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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renin-angiotensin (RA) system plays an important role in cardiovascular homeostasis. Here, we have described the recent progress in our study of renin release as well as the cellular action of angiotensin II. (1) Microdissection of an isolated afferent artery with or without macula densa (MD) has revealed that renin release is regulated by NaCl exposure to MD. Furosemide, prostaglandins (PGE2 and PGI2) and adenosine modulate its function. (2) Angiotensin (ang) II increases cytosolic free calcium and induces the formation of inositolphosphates in vascular smooth muscle cells. Deduced protein structure of ang II receptor (AT1-R) cDNA has indicated the presumed link of AT1-R with phospholipase C. Through the cellular action, ang II has been reported to regulate gene expression.
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PMID:[Mechanism of renin release and cellular action of angiotensin II]. 129 35

Angiotensin II (AII) can release arachidonic acid metabolites such as prostacyclin (PGI2) and PGE2 from cells in cultures. It has recently been reported that the AT1 selective nonpeptide AII receptor antagonist losartan had similar effects. The present study was undertaken to further evaluate the effects of AII and losartan on cells which synthesize prostaglandins, including vascular smooth muscle, endothelial, and glial cells. Inhibition of specific [125I]AII binding was demonstrated in porcine smooth muscle cell (PSMC) suspensions with unlabeled AII and losartan. The IC50 values were 1.3 x 10(-9) mol/L and 7.7 x 10(-9) mol/L, respectively. PD123177 (an AT2 selective antagonist) had no effect on binding. AII produced a concentration-related increase in calcium mobilization (fura-2 fluorescence) which was blocked by losartan (IC50 = 8.4 x 10(-8) mol/L) but not by PD123177 (10(-6) mol/L). AII (10(-7) to 10(-5) mol/L) stimulated the basal release of PGI2 by 100%. This response was blocked by losartan (10(-6) to 10(-5) mol/L) but not by PD123177 (10(-6) to 10(-5) mol/L) and neither agent stimulated basal release in PSMC. Similar effects of AII and antagonists were observed upon receptor binding and PGE2 release in primary rat astrocyte (RA) cultures. AII did not release PGI2 from porcine endothelial cells, bovine pulmonary arterial endothelial cells, or rat C6 glioma cells. Losartan had no significant effect at 10(-5) mol/L. By contrast, bradykinin or the calcium ionophore A23187 dramatically increased PGI2 release in each of these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:AT1 receptors mediate the release of prostaglandins in porcine smooth muscle cells and rat astrocytes. 141 54

This study was designed to identify the subtypes of angiotensin II (ANG II) receptors present on glomeruli and glomerular mesangial cells and establish their functional significance. Dup 753 and its metabolite EXP 3174, two nonpeptide ANG II-1 receptor (AT1) antagonists, displaced 125I-ANG II and its analogue 125I-[Sar1,Ala8]ANG II from their binding sites in rat and human glomeruli and cultured human mesangial cells, whereas CGP 42112 A and PD 123177, two ANG II-2 receptor (AT2) antagonists, exhibited little displacing activity. Dup 753 and EXP 3174 did not modify the dissociation constant (Kd) value but markedly decreased the number of sites of 125I-[Sar1,Ala8]ANG II binding. The addition of PD 123177 did not further inhibit binding when all AT1 sites were occupied by Dup 753. Binding was markedly reduced by dithiothreitol. EXP 3174 and Dup 753 inhibited the main biological functions of ANG II in mesangial cells including increases in intracellular calcium concentration, PGE2 production, and protein synthesis. PD 123177 was also active but at concentrations 1,000- to 10,000-fold greater than those of AT1 antagonists. These results indicate that 1) only AT1 receptors are present in glomeruli and glomerular mesangial cells; 2) these receptors mediate the functional responses to ANG II; 3) the nonpeptide AT1 antagonists behave as noncompetitive inhibitors; and 4) high concentrations of the nonpeptide AT2 antagonists can recognize AT1 sites.
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PMID:Characterization of angiotensin II receptor subtypes in human glomeruli and mesangial cells. 155 60

