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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this article, we have discussed the localization of components of the renal renin-angiotensin system, as well as the existing information on the regulation of this axis and the effects of Ang II on renal function. All the components of the renin-angiotensin system are present in both fetal and adult kidney. In the adult kidney, renin is principally localized to jg cells of the distal afferent arteriole, where release is stimulated by increases in intracellular cAMP and inhibited by increases in cytosolic calcium. Four distinct stimuli mediating renin release are (1) NaCl sensed at the macula densa, (2) the sympathetic nervous system, (3) humoral factors, with Ang II, vasopressin, endothelin, and adenosine inhibiting renin release, and (4) changes in intrarenal blood pressure. Alterations in renal renin gene expression have been reported in pathophysiological states, such as salt depletion, diabetes mellitus, ureteral obstruction, Bartter's syndrome, and with high protein feeding. The highest renal concentrations of mRNA for the renin substrate angiotensinogen are found in the PT, where the protein is localized to subapical granules. Both salt depletion and androgens upregulate renal angiotensinogen mRNA. Of interest, renal angiotensinogen mRNA levels are lower in SHR than in normotensive WKY rats. As with angiotensinogen, renal ACE is mainly localized to the PT, with highest concentration on the brush border. The mechanisms of regulation of both renal angiotensinogen and ACE require further study. Using recently developed specific nonpeptide Ang II receptor antagonists, it appears that adult renal Ang II receptors are principally of the AT1 class, whereas fetal kidney Ang II receptors are of the AT2 subtype. By binding to AT1 receptors, Ang II exerts constrictive effects on both afferent and efferent arterioles, with increased effect reported on efferent arterioles. Glomerular Ang II receptors are localized to mesangial cells, mediating contractile responses resulting in changes in glomerular surface area and Kf, and potentially regulating mesangial sieving and phagocytosis. These receptors are reduced with salt restriction or in experimental diabetes. The highest concentrations of tubular Ang II receptors are found in PT, on both brush border and basolateral membranes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The intrarenal renin-angiotensin system. 843 83

We investigated whether the elevated NaCl intake shown by calcium-deprived rats is mediated by the renin-angiotensin-aldosterone system. First, we looked for manifestations of altered renin-angiotensin-aldosterone system activity during the progression of calcium deficiency. There were no differences between control and calcium-deprived rats in plasma aldosterone concentrations, plasma renin activity, plasma sodium concentrations, sodium balance, or blood pressure. Second, we used selective pharmacological antagonists to examine whether disruption of the renin-aldosterone-angiotensin system influenced salt intake. Blockade of aldosterone receptors with spironolactone (25 mg.kg-1 x day-1 sc for 7 days) had no effect on NaCl intake of control or calcium-deprived rats. Angiotensin AT1 receptor blockade with losartan potassium (0.5-10 mg/kg orally) had no effect on NaCl intake of control or calcium-deprived rats but doses > 0.5 mg/kg decreased NaCl intake of adrenalectomized rats. Taken together, these findings indicate that the renin-angiotensin-aldosterone system does not mediate the increased NaCl intake produced by calcium deficiency. The appetite for salt produced by calcium deficiency involves a different physiological substrate from most other models of NaCl intake.
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PMID:Independence of salt intake induced by calcium deprivation from the renin-angiotensin-aldosterone system. 845 2

1. Experiments were performed using the selective AT1 receptor antagonist, GR117289, and the selective AT2 receptor antagonist, PD123177, to assess the relative importance of AT1 versus AT2 receptors in mediating the renal effects of angiotensin II (AII) in vivo, in salt-replete pentobarbitone-anaesthetized dogs. 2. The AT1 receptor antagonist, GR117289 (0.5 mg kg-1 + 1 microgram kg-1 min-1, i.v.), caused renal vasodilatation, characterized by a mean increase of 21 +/- 5% in renal blood flow, 45 min post-dose. GR117289 also caused a fall in mean blood pressure (12 +/- 4%), but despite this, sodium and urine excretion were not reduced. Indeed, there was a tendency for urine output and sodium excretion to increase, although the changes were not statistically significant. GR117289 caused a reduction in plasma aldosterone levels (-35 +/- 16%) 45 min post-dose, despite increasing plasma renin activity (+ 173 +/- 42%). In contrast to GR117289, the AT2 receptor antagonist, PD123177 (20 micrograms kg-1 min-1 intra-renal artery; i.r.a.) caused no significant change in blood pressure, renal blood flow, or sodium and urine excretion, indicating that the renal effects of endogenous AII in these salt-replete animals are mediated predominantly by AT1 receptors. 3. Intra-renal artery infusion of AII (1-300 ng kg-1 min-1) caused dose-related renal vasoconstriction, and decreases in urine output, sodium excretion, fractional excretion of sodium, and glomerular filtration rate (GFR). The AT1 receptor antagonist, GRI 17289 (0.5 mg kg-1 + 1 microg kg-1 min-1, i.v.)antagonized these renal effects of AII, causing 15-38 fold rightward displacements of mean dose response curves for these parameters. In contrast, PD123177 (20 microg kg-1 min-1, i.r.a.) failed to antagonize the renal haemodynamic and excretory effects of lower doses of All (1-10 ng kg-1 min-1,i.r.a.). However, at higher doses of AII (30-300 ng kg-l min-1, i.r.a.), while PD123177 still failed to antagonize the effects of the peptide on urine output, sodium excretion and GFR, it did cause a small,but significant, degree of inhibition of All-induced renal vasoconstriction. In addition, at a higher dose(50 microg kg-1 min-1, i.r.a.), PD123177 caused a greater degree of antagonism of AII-induced renal vasoconstriction, while renal excretory responses to AII remained unaffected.4. This study shows that the renal haemodynamic and excretory effects of AII in salt-replete anaesthetized dogs are mainly mediated by angiotensin AT1 receptors. However, the inhibitory effect of PD123177 on renal vasoconstrictor responses to high doses of AII, raises the possibility that functionally important AT2 receptors are present in the canine renal vasculature.
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PMID:Role of angiotensin AT1 and AT2 receptors in mediating the renal effects of angiotensin II in the anaesthetized dog. 849 37

