Showing papers on "Angiotensin II published in 1984"
TL;DR: Preliminary data suggest that inhibition of the sympathetic nervous system may be helpful, and inhibition of vasopressin in animals with heart failure is being studied, and data indicate that selective blockade of the renin-angiotensin system is useful.
Abstract: The incidence of congestive heart failure is increasing in the United States. This common syndrome is characterized not only by impaired ventricular function but also by an increase in some endogenous vasoconstrictor substances, including norepinephrine, angiotensin II, and arginine vasopressin. Although activation of the systems that release these substances is presumed to be compensatory (to maintain perfusion pressure during inadequate flow), the sympathetic nervous system, renin-angiotensin-aldosterone system, and arginine vasopressin may contribute to the pathogenesis of the syndrome. The excessive vasoconstriction present in heart failure likely produces a further burden on the failing myocardium. New strategies in therapy are being developed to counteract the activation of vasoconstrictor forces in congestive heart failure. Data indicate that selective blockade of the renin-angiotensin system is useful. Preliminary data suggest that inhibition of the sympathetic nervous system may be helpful, and inhibition of vasopressin in animals with heart failure is being studied. New and more selective therapy for heart failure may come from these studies.
592 citations
TL;DR: Data suggest that atrial natriuretic factor affects sodium excretion by the kidneys both directly and through the inhibition of aldosterone production.
Abstract: Crude extracts of rat atria reduced the basal amount of aldosterone released from rat zona glomerulosa cells and partially inhibited aldosterone stimulation by adrenocorticotropic hormone and angiotensin II. The destruction of this activity by trypsin suggests that the active factor is a peptide, possibly atrial natriuretic factor. These data suggest that atrial natriuretic factor affects sodium excretion by the kidneys both directly and through the inhibition of aldosterone production.
437 citations
TL;DR: Captopril seemed to be of considerable value in the long term treatment of severe cardiac failure in a double blind trial.
Abstract: The effect of the converting enzyme inhibitor captopril as long term treatment was investigated in 14 patients with severe congestive heart failure in a double blind trial. Captopril reduced plasma concentrations of angiotensin II and noradrenaline, with a converse increase in active renin concentration. Effective renal plasma flow increased and renal vascular resistance fell; glomerular filtration rate did not change. Serum urea and creatinine concentrations rose. Both serum and total body potassium contents increased; there were no long term changes in serum concentration or total body content of sodium. Exercise tolerance was appreciably improved, and dyspnoea and fatigue lessened. Left ventricular end systolic and end diastolic dimensions were reduced. There was an appreciable reduction in complex ventricular ectopic rhythms. Adverse effects were few: weight gain and fluid retention were evident in five patients when captopril was introduced and two patients initially experienced mild postural dizziness; rashes in two patients did not recur when the drug was reintroduced at a lower dose; there was a significant reduction in white cell count overall, but the lowest individual white cell count was 4000 X 10(6)/l. Captopril thus seemed to be of considerable value in the long term treatment of severe cardiac failure.
376 citations
TL;DR: It is concluded that AII in physiologic doses directly stimulates Jv in proximal convoluted tubules and this effect is probably receptor mediated and, within the limits of detection, electroneutral.
Abstract: Numerous previous studies have proposed a role for angiotensin II (AII) in the renal regulation of salt balance. At least one nephron site, the proximal convoluted segment, has been implicated in this role. We used in vitro microperfusion of rabbit proximal convoluted tubules to further examine this question. To insure use of appropriate in vivo concentrations as well as potency of the hormone in vitro, we measured plasma AII levels by radioimmunoassay in normal, sodium-depleted, and adrenalectomized rabbits, and measured AII activity by bioassay after incubation in various microperfusion baths. Plasma levels ranged from approximately 2 X 10(-11) to 5 X 10(-11) M. AII activity was stable in Ringer's solution plus albumin, but not in rabbit serum or Ringer's solution plus fetal calf serum. In Ringer's solution plus albumin, physiologic concentrations of AII stimulated volume reabsorption (Jv). 10(-11) M AII increased Jv by 16% (P less than 0.01). 10(-10) M AII produced a lesser increase, 7.5% (P less than 0.05). At a frequently studied, but probably pharmacologic dose, 10(-7) M AII inhibited Jv by 24% (P less than 0.001). AII at 10(-11) M did not stimulate Jv in the presence of 10(-7) M saralasin. Though previous studies have suggested agonistic effects of saralasin alone in epithelia, we found no significant effect of 10(-7) M saralasin on Jv. None of the AII doses measurably changed transepithelial voltage. We conclude that AII in physiologic doses directly stimulates Jv in proximal convoluted tubules and this effect is probably receptor mediated and, within the limits of detection, electroneutral.
