Increase In Angiotensin II Research Articles

Interactions between angiotensin II and the sympathetic nervous system in the the long-term control of arterial pressure.

1. The role of the renin-angiotensin system in long-term control of sympathetic activity and arterial pressure is reviewed. 2. There is evidence that favours a necessary role for the sympathetic nervous system in long-term arterial pressure regulation. First, appropriate changes in sympathetic activity appear to be produced in response to chronic changes in blood volume or blood pressure. Second, prevention of the normal homeostatic decrease in sympathetic activity in response to an increase in sodium intake produces hypertension. 3. Long-term changes in sympathetic activity cannot be mediated by the baroreceptor reflex, because it adapts to sustained changes in pressure. Therefore, an hypothesis is presented that evokes a key role for angiotensin II (AngII) in determining the chronic level of sympathetic activity. The key feature of this model is that the role of AngII is non-adaptive: chronic changes in extracellular fluid volume produce sustained reciprocal changes in AngII, and long-term increases in AngII produce sustained increases in sympathetic activity. 4. Evidence is reviewed that suggests that a lack of the normal suppression in AngII and/or sympathetic activity in response to an increase in sodium intake produces salt-sensitive hypertension.

Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure

Endogenous 17β-estradiol (E2) and low parenteral doses of exogenous E2 are vasodilators. High dose estrogens, especially ethinylestradiol (EE) and mestranol, stimulate the synthesis of hepatic proteins including coagulation factors, sex hormone binding globulin, and angiotensinogen (Aogen). In the steady state, high plasma levels of Aogen produce only a very small increase of angiotensin II (AII) and plasma renin activity, because AII inhibits the secretion of renin and lowers plasma renin concentration. However, the increase in AII is sufficient for a slight reduction in renal blood flow and a slight increase in exchangeable sodium and blood pressure; in susceptible women, blood pressure may rise considerably. Effects of estrogens on the brain may also be involved in blood pressure changes. Endogenous progesterone is a mineralocorticoid receptor antagonist. Endogenous or exogenous progesterone leads to sodium loss and a compensatory increase in renin secretion, plasma renin activity, AII, and plasma aldosterone, e.g. in the second half of the menstrual cycle. Synthetic progestogens are commonly devoid of the mineralocorticoid receptor antagonistic effect of progesterone, and some are weak estrogen receptor agonists. Combined use of EE and synthetic progestogens may therefore enhance estrogen effects on body sodium and blood pressure. A new progestogen (Drospirenone) with an antimineralocorticoid effect like that of progesterone is described that slightly lowers body weight and blood pressure in a contraceptive formulation together with EE. An almost ideal oral contraceptive would be a progestogen like Drospirenone together with a low dose natural estrogen that does not stimulate Aogen synthesis. Since most oral formulations for postmenopausal estrogen replacement also stimulate hepatic protein synthesis (including Aogen) to some extent, the transdermal route of E2 application for contraceptive purposes should also be investigated, since it has a reduced potential for undesirable side effects.

Pressor doses of angiotensin II increase hepatic glucose output and decrease insulin sensitivity in rats

The metabolic effects of angiotensin II (AII) were studied under steady-state conditions of euglycaemic hyperinsulinaemia in anaesthetized rats. Pressor doses of AII (50 and 400 ng/kg per min) had dose-dependent hypertensive and hyperglycaemic effects during glucose clamp studies. Glucose turnover measurements showed that hepatic glucose output (HGO) increased equally at both pressor doses compared with either saline infusion or AII infusion at a dose without a pressor effect (20 ng/kg per min); however, glucose disposal increased significantly only at 50 ng/kg per min. Infusion of the AII receptor antagonist, saralasin, did not itself alter glucose output or disposal significantly, but it abolished the effects of a simultaneous infusion of AII. It is concluded that pressor doses of AII increase HGO by a receptor-mediated mechanism that is not related to the pressor response to the hormone. The hyperglycaemic reaction to this metabolic effect of AII is partially offset by increased glucose disposal at lower doses. The physiological significance of these metabolic actions of AII remains to be established, but they raise the possibility that AII could potentially play a role in glucose homeostasis in vivo.