We have reported that overnight fasting stimulates bicarbonate reabsorption (JtCo2) in rat distal tubules. The present in vivo microperfusion studies evaluated the hypothesis that endogenous angiotensin II (AII) mediates this response. Rat late distal (LD) tubules were perfused at 8 nl/min in vivo with a hypotonic solution containing 28 mM bicarbonate. In overnight-fasted rats, LD JtCO2 was significantly higher than in normally fed rats (50 +/- 4 vs. 16 +/- 6 pmol/min.mm, P < 0.05). When overnight-fasted rats were salt-loaded, JtCO2 fell significantly (38 +/- 3 pmol/min.mm, P < 0.05). Conversely, in fed rats ingesting a zero-salt diet, JtCO2 increased three-fold (45 +/- 5 pmol/min.mm, P < 0.05). Enalaprilat infusion (0.25 micrograms/kg body wt, intravenously), in these zero-salt and overnight-fasted rats, reduced LD JtCO2 values to normal. Further, infusion of losartan (5 mg/kg body wt, intravenously), the specific AII AT1 receptor blocker, reduced JtCO2 in overnight-fasted rats by two-thirds (16 +/- 4 pmol/min.mm, P < 0.05). Finally, we perfused 10(-11) M AII intraluminally with and without 10(-6) M losartan: AII increased JtCO2 to 45 +/- 6 pmol/min.mm, equal to the zero-salt flux. This was completely abrogated by simultaneous losartan perfusion. Therefore, these results suggest that AII is an in vivo stimulator of late distal tubule bicarbonate reabsorption.
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PMID:Role of angiotensin II in dietary modulation of rat late distal tubule bicarbonate flux in vivo. 855 Aug 22

We performed studies to further elucidate the mechanisms of angiotensin II (Ang II)-induced angiogenesis of the microvasculature. Rats were placed on a high salt diet (4% NaCl), and Ang II was infused at a subpressor rate (5 ng/kg per minute) for 3 days. Blood pressure was measured daily for 2 control and 3 infusion days. Microvessel density in the cremaster muscle was measured at the end of the infusion. Vessel density in rats that received subpressor Ang II infusion increased by 12.6% compared with rats that received vehicle infusion. When the angiotensin type 2 (AT2) receptor antagonist PD 123319 was coinfused with Ang II, blood pressure was elevated and vessel density increased above that observed with Ang II infusion alone (23% increase). When the AT1 receptor antagonist losartan was coinfused with Ang II, blood pressure was lower than control and vessel density was reduced compared with the Ang II group but was still greater than control (7.8% increase). In this study, Ang II stimulated angiogenesis in the rat cremaster muscle; this effect was enhanced by AT2 antagonism and inhibited by AT1 antagonism. Ang II infusion at a subpressor dose resulted in a pressor response with AT2 antagonism and a depressor response with AT1 antagonism. This suggests that in the microvasculature, the AT1 receptor mediates angiogenesis and vasoconstriction, and the AT2 receptor mediates an inhibition of angiogenesis and vasodilation.
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PMID:Opposing actions of angiotensin II on microvascular growth and arterial blood pressure. 861 37

