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ACS Medicinal Chemistry Letters Oct 2014Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a...
Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists.
PubMed: 25313325
DOI: 10.1021/ml500278g -
PloS One 2017Our previous work on angiotensin II-mediated electrical-remodeling in canine left ventricle, in connection with a long history of other studies, suggested the...
Our previous work on angiotensin II-mediated electrical-remodeling in canine left ventricle, in connection with a long history of other studies, suggested the hypothesis: increases in mechanical load induce autocrine secretion of angiotensin II (A2), which coherently regulates a coterie of membrane ion transporters in a manner that increases contractility. However, the relation between load and A2 secretion was correlative. We subsequently showed a similar or identical system was present in murine heart. To investigate whether the relation between mechanical load and A2-mediated electrical remodeling was causal, we employed transverse aortic constriction in mice to subject the left ventricle to pressure overload for short-term (1 to 2 days) or long-term (1 to 2 weeks) periods. Heart-to-body weight ratios and cell capacitance measurements were used to determine hypertrophy. Whole-cell patch clamp recordings of the predominant repolarization currents Ito,fast and IK,slow were used to assess electrical remodeling. Hearts or myocytes subjected to long-term load displayed significant hypertrophy, which was not evident in short-term load. However, short-term load induced significant reductions in Ito,fast and IK,slow. Incubation of these myocytes with the angiotensin II type 1 receptor inhibitor saralasin for 2 hours restored Ito,fast and IK,slow to control levels. The number of Ito.fast or IK,slow channels did not change with A2 or long-term load, however the hypertrophic increase in membrane area reduced the current densities for both channels. For Ito,fast but not IK,slow there was an additional reduction that was reversed by inhibition of angiotensin receptors. These results suggest increased load activates an endogenous renin angiotensin system that initially reduces Ito,fast and IK,slow prior to the onset of hypertrophic growth. However, there are functional interactions between electrical and anatomical remodeling. First, hypertrophy tends to reduce all current densities. Second, the hypertrophic program can modify signaling between the angiotensin receptor and target current.
Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Cells, Cultured; Disease Models, Animal; Heart Diseases; Hypertrophy; Membrane Potentials; Mice, Inbred C57BL; Myocytes, Cardiac; Patch-Clamp Techniques; Pressure; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Saralasin; Stress, Physiological
PubMed: 28464037
DOI: 10.1371/journal.pone.0176713 -
Clinical Therapeutics 1996Blockade of angiotensin II receptors was first achieved in the 1970s using a peptide, saralasin acetate. Although it was effective in lowering blood pressure, it... (Review)
Review
Blockade of angiotensin II receptors was first achieved in the 1970s using a peptide, saralasin acetate. Although it was effective in lowering blood pressure, it required parenteral administration and had a short duration of action and partial agonist activity. These disadvantages are absent with losartan, a selective, orally administered, nonpeptide blocker of the angiotensin II type 1 receptor that recently became available for clinical use. Losartan has a sustained duration of action, permitting once-daily dosing in many patients, and lacks partial agonist activity. More than 3300 hypertensive patients have received losartan in Phase III, controlled clinical trials. Losartan given concomitantly with a low dose (12.5 mg) of hydrochlorothiazide further reduces blood pressure. Its overall incidence of adverse experiences is similar to that of placebo. Because of its efficacy, specificity, duration of action, and safety profile, losartan should be considered as first-line therapy for the treatment of patients with hypertension.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Hydrochlorothiazide; Hypertension; Imidazoles; Losartan; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Safety; Tetrazoles; Treatment Outcome
PubMed: 9001823
DOI: 10.1016/s0149-2918(96)80061-0 -
The Journal of Physiology Dec 19871. In eleven chronically catheterized fetal sheep aged 124-142 days, hypotension caused by infusion of sodium nitroprusside (1.6-3.3 mg/h) and competitive antagonism of...