322 citations
TL;DR: It was shown that AII induces the rapid hydrolysis of phosphatidylinositol 4-phosphate and -4,5-bisph phosphate, leading to the sustained production of inositol bis- and trisphosphates, and diacylglycerol rich in arachidonic acid, which underlies the observed pattern of cellular response.
310 citations
TL;DR: These studies show that a substance present in the atria, but not ventricles, blocks both hormone- and depolarization- induced vasoconstriction in aortic rings, suggesting that both the vasoactive and natriuretic properties of AE may reside in a single substance.
Abstract: We have previously shown that the natriuretic effect of rat atrial extract (AE) may be due, perhaps entirely, to its powerful renal hemodynamic actions. The present study was undertaken to test the hypothesis that mammalian atria contain a substance that behaves as a functional antagonist of endogenous vasoconstrictors, by examining the direct effects of AE and extensively purified atrial "natriuretic" factor on the contractile response of rabbit aortic rings to angiotensin II (AII), norepinephrine (NE), and K+-induced depolarization. Dose-response curves to AII and NE (i.e., change in tension vs log hormone concentration) were determined in the absence or presence of boiled AE or ventricular extracts (VE). Increasing concentrations of boiled AE caused a progressive right-ward shift of the AII and NE dose-response curves, whereas VE was without effect. A similar inhibitory effect was produced after extensive purification of atrial natriuretic factor by gel filtration and reversed-phase high performance liquid chromatography (HPLC). It appeared that this factor antagonized AII-induced contractility to a greater degree than that of NE. Moreover, the partially purified factor also inhibited the contraction induced by depolarization with 15 mM KCl in a concentration-dependent manner. These studies show that a substance present in the atria, but not ventricles, blocks both hormone- (receptor) and depolarization- (nonreceptor) induced vasoconstriction in aortic rings. Moreover, this antagonism is retained following extensive purification of an atrial factor that induces natriuresis in the intact rat and isolated rat kidney, suggesting that both the vasoactive and natriuretic properties of AE may reside in a single substance.(ABSTRACT TRUNCATED AT 250 WORDS)
301 citations
TL;DR: The results demonstrate that part of the natriuretic effect of this new factor might be due to inhibition of adrenal steroidogenesis by action through a distinct receptor.
Abstract: The effect of synthetic atrial natriuretic factor (ANF) on adrenal steroidogenesis has been studied in prijnary culture of bovine adrenal cells. ANF-(8-33) produced a potent 40-70% inhibition of angiotensin II-, ACTH-, PGE!-, and forskolin-stimulated secretion of aldosterone production from zona glorerulosa cells with an ED50 of 120 pM. An equipotent inhibitory effect of the natriuretic factor on cortisol production was also observed in cultured zona fasciculata cells. Nicotine-stimulated secretion of catecholamines from medullary cells was only slightly inhibited by the factor at doses above 10 nM. [125I]iodo-ANF-(8-33) binding to glomerulosa membranes displayed an apparent affinity of 100–150 pM for specific receptor sites and was not inhibited by angiotensin II or ACTH. Conversely, the natriuretic factor had no affinity for angiotensin II receptor sites. The results demonstrate that part of the natriuretic effect of this new factor might be due to inhibition of adrenal steroidogenesis by action through...
291 citations
TL;DR: In vivo, ANF blocked the effect of angiotensin II infused iv on aldosterone secretion in conscious unrestrained rats, concluding that ANF is a non-selective inhibitor of stimulated ald testosterone output.