Two distinct types of cell-surface angiotensin II receptors (AT1 and AT2) have been defined pharmacologically and cDNAs encoding each type have been identified by expression cloning. These pharmacological studies showed the AT1 receptors to mediate all the known functions of angiotensin II in regulating salt and fluid homeostasis. Further complexity in the angiotensin II receptor system was revealed when homology cloning showed the existence of two AT1 subtypes in rodents and in situ hybridization and reverse transcription-polymerase chain reaction analyses showed their level of expression to be regulated differently in different tissues: AT1A is the principal receptor in the vessels, brain, kidney, lung, liver, adrenal gland and fetal pituitary, while AT1B predominates in the adult pituitary and is only expressed in specific regions of the adrenal gland (zona glomerulosa) and kidney (glomeruli). Expression of AT1A appears to be induced by angiotensin II in vascular smooth-muscle cells but is inhibited in the adrenal gland. Preliminary analysis of the AT1 promoters is also suggestive of a high degree of complexity in their regulation. Investigation of a potential role for altered AT1 receptor function has commenced at a genetic level in several diseases of the cardiovascular system. No mutations affecting the coding sequence have been identified in Conn adenoma and no linkage has been demonstrated with human hypertension by sib-pair analysis. None the less, certain polymorphisms that do not alter the protein structure have been found to be associated with hypertension and to occur at an increased frequency in conjunction with specific polymorphisms in the ACE gene in individuals at increased risk for myocardial infarction. Further characterization of the regions of the AT1 gene that regulate its expression are therefore needed. The physiological importance of the AT2 gene product still remains a matter of debate.
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PMID:Angiotensin II receptors: protein and gene structures, expression and potential pathological involvements. 864 Feb 85

In the past decade there have been considerable advances in basic knowledge of the renin-angiotensin system (RAS). The most important new development has been the appreciation of a tissue based RAS that can be independently regulated from the renal and vascular RAS. Greater insight into the mechanism by which angiotension-II (AII) exerts its action has been achieved through the study of molecular biology and pharmacological characterization of multiple receptor subtypes. This review summarises the features and distribution of several binding subtypes that may mediate the diverse functions of AII. Of these AT1 subtype is the most well known receptor which preferentially binds AII and AIII. The AT1 receptor site appears to mediate the classic angiotensin responses concerned with the body water balance and the maintenance of blood pressure. Less is known about the AT2 sites which also bind AII and AIII and may play a role in vascular growth. Recently, an AT3 has been discovered in cultured neuroblastoma cells and an AT4 site which preferentially binds AIV. It has been implicated in memory aquisition and retrieval and in the regulation of blood flow. Another important aspect covered is the primary and secondary messengers involved during the signal transduction after the binding of AII with receptors. A stress has also been given on the regulation of density and affinity of AII receptors by various physiological parametres as they affect the responses of RAS. Autoregulation by RAS, salt intake, development and aging and some of the hormones are important variables which could affect the AII receptors. Interactions of AII with various neuroeffector transmission involved in the regulation of water-electrolyte balance and BP regulation play an important role in the maintenance of the homeostasis. AII has been suggested to increase the NAergic transmission by enhancing synthesis, release, inhibiting reuptake by the presynaptic nerve terminals as well as enhancing cell responsiveness to the transmitter. The finding of existence of AII receptors in vagal afferent nerve terminals suggests that its baroreflex inhibitory effect is mediated by inhibiting neurotransmitter release at NTS in the baroreflex arc. Moreover, AII acts on the central receptors to stimulate AVP and ACTH secretion, drinking and peripherally increase synthesis and secretion of aldosterone. Interactions of RAS with kallikrein-kinin system and prostaglandins strongly support the existence of a balance between renal depressor and pressor substances. AII is now considered a growth promotor in cardiovascular tissues and the resultant vascular hypertrophy could contribute in the maintenance of hypertension. AII also plays a role in the kidney, not only as a regulator of hemodynamics but also in the structural changes occurring in a variety of renal disorders. In addition to the more well studied functions of RAS in RVH the review also highlights the potential contribution by the RAS to other clinically relevant syndromes such as aortoarterities induced RVH, hyperaldosteronism, heavy metal induced cardiovascular effects, diabetes mellitus and thyroid dysfunction. Although the receptor subtypes involved in these pathological states have not been definitely identified, research efforts in this direction are ongoing.
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PMID:Angiotensin II--receptor subtypes characterization and pathophysiological implications. 864 21