Reactive Oxygen Intermediates Mediate Angiotensin II-induced c-Jun•c-Fos Heterodimer DNA Binding Activity and Proliferative Hypertrophic Responses in Myogenic Cells

Angiotensin II (Ang-II) receptor engagement activates many immediate early response genes in both vascular smooth muscle cells and cardiomyocytes whether a hyperplastic or hypertrophic response is taking place. Although the signaling pathways stimulated by Ang-II in different cell lines have been widely characterized, the correlation between the generation of different second messengers and specific physiological responses remains relatively unexplored. In this study, we report how in both C2C12 quiescent myoblasts and differentiated myotubes Ang-II significantly stimulates AP1-driven transcription and c-Jun.c-Fos heterodimer DNA binding activity. Using a set of different protein kinase inhibitors, we could demonstrate that Ang-II-induced increase in AP1 binding is not mediated by the cAMP-dependent pathway and that both protein kinase C and tyrosine kinases are involved. The observation that in quiescent myoblasts Ang-II increase of AP1 binding and induction of DNA synthesis and, in differentiated myotubes, Ang-II stimulation of protein synthesis are abolished by the cysteine-derivative and glutathione precursor N-acetyl-L-cysteine strongly suggests a role for reactive oxygen intermediates in the intracellular transduction of Ang-II signals for immediate early gene induction, cell proliferation, and hypertrophic responses.

Angiotensin II (AII)-induced myocyte necrosis: role of the AII receptor.

Pathophysiologic levels of angiotensin II (AII) produce myocyte necrosis. We investigated whether the cardiotoxic effects of AII are mediated through the AII type I receptor (AT1). Seven groups (4-6 rats/group) were given AII (150 ng/min) alone or in combination with the AT1 antagonist losartan (7.5 mg/day). Groups were as follows: A1, A4, and L1 received AII for 2 days; A2 and L2 received AII for 9 days; and A3 and L3 received AII for 2 days and again for 2 days 5 days later. Groups L1, L2, and L3 also received losartan 2 days before and throughout the AII infusion period. All rats except those in group A4 were killed at the end of their respective infusion periods (group A4 rats were killed 7 days after infusion). Group A1 had multifocal areas of recent myocyte injury. Groups A2 and A4 had multifocal scars and only a few new areas of myocyte damage. Group A3, in addition to scar formation, had de novo areas of necrosis. There was no evidence of myocyte necrosis in groups L1, L2, and L3. Thus, AII-related myocyte necrosis is receptor mediated. Moreover, a chronic increase in AII appears to cause cardioprotective downregulation of the AT1 receptor.

A pharmacodynamic study of SR 47436, a selective AT1 receptor antagonist, on blood pressure in conscious cynomolgus monkeys.

1. Conscious normotensive cynomolgus monkeys were chronically instrumented for the measurement of arterial blood pressure and heart rate to investigate the relationships between the plasma concentration, suppression of the pressor response to angiotensin II (AII), compensatory increase in plasma AII, and hypotensive effect obtained after a single oral dose of SR 47436, a potent and specific nonpeptide AT1 receptor antagonist. As blood sampling could influence the hypotensive effect of SR 47436 through activation of the renin angiotensin system (RAS), drug effects were studied in groups of animals with or without blood samplings. 2. SR 47436 at 10 mg kg-1 induced a hypotensive effect which was not greater following a second dose of 30 mg kg-1, indicating that a maximal hypotensive effect had already been obtained. 3. A single oral dose of SR 47436 (10 mg kg-1) caused a sustained hypotension and a marked inhibition of the AII-induced pressor response, lasting for up to 28 h. These effects of SR 47436 are consistent with good oral bioavailability and a slow elimination of the drug (t 1/2 approximately 20 h), and were accompanied by a sustained increase in plasma AII concentration. Taken together, both the hypotensive response and the compensatory increase in AII indicated that vascular and juxtaglomerular AII receptors were blocked. 4. Although a fair correlation between individual plasma drug concentrations and inhibition of AII-induced pressor response was observed, neither the hypotensive effect nor the compensatory increase in AII correlated with the plasma drug levels. 5. Basal arterial pressure and AII-induced pressor response were not affected by blood samplings. 6. These results suggest that SR 47436 is an effective and long lasting AT1 receptor antagonist with a potent hypotensive action in normotensive cynomolgus monkeys. It may be an efficacious blocker of the RAS in man and suitable for once-a-day dosing.