1. In eleven chronically catheterized fetal sheep aged 124-142 days, hypotension caused by infusion of sodium nitroprusside (1.6-3.3 mg/h) and competitive antagonism of angiotensin II by saralasin (3.3 mg/h) both caused a fall in fetal urine flow (P less than 0.02 and P less than 0.05, respectively), and in sodium excretion (P less than 0.05 and P less than 0.01) because they both caused a fall in glomerular filtration rate (G.F.R., P less than 0.02 and P less than 0.01). Neither hypotension nor saralasin had any significant effect on fractional sodium reabsorption. Saralasin only caused a significant fall in systolic pressure (P = 0.05) while infusion of sodium nitroprusside caused a fall in both systolic and diastolic pressure (P less than 0.005 and P less than 0.02). 2. Frusemide (6 mg I.V) caused a marked natriuresis and diuresis (F = 24.9, P less than 0.005 and F = 30.5, P less than 0.005). This effect was maximal within 30 min. There was no change in fetal G.F.R. and there was a significant decrease in the fraction of the filtered sodium load that was reabsorbed (F = 10.44, P less than 0.0025). Fetal mean plasma renin activity (p.r.a.) rose progressively throughout (F = 9.3, P less than 0.005). When frusemide was given to fetal sheep which were hypotensive because they were infused with sodium nitroprusside, it still caused a diuresis (F = 5.73, P less than 0.025) and the fraction of the filtered sodium load that was reabsorbed decreased (F = 4.06, P less than 0.05) to a similar extent to that seen in animals given frusemide alone. On the other hand, frusemide was ineffective as a diuretic i.e. it had no effect on fractional sodium reabsorption, when given to fetal sheep which were infused with saralasin. 3. Injection of frusemide was associated with a significant rise in the diastolic pressures of hypotensive fetuses (P less than 0.05). Furthermore, when the infusion of saralasin was terminated 1.5 h after frusemide injection, blood pressure rose significantly (F = 11.19, P less than 0.0005 for systolic pressure and F = 7.15, P less than 0.005 for diastolic pressure) and p.r.a. fell (F = 4.78, P less than 0.025). 4. It is concluded that the fetal renin-angiotensin system can play a significant role in regulation of fetal blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Blood Pressure; Fetal Blood; Fetus; Furosemide; Kidney; Nitroprusside; Renin; Saralasin; Sheep
PubMed: 3328781
DOI: 10.1113/jphysiol.1987.sp016834 -
British Journal of Clinical Pharmacology Nov 1981
Topics: Angiotensin II; Angiotensins; Blood Pressure; Captopril; Humans; Hypertension; Ischemia; Kidney; Peptidyl-Dipeptidase A; Posture; Renin; Saralasin; Teprotide
PubMed: 6174135
DOI: 10.1111/j.1365-2125.1981.tb01278.x -
Heart Rhythm Jul 2010Left ventricular pacing (LVP) to induce cardiac memory (CM) in dogs results in a decreased transient outward K current (I(to)) and reduced mRNA and protein of the I(to)...
BACKGROUND
Left ventricular pacing (LVP) to induce cardiac memory (CM) in dogs results in a decreased transient outward K current (I(to)) and reduced mRNA and protein of the I(to) channel accessory subunit, KChIP2. The KChIP2 decrease is attributed to a decrease in its transcription factor, cyclic adenosine monophosphate response element binding protein (CREB).
OBJECTIVE
This study sought to determine the mechanisms responsible for the CREB decrease that is initiated by LVP.
METHODS
CM was quantified as T-wave vector displacement in 18 LVP dogs. In 5 dogs, angiotensin II receptor blocker, saralasin, was infused before and during pacing. In 3 dogs, proteasomal inhibitor, lactacystin, was injected into the left anterior descending artery before LVP. Epicardial biopsy samples were taken before and after LVP. Neonatal rat cardiomyocytes (NRCM) were incubated with H(2)O(2) (50 micromol/l) for 1 hour with or without lactacystin.
RESULTS
LVP significantly displaced the T-wave vector and was associated with increased lipid peroxidation and increased tissue angiotensin II levels. Saralasin prevented T-vector displacement and lipid peroxidation. CREB was significantly decreased after 2 hours of LVP and was comparably decreased in H(2)O(2)-treated NRCM. Lactacystin inhibited the CREB decrease in LVP dogs and H(2)O(2)-treated NRCM. LVP and H(2)O(2) both induced CREB ubiquitination, and the H(2)O(2)-induced CREB decrease was prevented by knocking down ubiquitin.
CONCLUSION
LVP initiates myocardial angiotensin II production and reactive oxygen species synthesis, leading to CREB ubiquitination and its proteasomal degradation. This sequence of events would explain the pacing-induced reduction in KChIP2, and contribute to altered repolarization and the T-wave changes of cardiac memory.