Abstract: Since atrial natriuretic factor (ANF) blocks the contractile effect of angiotensin II on vascular strips, we investigated the action of the synthetic 48–73 ANF (previously called 8–33 ANF) on another target tissue of angiotensin II, the adrenal glomerulosa. ANF did not affect basal aldosterone output by isolated rat adrenal glomerulosa cells. ANF inhibited aldosterone secretion stimulated by 10–8M angiotensin II with an IC50 of 1.3 × 10–9M. Aldosterone secretion stimulated by 2.9 × 10–10M ACTH and by 15 mM potassium was similarly inhibited by ANF. In vivo, ANF blocked the effect of angiotensin II infused iv on aldosterone secretion in conscious unrestrained rats. We conclude that ANF is a non-selective inhibitor of stimulated aldosterone output.
267 citations
TL;DR: Microinjection of arginine vasopressin into the medial preoptic area of the hypothalamus of male and female golden hamsters triggered a complex, stereotypic behavior--flank marking--a type of scent marking used in olfactory communication.
Abstract: Microinjection of arginine vasopressin into the medial preoptic area of the hypothalamus of male and female golden hamsters triggered a complex, stereotypic behavior--flank marking--a type of scent marking used in olfactory communication. The flank marking was not elicited by saline, oxytocin, neurotensin, or angiotensin II. Vasopressin was ineffective when injected into other areas of the hypothalamus or into the lateral cerebroventricle.
255 citations
TL;DR: Angiotensin II (AII) immunoreactive cells and fibers were identified in the subfornical organ of the rat and it is suggested that these biochemically defined connections of the SFO participate in the central neural control of fluid balance.
252 citations
TL;DR: It is proposed that the inhibitory action of the Ca2-dependent hormones on the plasma membrane Ca2+ pump plays an important role in the actions of these hormones by prolonging the elevation in cytosolic Ca2+.
TL;DR: Results of fractionation studies suggest that the receptors for ANF in vascular and renal tissues are responsible for mediating the physiological actions of this peptide in these target tissues.
Abstract: Membranes from rabbit aorta and from rabbit and rat kidney cortex possess high-affinity (Kd = 10(-10) M) specific binding sites for atrial natriuretic factor (ANF) Similar high-affinity sites are present in an established cell line from pig kidney, LLC-PK1 Results of fractionation studies indicate that the receptors are localized in the plasma membrane of these tissues The binding is time-dependent and saturable An excellent quantitative correlation was found between the affinity of synthetic ANF and analogs of intermediate activity to aorta membranes and the half-maximal concentration needed for relaxation of rabbit aorta rings contracted by addition of serotonin Furthermore, the binding affinity of the receptor in kidney membranes is consistent with the concentration required for in vivo natriuresis in the rat Biologically inactive synthetic ANF fragments and other peptide hormones such as angiotensin II and vasopressin do not significantly inhibit binding These data suggest that the receptors for ANF in vascular and renal tissues are responsible for mediating the physiological actions of this peptide in these target tissues
TL;DR: Synthetic atrial natriuretic factor inhibited aldosterone production by suspensions of bovine adrenal glomerulosa cells and had no effect on binding of AII to receptors, on the stimulation by A II of phospholipid turnover, or on the alteration by AII of calcium fluxes.
TL;DR: The high intrinsic activity of a synthetic replicate of one form of this molecule, ANF, is reported to inhibit directly basal aldosterone secretion and its ability to antagonize the stimulatory effects of adrenocorticotropin and angiotensin II on the secretion of ald testosterone by rat adrenoglomerulosa cells in vitro.
Abstract: Several forms of the polypeptide atrial natriuretic factor (ANF) have been isolated recently from rat and human atria and identified1–3; they are probably associated with the secretory granules of atrial tissue4 The potent ability of ANFs to increase urine sodium content is mediated by their direct action on the kidney5,6 We report here the high intrinsic activity of a synthetic replicate of one form of this molecule, ANF(8-33) (ref 7), to inhibit directly basal aldosterone secretion and its ability to antagonize the stimulatory effects of adrenocorticotropin (ACTH) and angiotensin II (AN-II) on the secretion of aldosterone by rat adrenoglomerulosa cells in vitro Our results suggest that ANF is of clinical importance in the management of aldosterone-dependent hypertension by modifying the adrenocortical response to endogenous ACTH and AN-II
TL;DR: Two important physiological regulators of aldosterone secretion, extracellular potassium, by the opening of voltage-dependent calcium channels, and angiotensin II, by a receptor-mediated mechanism, induce rapid rises in cytosolic free calcium, which precede, and presumably trigger the steroidogenic response.