In hypertensive heart disease, after myocardial infarction or in congestive heart failure, myocardial fibrosis presenting as a diffuse perivascular and interstitial accumulation of fibrillar collagens within the normal connective tissue structures of the myocardium is associated with an activated renin-angiotensin system (RAS). This reactive fibrosis occurs in the overloaded left ventricle and the nonoverloaded right ventricle irrespective of myocyte necrosis or the development of myocyte hypertrophy. Therefore, it appears that hemodynamic factors or the load of the ventricle are not primarily responsible for the adverse fibrous tissue response in the myocardium, and humoral factors may play a key role in regulating the myocardial collagen matrix. The neurohumoral response in hypertensive heart disease, after myocardial infarction with overall deterioration of left ventricular function or congestive heart failure leads to an activation of either the cardiac or the circulating RAS, which closely interacts with the bradykinin-prostaglandin system. To ascertain whether the RAS modulates collagen fibroblasts that express mRNAs for types I and III collagens (the major fibrillar collagens in the heart) and matrix metalloproteinase 1 (MMP1; the key enzyme for collagen degradation), collagen synthesis was measured by [3H]proline incorporation normalized to total protein synthesis and MMP1 activity was determined by degradation of [14C]collagen in cultured fibroblasts after 24-hour incubation with various concentrations of angiotensin II or PGE2 (10(-11)-10(-3) M) under serum-free conditions. In addition, effects of angiotensin II were evaluated in the presence or absence of either type 1 (ICI D8731) or type 2 (PD 123177) angiotensin II (AT1 or PGE2 (10(-11)-10(-3) M) under serum-free conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of angiotensin II and prostaglandin E2 in regulating cardiac fibroblast collagen turnover. 749 21

The objective of this study was to evaluate the mechanisms of the renin secretion response to the angiotensin II (AII) receptor type 1 (AT1) antagonist losartan (DuP 753) in anesthetized rabbits. All receptor blockade with losartan (4 mg/kg bolus and 2 mg/kg/hr i.v.) decreased blood pressure (BP) and increased plasma renin activity (PRA) and heart rate (HR) significantly, whereas the beta-1 adrenoceptor antagonist atenolol (0.02 mg/kg/min i.v.) caused significant reductions in these parameters. Atenolol blocked HR and PRA responses but not the effect of losartan on BP. Cyclooxygenase inhibition with indomethacin (5 mg/kg bolus and 40 micrograms/kg/min i.v.) did not result in significant effects, and the coadministration of indomethacin and losartan resulted in a greater PRA effect than with losartan alone. These results preclude the involvement of prostaglandins, such as PGE2 and PGI2, in the renin response to losartan. The PRA response to atenolol alone suggests that renin release in anesthetized rabbits is under tonic control by beta adrenergic receptors. Furthermore, the discrepancy in the PRA responses to equipotent hypotensive doses of hydralazine and losartan indicates that beta adrenoceptor activation in the kidney, probably the result of blockade of AII-mediated inhibition of renin secretion, contributes to the renin-releasing effect of the AT1 receptor antagonist losartan.
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PMID:Beta adrenoceptor blockade in rabbit inhibits the renin-releasing effect of AT1 receptor antagonist losartan. 790 89

We determined the role of AT1 and AT2 angiotensin receptors as mediators of prostaglandin (PG) release and mobilization of intracellular Ca++ in cultures of porcine vascular smooth muscle cells (VSMC) with subtype-selective angiotensin (Ang) II receptor antagonists. The binding of [125I]Ang II to porcine VSMC showed an equilibrium constant (KD) of 0.52 nM and a binding capacity (Bmax) of 14.8 fmol/mg protein. Using the AT1 antagonists DuP 753, its metabolite EXP 3174, and L-158,809, [125I]Ang II binding was displaced in a clearly biphasic manner, indicating the presence of two binding sites. Consistent with this, the AT2 antagonist CGP 42112A also displayed a biphasic curve, whereas another AT2 antagonist, PD 123177, showed a 20% reduction in binding. Ang I, Ang II and Ang-(1-7) stimulated PGE2 as well as PGI2 synthesis in a dose-dependent pattern. Ang II but not Ang I or Ang-(1-7) also caused an increase in the intracellular concentration of Ca++. Ca++ mobilization by Ang II was blocked by the AT1 antagonist DuP 753, but not by the AT2 antagonists. Ang II- and Ang I-stimulated (10 nM) PG production was attenuated by all three AT1 antagonists. However, both CGP 42112A (100 nM) and PD 123177 (100 nM) also attenuated PG release in response to Ang II. The enhancement in PG release by Ang I (10 nM) was significantly reduced by CGP 42112A (100 nM), but not by PD 123177 (1 microM). Of the AT1 antagonists, only high doses of DuP 753 or L-158,809 partially reduced the Ang-(1-7)-induced release of PG. CGP 42112A was ineffective for blocking Ang-(1-7)-stimulated PG release. Ang-(1-7)-stimulated PGE2 and PGI2 production was significantly reduced by PD 123177. Unlike DuP 753 or L-158,809, but similar to the sarcosine antagonists, EXP 3174 (10 nM) abolished the angiotensin peptide-induced PG production. These data show that Ang I and Ang II stimulate PGE2 and PGI2 release via activation of both AT1 and AT2 receptors in porcine VSMC. Ang II stimulates intracellular Ca++ mobilization via activation of AT1 receptors only. Because Ang-(1-7) enhanced PGE2 and PGI2 release via activation of angiotensin receptors having greater affinity for PD 123177 than CGP 42112A, although CGP 42112A showed a greater ability to block the Ang I response, these data further suggest differences in these two compounds at AT2 receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Differential regulation of prostaglandin synthesis by angiotensin peptides in porcine aortic smooth muscle cells: subtypes of angiotensin receptors involved. 849 14

