin II (1 microM, 48 h) increased cell-number in sham operated and non-infarct, but not in infarct myofibroblasts. Angiotensin II elevated total protein in sham operated, non-infarct, and infarct myofibroblasts. In addition, Angiotensin II increased cell area in sham operated and infarct myofibroblasts. These data demonstrate that Angiotensin II acted as a mitogen in sham operated and non-infarct myofibroblasts and stimulated hypertrophy in infarct myofibroblasts. These regional different effects of Angiotensin II might participate in the remodeling post myocardial infarction.     

Biphasic effect of angiotensin II on conditioned reflectory reaction patterns in albino rats]

40 male albino rats were used to investigate the influence of one single i. v. dose of 10 ng/kg Angiotensin II upon established and stabilized conditional-reflectory response pattern (two-dimensional conditional-reflectory decision process and periodicities of conditional-reflectory processes). At normotonous blood-pressure values, Angiotensin II exerted a biphasic action on the conditional-reflectory response pattern. In the first phase of action (up to 30 min after injection) there prevailed centralnervous inhibition processes, while the second phase of action (30-70 min after injection) was marked by a general centralnervous excitation, which is reflected by extremely short times of response, and a pronounced sensitivity to optic, acoustic and tactile stimuli. The decision capacity of the animals was considerably reduced in both phases. The periodicities of conditional-reflectory processes (duration of periods in the minute range) are strongly disturbed in the first phase of action, and tend to normal in the second phase. Furthermore, Angiotensin II was found to have a selective, hierarchically ordered influence with regard to the duration and intensity of action. Thus, the information processing activity of the CNS underwent most pronounced changes. The centralnervous regulatory functions were less affected; the blood pressure regulation showed little and transient influence by Angiotensin II. In the discussion, the neurotropic and algogenic action of Angiotensin II, and the relation of the octapeptide effect with pathogenetic mechanisms of experimental neurotically induced hypertonia are dealt with.     

Immunocytochemical and biochemical identification of angiotensin II in human nasal tissue

Angiotensin II (ANG II) was identified immunocytochemically and biochemically in biopsy samples of human nasal tissue. Staining for ANG II was predominantly found in structures similar to a string of pearls with consecutive short varicose areas, which is characteristic for neuronal tissue. The localization of ANG II in neurons was confirmed by positive staining of adjacent tissue sections with a specific antibody to neurofilament or doublestaining with both antibodies in one section. Likewise, ANG II-like material was also determined radioimmunologically in nasal tissue extracts. The concentrations of ANG II varied form 1.28 to 332.78 fmol/g wet tissue weight with an average concentration of 79.61+/-44.09 fmol ANG II/g wet tissue weight (mean+/-SEM, n=7). The ANG II-immunoreactive material was further characterized biochemically by HPLC on a reversed phase C(18) column in an acetonitrile and methanol gradient as Ile(5)-ANG II and ANG II metabolites such as Ile(4)-ANG III, Ile(3)-ANG II(3-8)hexapeptide and Ile(2)-ANG II(4-8)pentapeptide.     

The multiple actions of angiotensin II in atherosclerosis

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system, has been implied in the pathogenesis of atherosclerosis on various levels. There is abundant experimental evidence that pharmacological antagonism of Ang II formation by angiotensin converting enzyme inhibition or blockade of the cellular effects of Ang II by angiotensin type 1 receptor blockade inhibits formation and progression of atherosclerotic lesions. Angiotensin promotes generation of oxidative stress in the vasculature, which appears to be a key mediator of Ang II-induced endothelial dysfunction, endothelial cell apoptosis, and lipoprotein peroxidation. Ang II also induces cellular adhesion molecules, chemotactic and proinflammatory cytokines, all of which participate in the induction of an inflammatory response in the vessel wall. In addition, Ang II triggers responses in vascular smooth muscle cells that lead to proliferation, migration, and a phenotypic modulation resulting in production of growth factors and extracellular matrix. While all of these effects contribute to neointima formation and development of atherosclerotic lesions, Ang II may also be involved in acute complications of atherosclerosis by promoting plaque rupture and a hyperthrombotic state. Accordingly, Ang II appears to have a central role in the pathophysiology of atherosclerosis.     