TL;DR: This editorial focuses on the renal hemodynamic influences exerted by the RAS as a local regulatory mechanism and the possibility that locally formed angiotensin II (All) may participate as an important modulator of renal vascular tone.
TL;DR: This first demonstration of the vascular activity of synthetic ANF depicts this substance as a nonselective vasodilator of agonist-induced contractions and suggests a common mechanism of action with sodium nitroprusside.
TL;DR: Angiotensin II has a selective effect on the arterial baroreflex; it impairs reflex decreases inHR and LSNA during hypertension but not reflex increases in HR and LS NA during hypotension.
Abstract: We determined whether angiotensin II (ANG II) modulates the arterial baroreflex control of lumbar sympathetic nerve activity (LSNA) in chloralose-anesthetized rabbits. Intravenous infusion (iv) of ANG II caused significantly less reflex bradycardia and less inhibition of LSNA than iv phenylephrine (PE) for equivalent increments in arterial pressure. During a background iv infusion of ANG II, which caused a small sustained increase in arterial pressure, the reflex inhibition of heart rate (HR) and LSNA in response to further increases in pressure with graded doses of PE was attenuated, but the reflex increase in HR and LSNA in response to hypotension with graded doses of nitroprusside was unchanged. This modulation of the baroreflex by ANG II is specific since a similar background infusion of PE did not alter baroreflex responses to further increases or to decreases in arterial pressure. The frequency of aortic baroreceptors was comparable for equivalent increases in pressure caused by iv ANG II or PE. When ANG II was confined to the isolated carotid sinuses, the reflex inhibition of HR and LSNA during distension of carotid sinuses was unchanged. An excitatory effect of ANG II on the efferent limb of the baroreflex that would oppose the reflex bradycardia or inhibition of LSNA is unlikely because when the pressor effect of ANG II was prevented by nitroprusside, there were no changes in HR and LSNA. We conclude that through an effect on the central nervous system iv ANG II has a selective effect on the arterial baroreflex; it impairs reflex decreases in HR and LSNA during hypertension but not reflex increases in HR and LSNA during hypotension.
TL;DR: It is concluded that linear end-systolic pressure-volume relationships can be derived in conscious dogs with intact sympathetic reflexes, and appears to reflect left ventricular contractile function and is indepednent of the level of afterload and preload.
Abstract: The relationship between left ventricular end-systolic pressure and volume has been proposed as a model of left ventricular contraction which may be useful for quantifying inotropic state independent of preload and afterload. Although the model has been well-validated in isolated hearts, systematic evaluation in conscious animals with an intact peripheral circulation has been limited. Accordingly, we derived end-systolic pressure-volume relationships in twelve conscious dogs, chronically instrumented to measure left ventricular pressure and dimensions from endocardial ultrasonic crystals in three orthogonal axes. We examined the linearity of the end-systolic pressure-volume relationship, its response to alterations of inotropic state and the peripheral circulation, and the influence of beta-adrenergic reflexes. End-systolic pressure-volume relationships were constructed by linear regression of end-systolic pressure-volume coordinates produced by transient inferior vena caval occlusions during atrial pacing. The relations were highly linear; of 127 inferior vena caval occlusions, the correlation coefficient was 0.96 +/- 0.05 (mean +/- SD). The slope of the end-systolic pressure-volume relationship was not significantly altered either by a moderate resistive afterload induced by angiotensin II infusion, or by a moderate increase in preload produced by dextran, but was increased from 4.7 +/- 2.3 to 6.5 +/- 2.2 mm Hg/ml (P less than 0.05) in response to the positive inotropic stimulus of dobutamine. The volume intercept at zero end-systolic pressure was unaffected by dextran or dobutamine, but was decreased from 12 +/- 8 to 5 +/- 11 ml (P less than 0.01) by angiotensin II infusion, indicating a leftward shift of the end-systolic pressure-volume relationship.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The effects of ANF on vascular smooth muscle are not mediated by prostaglandins, by alpha- and beta-adrenergic and muscarinic receptors, or by an impairment of Ca2+ influx, but they are mimicked by sodium nitroprusside.