The renin-angiotensin system regulates normal cardiovascular homeostasis and is activated in certain forms of hypertension and in heart failure. Angiotensin II has multiple physiological effects and we have shown recently that its growth-promoting effects on vascular smooth muscle require autocrine activation of the IGF I receptor. To study the effect of angiotensin II on circulating IGF I, we infused rats with 500 ng/kg/min angiotensin II for up to 14 d. Angiotensin II markedly reduced plasma IGF I levels (56 and 41% decrease at 1 and 2 wk, respectively) and IGF binding protein-3 levels, and increased IGF binding protein-2 levels, a pattern suggestive of dietary restriction. Compared with sham, angiotensin II-infused hypertensive rats lost 18-26% of body weight by 1 wk, and pair-feeding experiments indicated that 74% of this loss was attributable to a reduction in food intake. The vasodilator hydralazine and the AT1 receptor antagonist losartan had comparable effects to reverse angiotensin II-induced hypertension, but only losartan blocked the changes in body weight and in circulating IGF I and its binding proteins produced by angiotensin II. Moreover, in Dahl rats that were hypertensive in response to a high-salt diet, none of these changes occurred. Thus, angiotensin II produces weight loss through a pressor-independent mechanism that includes a marked anorexigenic effect and an additional (likely metabolic) effect. These findings have profound implications for understanding the pathophysiology of conditions, such as congestive heart failure, in which the renin-angiotensin system is activated.
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PMID:Angiotensin II causes weight loss and decreases circulating insulin-like growth factor I in rats through a pressor-independent mechanism. 864 43

Systemic and/or locally produced angiotensin II stimulates salt and water reabsorption in the renal proximal tubule. In vivo, dopamine (DA) may serve as a counterregulatory hormone to angiotensin II's acute actions on the proximal tubule. We examined whether dopamine modulates AT1 receptor expression in cultured proximal tubule cells (RPTC) expressing DA1 receptors. Dopamine decreased basal RPTC AT1 receptor mRNA levels by 67 +/- 7% (n = 10; P < 0.005) and decreased 125I-angiotensin II binding by 41 +/- 7% (n = 4; P < 0.05). The DA1-specific agonist, SKF38393 decreased basal AT1 receptor mRNA levels (65 +/- 5% inhibition; n = 5; P < 0.025), and the DA1-specific antagonist, SCH23390 reversed dopamine's inhibition of AT1 receptor mRNA expression (24 +/- 10% inhibition; n = 8; NS) and angiotensin II binding (5 +/- 15%; n = 4; NS). DA2-specific antagonists were ineffective. In rats given L-DOPA in the drinking water for 5 d, there were decreases in both proximal tubule AT1 receptor mRNA expression (80 +/- 5%; n = 6; P < 0.005) and specific [125I] Ang II binding (control: 0.74 +/- 0.13 fmol/mg pro vs. 0.40 +/- 0.63 fmol/mg pro; n = 5; P < 0.05). In summary, dopamine, acting through DA1 receptors, decreased AT1 receptor expression in proximal tubule, an effect likely mediated by increased intracellular cAMP levels. Local dopamine production also led to decreased AT1 receptor expression, suggesting dopamine may reset sensitivity of the proximal tubule to angiotensin II.
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PMID:Dopamine decreases expression of type-1 angiotensin II receptors in renal proximal tubule. 867 85

To determine the effect of the angiotensin II AT1 receptor antagonist losartan (DuP753) on echocardiographic left ventricular (LV) anatomy in Dahl rats on high sodium diet, 27 Dahl salt-sensitive (Dahl-S, 13 on drug and 14 receiving tap water) and 27 Dahl salt-resistant rats (Dahl-R, 13 on drug and 14 receiving tap water) were studied by M-mode echocardiography during 8 weeks of 8% NaCl diet. At the endpoint (after 8 weeks or the last echocardiogram for animals who died earlier), Dahl-S receiving losartan had lower LV mass (1.6 +/- 0.4 g/kg 0.59) than Dahl-S receiving tap water (2.2 +/- 0.7 g/kg 0.59; P < .005), although blood pressure was only partially reduced (167 +/- 29 v 195 +/- 52; P = .05). This difference was mainly due to lower LV wall thickness (P < .02), with a less consistent decrease in LV chamber size in Dahl-S receiving losartan. Blood pressure was normal in Dahl-R (tap water group = 116 +/- 11 mm Hg; losartan group = 115 +/- 13 mm Hg) and losartan had no effect on LV mass (1.6 +/- 0.4 g/kg 0.59) in both groups). In the majority of rats, echocardiographic measurements were compared between the end of second or third week and the last available study: LV mass increased in salt-loaded Dahl-S receiving tap water (1.6+/- 0.6 to 2.1 +/- 0.7 g/kg 0.59, P < .04) and was stable in Dahl-S receiving losartan (1.5 +/- 0.1 to 1.5 +/- 0.3 g/kg 0.59), paralleling changes in LV chamber dimension. Thus, a high salt diet leads to hypertension and eccentric LV hypertrophy in Dahl-S but not in Dahl-R. Inhibition of angiotensin II AT1 receptors reduces the development of LV hypertrophy in Dahl-S rats despite lack of efficient control of blood pressure.
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PMID:Reduction of development of left ventricular hypertrophy in salt-loaded Dahl salt-sensitive rats by angiotensin II receptor inhibition. 869 19


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