The adequate biological function of the renin-angiotensin system in blood pressure regulation and volume control involves additional factors for a fully balanced response. This includes arachidonic acid-derived lipid mediators, the eicosanoids. Angiotensin II (Ang II) causes (AT1)-receptor mediated stimulation of phospholipase C, resulting in generation of IP3 (inositol triphosphate) and activation of protein kinase C, elevated cytosolic Ca+ and stimulation phospholipase A2. These processes culminate in the generation of cell-specific eicosanoids and their autocrine action on the generating cell or paracrine effects on cells in the vicinity. In vascular tissue, liberated arachidonic acid is mainly converted into vasodilator prostaglandins, i.e. prostacyclin (PGI2) and PGE2. These prostaglandins may attenuate any direct Ang II-induced vasoconstriction, lower systemic vascular resistance and stimulate renal sodium excretion. In some vessels, arachidonic acid released by Ang II may also be converted to vasoconstrictor eicosanoids, i.e. thromboxane A2, PGF2 alpha and 12-HETE. The biological significance of endogenous eicosanoid generation becomes evident if vasoactive eicosanoids become limiting factors for maintaining homoiostasis, i.e. in the fetal circulation, Bartter's syndrome and congestive heart failure where vasodilating eicosanoids (PGE2, PGI2) are involved in maintenance of low vascular resistance and reduced or absent vasoconstriction by Ang II. Vasoconstrictor eicosanoids (thromboxane A2, PGF2 alpha, 12-HETE) contribute to high blood pressure in (renovascular) hypertension and pregnancy-induced hypertension. Alternatively, generation of vasodilator prostaglandins may be reduced in these situations. The vascular renin-angiotensin system is subject to the action of a number of drugs and chemicals, most notably specific inhibitors of the angiotensin-converging enzyme and drugs affecting kidney function (furosemide) and/or vessel tone (propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin-mediated actions of the renin-angiotensin system. 849 70

In the present study we investigated the role of angiotensin II (Ang II) receptor subtypes in gonadotropin-induced ovulation, oocyte maturation, and ovarian steroidogenesis and prostaglandin (PG) production in in vitro-perfused rabbit ovaries. The addition to the perfusate of PD123319, a nonpeptide Ang II antagonist with a high affinity for AT2 receptors, inhibited hCG-induced ovulation in a dose-dependent manner, whereas CV-11974, a nonpeptide AT1 receptor antagonist, had no effect. The majority of ovulated ova and follicular oocytes resumed meiotic maturation in response to hCG; and PD123319, but not CV-11974, significantly inhibited hCG-induced oocyte maturation. The addition of both Ang II receptor antagonists to the perfusate had no significant effect on the concentration of progesterone in the perfusate of hCG-treated ovaries, whereas PD123319 inhibited the hCG-stimulated production of estradiol. The production of PGE2 and PGF2 alpha was significantly increased at 6 h in hCG-treated ovaries compared with ovaries before hCG administration. PD123319 inhibited the hCG-stimulated production of PGs by perfused rabbit ovaries in a dose-dependent manner, indicating that hCG-induced PG synthesis is mediated, at least in part, via the activation of AT2 receptors. Ovulatory efficiency in ovaries perfused with or without PD123319 in the presence of hCG was significantly correlated with PG production by perfused rabbit ovaries 12 h after exposure to hCG (r = 0.6553 for PGE2, p < 0.001; r = 0.4758 for PGF2 alpha, p < 0.05). In conclusion, Ang II exerts complex and coordinated control on at least two distinct aspects in the normal ovulatory process, ovulation and oocyte maturation. Ang II produced locally by gonadotropin exposure may be a part of a novel intraovarian paracrine or autocrine control mechanism that operates via the AT2 receptor in the ovary.
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PMID:Involvement of angiotensin II in the process of gonadotropin-induced ovulation in rabbits. 890 7