Abstract: Rat atrium cardiocytes contain a powerful natriuretic and diuretic peptide that has been localized in the specific granules. This atrial natriuretic factor (ANF) produced a potent, dose-dependent relaxant effect on rabbit and rat arterial strips previously made to contract by application of either norepinephrine (NE) or angiotensin II. The effect was not seen if KCl was used as contractile agent or under any conditions with rabbit mesenteric strips. After the application of ANF the vascular strips were refractory to subsequent stimulation by either NE or angiotensin II. The infusion of ANF into a high-resistance isolated perfused rat kidney produced a rapid decrease (33 +/- 5 mmHg) in perfusion pressure that lasted for 18 +/- 3 min. This effect was not seen in the isolated rat mesenteric arterial preparation, even when the perfusion pressure was raised by the infusion of NE. These effects of ANF on vascular smooth muscle are not mediated by prostaglandins, by alpha- and beta-adrenergic and muscarinic receptors, or by an impairment of Ca2+ influx, but they are mimicked by sodium nitroprusside. A low- and a high-molecular-weight ANF produced the same effects. The existence of specific receptive sites for these peptides is suggested.
TL;DR: It is demonstrated that AE acts directly on the kidney, eliciting powerful Ca-dependent hemodynamic and natriuretic responses, and the hypothesis is advanced that AE contains a substance which behaves as a functional agonist/antagonist of endogenous vasoconstrictors with a preferential site of action on the efferent arterioles of the renal vasculature.
Abstract: The effects of rat atrial tissue extract on renal hemodynamics and fluid and electrolyte excretion were investigated in the isolated perfused rat kidney (IK). IK were perfused at a constant effective perfusion pressure of about 90 mmHg. After control clearance periods (C), extracts of rat atria (AE) or ventricles (VE) were added to the perfusate and three 10-min experimental periods followed. AE, but not VE, significantly increased (P less than 0.001) renal vascular resistance (RVR) to 133 +/- 8% of C, GFR to 201 +/- 34%, filtration fraction to 245 +/- 41%, urine flow (V) to 675 +/- 131%, fractional excretion (FE) of H2O to 336 +/- 29%, absolute Na excretion (UNaV) to 1,259 +/- 290%, FENa to 642 +/- 129%, UKV to 2,226 +/- 1,237%, and FEK to 542 +/- 119%. Despite the marked natriuresis, since GFR doubled, Na reabsorption rose from 78.3 +/- 36.3 in C to 132 +/- 36.3 mueq/min after AE. The effects of AE were immediate and lasted to the end of the perfusion. The lower the initial control GFR, the larger was the AE-induced increase in GFR. Perfusion with low [Ca] (0.2 mM) or verapamil (10(-5) M) severely blunted the hemodynamic, diuretic, kaliuretic, and natriuretic effects of AE. AE decreased rather than increased the RVR when IK were perfused with vasoconstrictors such as angiotensin II, norepinephrine, or vasopressin. The results demonstrate that AE acts directly on the kidney, eliciting powerful Ca-dependent hemodynamic and natriuretic responses. The natriuresis induced by AE can be accounted for, at least in part, by its renal hemodynamic effects rather than by the presence of a putative tubular natriuretic factor. The hypothesis is advanced that AE contains a substance(s) which behaves as a functional agonist/antagonist of endogenous vasoconstrictors with a preferential site of action on the efferent arterioles of the renal vasculature.
TL;DR: The results document the specific receptor involved in the potent inhibitory effect of ANF on adrenal steroidogenesis and indicate that bovine adrenal zonal glomerulosa provide a highly sensitive system for studying the recently discovered atrial natriuretic factor.