Topics: Action Potentials; Angiotensin II; Animals; Arrhythmias, Cardiac; Blotting, Western; Cardiac Pacing, Artificial; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Dogs; Heart Conduction System; Ion Channels; Kv Channel-Interacting Proteins; Lipid Peroxidation; Male; Models, Animal; Models, Cardiovascular; Myocardium; Myocytes, Cardiac; Oxidative Stress; Proteasome Endopeptidase Complex; Reactive Oxygen Species; Ubiquitin; Ubiquitination; Ventricular Function, Left; Ventricular Remodeling
PubMed: 20346417
DOI: 10.1016/j.hrthm.2010.03.024 -
The Journal of Physiology Jan 19881. Twelve normal volunteers were studied on 2 separate days, having taken a range of diets providing 50-300 mmol sodium per day for 3 days and having been dehydrated... (Clinical Trial)
Clinical Trial
1. Twelve normal volunteers were studied on 2 separate days, having taken a range of diets providing 50-300 mmol sodium per day for 3 days and having been dehydrated overnight. Each volunteer received a background intravenous infusion of arginine vasopressin (5 x 10(-7) i.u. kg-1 min-1) on both days, and also received 6 mg captopril orally on one day and a placebo tablet on the other. The ensuing changes in arterial pressure, and in urinary solute and solute-free water excretion were recorded. 2. Captopril did not significantly alter arterial pressure. It increased the rate of excretion of sodium but not of potassium, and it did not significantly change urinary osmolality or creatinine clearance. 3. Captopril increased the rate of solute-free water reabsorption and did so in direct proportion to its effect of increasing sodium excretion. 4. A further twelve normal, dehydrated volunteers on free diets were studied on each of 2 days, after taking 500 mg lithium carbonate on the previous evening. On each day, they also received a loading dose and maintenance infusion of inulin. On one day they received 50 mg captopril orally, and, on the other, they received a placebo tablet. The arterial pressure, urinary excretion of electrolytes, and inulin clearance were recorded. 5. Captopril increased the rates of excretion of sodium, lithium and potassium, but there were no significant changes in inulin clearance or arterial pressure. 6. The natriuretic effect of captopril in either group of twelve volunteers was not significantly less in those volunteers who were already excreting more sodium, at least over the range of dietary sodium loading to which the volunteers were subjected. 7. Six normal volunteers were studied on a further 2 days, having taken a diet supplying 30 mmol sodium per day for 3 days and being dehydrated overnight. Each volunteer received a background intravenous infusion of arginine vasopressin (5 x 10(-7) i.u. kg-1 min-1) on both days and also received an intravenous infusion of saralasin acetate (50 ng kg-1 min-1) plus carrier on one day and carrier alone on the other. The ensuing changes in arterial pressure, and in urinary solute and solute-free water excretion were recorded. 8. There was a small but significant fall in systolic arterial pressure during the infusion of saralasin.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Arginine Vasopressin; Blood Pressure; Captopril; Creatinine; Glomerular Filtration Rate; Humans; Inulin; Male; Natriuresis; Osmolar Concentration; Renin-Angiotensin System; Saralasin; Sodium; Urine
PubMed: 3045295
DOI: 10.1113/jphysiol.1988.sp016906 -
American Journal of Physiology. Lung... Jul 2013Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of...
Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of angiotensin (ANG) II and its counterregulatory peptide ANG1-7. Mutations in surfactant protein C (SP-C) induce endoplasmic reticulum (ER) stress and apoptosis in AECs and cause lung fibrosis. This study tested the hypothesis that ER stress-induced apoptosis of AECs might also be regulated by the autocrine ANGII/ANG1-7 system of AECs. ER stress was induced in A549 cells or primary cultures of human AECs with the proteasome inhibitor MG132 or the SP-C BRICHOS domain mutant G100S. ER stress activated the ANGII-generating enzyme cathepsin D and simultaneously decreased the ANGII-degrading enzyme ACE-2, which normally generates the antiapoptotic peptide ANG1-7. TAPI-2, an inhibitor of ADAM17/TACE, significantly reduced both the activation of cathepsin D and the loss of ACE-2. Apoptosis of AECs induced by ER stress was measured by assays of mitochondrial function, JNK activation, caspase activation, and nuclear fragmentation. Apoptosis induced by either MG132 or the SP-C BRICHOS mutant G100S was significantly inhibited by the ANG receptor blocker saralasin and was completely abrogated by ANG1-7. Inhibition by ANG1-7 was blocked by the specific mas antagonist A779. These data show that ER stress-induced apoptosis is mediated by the autocrine ANGII/ANG1-7 system in human AECs and demonstrate effective blockade of SP-C mutation-induced apoptosis by ANG1-7. They also suggest that therapeutic strategies aimed at administering ANG1-7 or stimulating ACE-2 may hold potential for the management of ER stress-induced fibrotic lung disorders.