The angiotensin AT1 receptor mediates renal prostaglandin (PG) E2 production through stimulation of phospholipase A2. Blockade of the AT2 receptor potentiates the angiotensin II-induced increase in PGE2 levels. In the kidney, PGE2 is converted to PGF2 alpha mainly by the enzyme PGE 9-ketoreductase. We hypothesized that the conversion of PGE2 to PGF2 alpha is inhibited by AT2 receptor blockade, resulting in the observed increase in PGE2 levels. Using a microdialysis technique, we monitored changes in renal interstitial fluid PGE2 and PGF2 alpha in response to 5 days of sodium depletion alone or a combination of sodium depletion and intravenous infusion of the AT1 receptor blocker losartan or the AT2 receptor blocker PD-123319 in conscious rats. We utilized the PGF2 alpha-to-PGE2 ratio as an indirect measure of the rate of renal PGF2 alpha formation. Sodium depletion increased PGE2, PGF2 alpha, and the PGF2 alpha-to-PGE2 ratio. During sodium depletion, losartan decreased PGE2 and PGF2 alpha and did not change the PGF2 alpha-to-PGE2 ratio. In contrast, PD-123319 increased PGE2, decreased PGF2 alpha, and decreased the PGF2 alpha-to-PGE2 ratio. These data demonstrate that activation of the renin-angiotensin system during sodium depletion physiologically increases renal conversion of PGE2 to PGF2 alpha. The increase in renal production of PGF2 alpha is mediated through stimulation of the angiotensin AT2 receptor.
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PMID:The subtype 2 angiotensin receptor regulates renal prostaglandin F2 alpha formation in conscious rats. 932 92

In chronic hypercalcemia, inhibition of thick ascending limb sodium chloride reabsorption is mediated by elevated intrarenal PGE2. The mechanisms and source of elevated PGE2 in hypercalcemia are not known. We determined the effect of hypercalcemia on intrarenal expression of cytosolic phospholipase A2 (cPLA2), prostaglandin H synthase-1 (PGHS-1), and prostaglandin H synthase-2 (PGHS-2), enzymes important in prostaglandin production. In rats fed dihydrotachysterol to induce hypercalcemia, Western blot analysis revealed significant upregulation of both cPLA2 and PGHS-2 in the kidney cortex and the inner and outer medulla. Immunofluorescence localized intrarenal cPLA2 and PGHS-2 to interstitial cells of the inner and outer medulla, and to macula densa and cortical thick ascending limbs in both control and hypercalcemic rats. Hypercalcemia had no effect on intrarenal expression of PGHS-1. To determine if AT1 angiotensin II receptor activation was involved in the stimulation of cPLA2 and PGHS-2 in hypercalcemia, we treated rats with the AT1 receptor antagonist, losartan. Losartan abolished the polydipsia associated with hypercalcemia, prevented the increase in cPLA2 protein in all regions of the kidney, and diminished PGHS-2 expression in the inner medulla. In addition, losartan completely prevented the increase in urinary PGE2 excretion in hypercalcemic rats. Intrarenal levels of angiotensin II were unchanged in hypercalcemia. These data indicate that hypercalcemia stimulates intrarenal cPLA2 and PGHS-2 protein expression. Our results further support a role for angiotensin II, acting on AT1 receptors, in mediating this stimulation.
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PMID:Hypercalcemia stimulates expression of intrarenal phospholipase A2 and prostaglandin H synthase-2 in rats. Role of angiotensin II AT1 receptors. 932 57


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