TL;DR: The renal cortical microcirculatory and proximal tubule functions of rats with congestive heart failure are profoundly influenced by the vasoconstrictor properties of angiotensin II.
Abstract: Glomerular and tubule functions were assessed by micropuncture in rats with extensive myocardial infarction produced by ligation of the left coronary artery 4 weeks prior to study. When compared to sham-operated control rats, rats with myocardial infarction involving 40 +/- 4% of the left ventricular circumference had lower mean arterial pressure (96 +/- 5 vs. 122 +/- 4 mm Hg, P less than 0.005), and higher left ventricular end-diastolic pressure (24 +/- 3 vs. 5 +/- 0 mm Hg, P less than 0.001). Renal cortical microcirculatory dynamics of rats with myocardial infarction were characterized by reduced glomerular plasma flow rate (75 +/- 8 vs. 165 +/- 17 nl/min, P less than 0.005), but a proportionately lesser decline in single nephron glomerular filtration rate (28.0 +/- 2.8 vs. 41.7 +/- 3.1 nl/min, P less than 0.025), accounting for the observed rise in single nephron filtration fraction (0.38 +/- 0.02 vs. 0.25 +/- 0.02, P less than 0.005). These renal hemodynamic alterations in myocardial-infarcted rats were accompanied by a striking elevation in efferent arteriolar resistance (3.03 +/- 0.31 vs. 0.95 +/- 0.16 X 10(10) dyn X sec X cm-5, P less than 0.001). In addition, fractional proximal fluid reabsorption, assessed by end-proximal tubule fluid-to-plasma inulin concentration ratio, was elevated (2.21 +/- 0.12 vs. 1.64 +/- 0.09, P less than 0.025). The intravenous infusion of teprotide, an angiotensin I-converting enzyme inhibitor, led to the return of glomerular plasma flow rate, single nephron filtration fraction, single nephron glomerular filtration rate, efferent arteriolar resistance, and fractional proximal fluid reabsorption in myocardial-infarcted rats to, or toward, the levels found in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The results demonstrate that at least three Ca2-sensitive protein kinases are involved in the response of hepatocytes to Ca2+-linked hormones, and imply that hormones such as vasopressin generate two intracellular messengers, diacylglycerol andCa2+ ion.
TL;DR: Results strongly suggest that besides the ANG I converting enzyme, another enzyme which generates ANG II is present in vascular tissues and lungs, and may play an important role in the local generation of ANG II, which possibly regulates the regional vascular tone.
Abstract: An inhibitor of angiotensin I (ANG I) converting enzyme, SA446, reduced the response to ANG I of blood vessels isolated from dogs and monkeys, but did not abolish the response even at high concentrations. The residual action of ANG I in the presence of high concentrations of SA446 could be abolished by (Sar1, Ala8)-ANG II. Vascular strips and crude extracts of vessels and lungs possessed the enzymic activity generating ANG II from ANG I, or hippuric acid from hippuryl-histidyl-leucine (HHL). The HHL-hydrolysing activity of the crude extracts was completely inhibited by SA446 (10(-7) mol/l) and/or Na2-EDTA (10(-3) mol/l). However, the octapeptide generation was not abolished despite the combined treatment with SA446 (5 X 10(-4) mol/l) and Na2-EDTA (5 x 10(-3) mol/l). The residual activity forming ANG II was inhibited by chymostatin and soybean trypsin inhibitor, which however did not affect the HHL-hydrolysis. Combined treatment with SA446 (10(-5) mol/l) and chymostatin (2.5 X 10(-5) mol/l) abolished the vascular action of ANG I but did not alter the action of ANG II. These results strongly suggest that besides the ANG I converting enzyme, another enzyme which generates ANG II is present in vascular tissues and lungs, and may play an important role in the local generation of ANG II, which possibly regulates the regional vascular tone.
TL;DR: The synthetic atrial natriuretic factor (ANF) inhibited adenylate cyclase activity in aorta washed particles, mesenteric artery, and renal artery homogenates in a concentration dependent manner with an apparent Ki between 0.1 to 1nM .
TL;DR: Much additional research will be required before the actions of angiotensin II on the brain are completely understood, and the physiologic significance of these actions is beginning to be understood.