血管損傷修復とマスト細胞キマーゼ

This study has analyzed the pathogenetic mechanism of the intimal thickening after baloon injury, which is currently a serious problem on the balloon angioplasty for coronary arteriosclerosis, from the aspect of wound-healing inflammation. The locally generated angiotensin II (AII), which is known for its aggravating effect on vascular hypertrophy, has been implicated to participate in the pathogenic mechanism. One month after the balloon injury, dog arteries showed myointimal hyperplasia as well as the increases in AII and AII-generating enzymes, angiotensin-converting enzyme and mast cell chymase, with the latter enzyme increasing more markedly. In the adventitia of lesioned vessels, the density of mast cells and fibrolasts was increased with apparent fibrosis and angiogenesis. These pathohistological findings suggest that the adventitial fibrosis reflects an excessive woundhealing response to the injury, and that the mast cell-fibroblast cross-talk may couple the adventitial fibrosis with the intimal hyperplasia. In this hyperplastic lesion, mast cell chymase seems to play a pivotal role by generating AII, and also by chymase's proinflammatory actions which are not yet fully defined. Thus, it is reasonable to regard the intimal thickening as a manifestation of exaggerated wound-healing response to an injury.

Angiotensin II stimulates respiration in awake dogs and antagonizes baroreceptor inhibition

The effects of intravenous infusions of physiologic doses of angiotensin II (AII) on expired ventilation (V̇ E) and acid-base balance were examined in awake dogs. A control infusion of saline was followed by AII infusion, initially with mean arterial pressure (MAP) raised 15%, and then with MAP at control levels of concurrent infusion of sodium nitroprusside (SNP). To control for SNP, the protocol was repeated using arginine vasopressin (AVP). Ventilatory responses of CO 2 (VRC) were measured at the end of these protocols and separately with MAP elevated during infusion of AII. With AVP, increased MAP inhibitedV̇ E, heart rate (HR) and metabolism. However, with MAP elevated during AII infusion, stimulation by AII opposed baroreceptor reflexes and these variables, as well as plasma AVP, did not change. When MAP was lowered to control during AII infusion all variables increased. With AII, Pa CO 2 followedV̇ E changes, decreasing 3 Torr with MAP at control levels; however, [H +] remained constant due to a decrease in arterial strong ion difference. The stimulatory effects of AII were not due to SNP; SNP did not stimulateV̇ E during AVP infusion. The slope of the VRC was unaltered by AII infusion or MAP; however, AVP reduced the VRC slope. Physiological increases in AII stimulateV̇ E and other systems at normal MAP and maintain several regulatory systems at control levels during baroreceptor inhibition.

Increases in cellular sodium concentration by arginine vasopressin and endothelin in cultured rat glomerular mesangial cells

The present study was undertaken to determine whether arginine vasopressin (AVP), angiotensin-II, and endothelin (ET) increase the cellular sodium concentration ([Na+]i) in cultured rat glomerular mesangial cells. [Na+]i was measured using the fluorescence indicator dye sodium-binding benzofuran isophthalate. These three vasoconstrictor hormones increased cellular free calcium ([Ca2+]i) and [Na+]i in a dose-dependent manner ([Na+]i: basal, 11.5; 10(-7) M AVP, 20.5; 10(-7) M angiotensin-II, 13.8; and 10(-7) M ET, 21.2 mM). The mobilization of [Ca2+]i was faster than that of [Na+]i. The AVP-induced increase in [Na+]i was completely blunted by the potent V1 antagonist d(CH2)5Tyr(Me)AVP. Vasoconstrictor hormones produced a biphasic cellular pH (pHi) change, characterized by a transient acidification, followed by a sustained alkalinization. The Ca(2+)-free condition markedly reduced AVP- and ET-induced increases in [Ca2+]i and [Na+]i and biphasic changes in pHi. In the Na(+)-free state, the hormonally mobilized [Ca2+]i was significantly enhanced. Basal [Na+]i decreased to below 3 mM, and there was little increase in [Na+]i after the addition of vasoconstrictor hormones, suggesting that the source of [Na+]i is extracellular space. Only early acidification was obtained in the absence of a sustained alkalinization. The [Na+]i mobilization was closely related to the biphasic change in pHi. These results indicate that AVP, ET, and angiotensin-II increase [Na+]i in glomerular mesangial cells, and that the early mobilization of [Na+]i depends on Na+/Ca2+ exchange, and the sustained phase depends on Na+/H+ exchange. The hormonally mobilized [Ca2+]i is essential for the activation of Na+/H+ exchange, and an increase in [Na+]i is suggested to play an important role in cellular alkalinization.