Phospholipid metabolism in rat kidney cortical tubules. II. Effects of hormones on 32P incorporation

To evaluate the effect of hormones on renal phospholipid metabolism and turnover, we studied the changes in 32P-labeling of phospholipids in rat cortical tubule suspension. Angiotensin II, phenylephrine and parathyroid hormone (PTH) stimulate 32P incorporation into PC by 25, 29 and 26% and into PI by 189, 328 and 33% above control rates, respectively, whereas phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate labeling was not affected. However, when phospholipids were prelabeled with [32P]Pi, addition of angiotensin II led to a significant decrease in phosphatidylinositol 4,5-bisphosphate labeling in the first 2 min with no effect on the other phospholipid fractions. The phenylephrine effect on phospholipid labeling was blocked by prazosin but not by yohimbine, indicating an alpha 1-mediated action. In contrast, the effect of angiotensin II was not inhibited by either antagonist. The stimulating effect of substrates on 32P incorporation reported in the preceding paper was additive to that of hormones. Our results confirm previous studies on renal gluconeogenesis that catecholamines act by an alpha 1-type receptor on proximal tubules, and indicate that phenylephrine and angiotensin II act by different receptor sites exerting the same metabolic effect. The additivity of hormone effects with that of renal substrates indicates that the former are not secondary to release of precursors for phospholipid biosynthesis. The rapid decrease in phosphatidylinositol 4,5-bisphosphate labeling after angiotensin II suggests that the polyphosphoinositide is degraded after hormone binding to the receptor and that PI labeling is a secondary event.     

Angiotensin II Type 2 Receptor-Mediated Stimulation of Protein Phosphatase 2A in Rat Hypothalamic/Brainstem Neuronal Cocultures

Abstract: Recent studies have suggested a role for an inhibitory guanine nucleotide binding (G_i) protein and protein (serine/threonine) phosphatase 2A (PP2A) in the angiotensin II type 2 (AT₂) receptor-mediated stimulation of neuronal K⁺ currents. In the present study we have directly analyzed the effects of angiotensin II on PP2A activity in neurons cultured from newborn rat hypothalamus and brainstem. Angiotensin II elicited time (30 min–24 h)- and concentration (10 n M -1 µ M )-dependent increases in PP2A activity in these cells, an effect mimicked by the AT₂ receptor ligand CGP-42112A. These effects of angiotensin II and CGP-42112A involve AT₂ receptors, because they were inhibited by the AT₂ receptor-selective ligand PD 123,319 (1 µ M ) but not by the angiotensin II type 1 receptor antagonist losartan (1 µ M ). Furthermore, the stimulatory effects of angiotensin II and CGP-42112A on PP2A activity were inhibited by pretreatment of cultures with pertussis toxin (200 ng/ml; 24 h), indicating the involvement of a G_i protein. These effects of angiotensin II and CGP-42112A appear to be via activation of PP2A, and western blot analyses revealed no effects of either peptide on the protein levels of the catalytic subunit of PP2A in cultured neurons. In summary, these data suggest that PP2A is a cellular target modified following neuronal AT₂ receptor activation.     

Induction of the proto-oncogene c-jun by angiotensin II.

Angiotensin (Ang) II causes hypertrophy of rat aortic smooth muscle cells in culture and results in the rapid activation of c-fos. This study demonstrated that Ang II also activated c-jun and, in addition, could activate the AP-1 enhancer element. These data add support for a role of Ang II as an important mediator of vascular smooth muscle cell growth.     

Angiotensin II stimulation of 5'-adenylic acid deaminase.

Angiotensin II has been found to stimulate 5'-adenylic acid deaminase from rabbit skeletal muscle. Stimulation was discernible around 10(-9) M and peak stimulation of about threefold was seen at 10(-7) M, concentrations approximating those required for stimulation of vascular smooth muscle or adrenal glomerulosa cells. Higher concentrations produced less stimulation. Adenosine triphosphate stimulated to the same degree, but a concentration of 10(-5) M was required for maximum stimulation, while maximum stimulation with sodium or potassium required 0.5 M and 0.75 M, respectively. Although the physiologic significance of these observations has not been established, these data suggest an intracellular role for angiotensin II.