Topics: Angiotensin I; Angiotensin II; Angiotensin Receptor Antagonists; Antihypertensive Agents; Antineoplastic Agents; Apoptosis; Autocrine Communication; Cells, Cultured; Endoplasmic Reticulum Stress; Epithelial Cells; Humans; Leupeptins; Peptide Fragments; Pulmonary Alveoli; Pulmonary Surfactant-Associated Protein C; Receptors, Angiotensin; Signal Transduction; Vasoconstrictor Agents
PubMed: 23624786
DOI: 10.1152/ajplung.00001.2013 -
Kidney International Oct 1981Angiotensin II (AII) and arginine vasopressin are capable of triggering glomerular mesangial cell contraction in vitro. A similar mechanism acting in vivo to reduce...
Angiotensin II (AII) and arginine vasopressin are capable of triggering glomerular mesangial cell contraction in vitro. A similar mechanism acting in vivo to reduce glomerular capillary surface area could account for the decline in the ultrafiltration coefficient (Kf)( that occurs in single glomeruli in response to infusion of these substances. Less clear is the mechanism whereby similar declines in Kf are induced with infusions of dibutyryl cyclic AMP (DBcAMP), parathyroid hormone (PTH), and prostaglandins, because PTH and PGE2, at least, are incapable of eliciting mesangial cell contraction in vitro. To further explore the factors that regulate Kf in vivo, we performed micropuncture experiments in 47 euvolemic Munich-Wistar rats. Infusions of DBcAMP, PTH, prostaglandins I2 and E2 led to lower mean values for plasma flow rate (QA) and Kf in superficial glomeruli than were found in animals given vehicle alone (control group), whereas average values for glomerular transcapillary hydraulic pressure difference (delta P) and total renal arteriolar resistance (RTA) tended to be higher. These increases in delta P and RTA, and decreases in QA and Kf, with DBcAMP, PTH, PGI2, and PGE2 are typical of changes induced by AII. Indeed, when saralasin, a competitive AII antagonist, was infused together with these various vasoactive substances, the effects on delta P, QA, RTA, and Kf were largely abolished. Therefore, the actions of DBcAMP, PTH, PGI2, and PGE2 on the glomerular microcirculation appear to depend on an intermediate action of AII. By contrast, although pitressin (ADH) infusion also led to a significant decline in Kf, saralasin administration did not reverse this change, suggesting that the action of ADH on the glomerular microcirculation is independent of a pathway involving AII. Based on these studies, it seems reasonable to propose that AII and ADH are both potentially important regulators of mesangial cell contraction, and thereby, glomerular capillary filtering surface area and Kf.
Topics: Animals; Bucladesine; Epoprostenol; Glomerular Filtration Rate; Kidney Glomerulus; Parathyroid Hormone; Prostaglandins E; Rats; Saralasin; Vasopressins
PubMed: 6273643
DOI: 10.1038/ki.1981.160 -
The Journal of Biological Chemistry Jul 1984Quantitative changes in cytosolic free calcium [( Ca2+]i), membrane potential, and aldosterone production in response to angiotensin II and extracellular potassium were...
Correlation between cytosolic free Ca2+ and aldosterone production in bovine adrenal glomerulosa cells. Evidence for a difference in the mode of action of angiotensin II and potassium.
Quantitative changes in cytosolic free calcium [( Ca2+]i), membrane potential, and aldosterone production in response to angiotensin II and extracellular potassium were measured in intact bovine adrenal glomerulosa cells loaded with the fluorescent calcium indicator quin 2. Angiotensin II (10(-9) M) induced a rapid rise in [Ca2+]i from 124 +/- 26 nM to 204 +/- 63 nM (n = 7), which was followed by steroid production, as measured in dynamic studies with superfused adrenal cells, and by slower changes in membrane potential, as assessed with the fluorescent probe 3,3'-dipropylthiadicarbocyanine. Both [Ca2+]i rises and functional response were blocked by the antagonist analogue [Sar1,Ala8]angiotensin II in a dose-dependent manner. Potassium (3-10 mM) provoked dose-dependent increases in [Ca2+]i, with ED50 of 6.5 mM, associated with rapid changes in membrane potential, a response superimposable upon the dose-related aldosterone production induced by potassium in static incubations of quin 2-loaded glomerulosa cells (ED50 = 6.8 mM). Verapamil (2 X 10(-5) M) and nifedipine (10(-7)-10(-6) M) decreased resting [Ca2+]i and blocked entirely the rise in [Ca2+]i induced by potassium, but did not suppress the [Ca2+]i rises induced by angiotensin II. These findings indicate that 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.
Topics: Adrenal Cortex; Aldosterone; Aminoquinolines; Angiotensin II; Animals; Calcium; Cattle; Cytosol; Ethers; Fluorescent Dyes; Ionomycin; Kinetics; Nifedipine; Potassium; Saralasin; Spectrometry, Fluorescence; Verapamil
PubMed: 6746627
DOI: No ID Found