Abstract: Angiotensin II acts on the brain to produce a variety of effects including elevation of arterial blood pressure, increased release of vasopressin and ACTH, stimulation of drinking and sodium appetite, and natriuresis. Many, and possibly all, of these effects can be produced by centrally administered angiotensin II or by circulating angiotensin II, which appear to act at common receptor sites located in the circumventricular organs. Whether these effects are normally produced by blood-borne angiotensin II formed by the renal renin-angiotensin system, by angiotensin II formed centrally by the putative brain renin-angiotensin system, or by both, remains to be determined. A large body of information concerning the site and mechanism of these different central actions of angiotensin II is available, and the physiologic significance of these actions is beginning to be understood. Nevertheless, much additional research will be required before the actions of angiotensin II on the brain are completely understood.
TL;DR: It appears that AII simultaneously increases phosphoinositide hydrolysis and synthesis in vascular smooth muscle, and both phospholipid effects may contribute to inositol triphosphate generation, which was sufficiently rapid to have a role in intracellular Ca2+ mobilization.
Abstract: Smooth muscle cells were cultured from rat thoracic aorta and labeled to a stable specific activity with 45Ca2+, myo-[2-3H]inositol, or 32Pi. The efflux of 45Ca2+ was monitored over 10-sec intervals. Angiotensin II (AII) increased the amount of 45Ca2+ lost by 5-fold in the first 10-sec interval after the addition of AII and by 10-fold in the second 10-sec interval. AII-stimulated 45Ca2+ release was blocked by the angiotensin antagonist [1-sarcosine, 8-leucine]AII and by La3+. The removal of external Ca2+ had no effect on AII-stimulated 45Ca2+ release. Depolarization with high external K+ only slightly increased 45Ca2+ efflux and had no effect on AII-induced 45Ca2+ release. AII had no effect on the initial rate of 45Ca2+ influx. These results indicate that the rapid 45Ca2+ efflux evoked by AII is probably due to the release of 45Ca2+ sequestered intracellularly rather than to an increase in the Ca2+ permeability of the plasma membrane. AII provoked rapid increases in the levels of phosphatidic acid and phosphoinositides in the cells. These increases in phospholipids were associated with increases in phospholipase C-generated inositol phosphates (tri-, di-, and mono-). It appears that AII simultaneously increases phosphoinositide hydrolysis and synthesis in vascular smooth muscle, and both phospholipid effects may contribute to inositol triphosphate generation, which was sufficiently rapid to have a role in intracellular Ca2+ mobilization.
TL;DR: Reduced glomerular ANG II receptor density in the presence of a suppressed renin-ANG II axis may underlie the altered renal vascular responsiveness to ANG II known to occur in diabetes mellitus.
Abstract: Density and affinity of glomerular angiotensin II (ANG II) receptors were determined in normal, untreated, and insulin-treated streptozotocin-diabetic rats 3-4 wk after the onset of diabetes mellitus. With low, intermediate, and high salt intake, angiotensin II receptor density varied inversely with the plasma renin concentration (PRC) in normal, insulin-treated, and untreated diabetic rats. PRC values with all three dietary regimens were lower in the untreated diabetic rats when compared with the other groups. Despite lower plasma renin concentration, however, untreated diabetic rats were also found to have significantly lower glomerular ANG II receptor concentrations at all levels of salt intake. On a normal salt intake, glomerular ANG II receptor density was reduced significantly in untreated diabetic rats (853 +/- 74 (SE) fmol/mg protein), compared with insulin-treated diabetic rats (1,185 +/- 118 fmol/mg) and normal controls (1,058 +/- 83 fmol/mg). ANG II receptor affinity did not change with alternations in salt intake or degree of diabetic control. Reduced glomerular ANG II receptor density in the presence of a suppressed renin-ANG II axis may underlie the altered renal vascular responsiveness to ANG II known to occur in diabetes mellitus.
TL;DR: Human skin chymotryptic proteinase, cathepsin G, and tonin provide unique pathways for the generation of angiotensin II in tissue and may be of significance in regulation of biologic processes of the tissue microenvironment.