Angiotensin II stimulates sodium-dependent proton extrusion in perfused ferret heart

1996 ◽  
Vol 270 (6) ◽  
pp. C1687-C1694 ◽  
Author(s):  
A. A. Grace ◽  
J. C. Metcalfe ◽  
P. L. Weissberg ◽  
H. W. Bethell ◽  
J. I. Vandenberg
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Tissue ◽  
At1 Receptor ◽  
Intracellular Acidosis ◽  
Physiological Homeostasis ◽  
Cellular Dysfunction ◽  
Acid Loading ◽  
Contractile Recovery ◽  
Ferret Heart ◽  
Stimulation Of

The Na+/H+ antiport and Na(+)-HCO3- coinflux carrier contribute to recovery from intracellular acidosis in cardiac tissue. The effects of angiotensin II (10(-12)-10(-6) M) on H+ fluxes after intracellular acid loading and during reperfusion after myocardial ischemia have been investigated in the isovolumic, Langendorff-perfused ferret heart. Intracellular pH (pHi) was estimated using 31P nuclear magnetic resonance (NMR) spectroscopy from the chemical shift of intracellular deoxyglucose-6-phosphate or inorganic phosphate. Angiotensin II produced concentration-dependent stimulation (maximum at 10(-6) M: 67%) of 5-(N-ethyl-N-isopropyl)amiloride (EIPA)-sensitive Na(+)-dependent of H+ efflux consistent with stimulation of the Na+/H+ antiport. Half-maximal stimulation of H+ efflux occurred at approximately 10(-9) M, which is close to the dissociation constant of the cardiac angiotensin AT1 receptor. Stimulation via this receptor was confirmed with the nonpeptide AT1 receptor blocker, GR-117289. Angiotensin II had less pronounced effects on HCO3(-)-dependent pHi recovery after acid loading with no effect on pHi recovery after intracellular alkalosis. During reperfusion, angiotensin II significantly increased H+ extrusion but impaired contractile recovery. The results support the hypothesis that angiotensin II facilitates H+ extrusion in the heart. This may help maintain physiological homeostasis, but the hypothesized obligated Na+ influx could exacerbate cellular dysfunction during reperfusion.

Angiotensin II type 1 receptor modulation of neuronal K+ and Ca2+ currents: intracellular mechanisms

1996 ◽  
Vol 271 (1) ◽  
pp. C154-C163 ◽  
Author(s):  
C. Sumners ◽  
M. Zhu ◽  
C. H. Gelband ◽  
P. Posner
Keyword(s):  
Angiotensin Ii ◽  
At1 Receptor ◽  
Ang Ii ◽  
Receptor Modulation ◽  
Kinase C ◽  
Intracellular Messengers ◽  
Voltage Dependent ◽  
K Current ◽  
Stimulation Of

Angiotensin II (ANG II) elicits an ANG II type 1 (AT1) receptor-mediated decrease in voltage-dependent K+ current (Ik) and an incrase in voltage-dependent Ca2+ current (ICa) in neurons cocultured from newborn rat hypothalamus and brain stem. Modulation of these currents by ANG II involves intracellular messengers that result from an AT1 receptor-mediated stimulation of phosphoinositide hydrolysis. For example, the effects of ANG II on IK and ICa were abolished by phospholipase C antagonists. The reduction in IK produced by ANG II was attenuated by either protein kinase C (PKC) antagonists or by chelation of intracellular Ca2+. By contrast, PKC antagonism abolished the stimulatory effect of ANG II on ICa. Superfusion of the PKC activator phorbol 12-myristate 13-acetate produced effects on IK and ICa similar to those observed after ANG II. Furthermore, intracellular application of inositol 1,4,5-trisphosphate (IP3) elicited a significant reduction in IK. This suggests that the AT1 receptor-mediated changes in neuronal K+ and Ca2+ currents involve PKC (both IK and ICa) and IP3 and/or intracellular Ca2+ (IK).

scholarly journals Angiotensin II stimulates phosphorylation of an ectodomain-truncated platelet-derived growth factor receptor-β and its binding to class IA PI3K in vascular smooth muscle cells

2006 ◽  
Vol 397 (2) ◽  
pp. 337-344 ◽  
Author(s):  
Ben-Bo Gao ◽  
Hans Hansen ◽  
Hong-Chi Chen ◽  
Edward P. Feener
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Growth Factor Receptor ◽  
At1 Receptor ◽  
Dominant Negative ◽  
Platelet Derived Growth Factor ◽  
Ang Ii ◽  
Stimulation Of

PI3K (phosphoinositide 3-kinase) activity is involved in Ang (angiotensin) II-stimulated VSMC (vascular smooth muscle cell) growth and hypertrophy. In the present study, we demonstrate that the inhibition of PI3K in VSMCs by expression of a dominant-negative p85α mutant lacking the p110-binding domain (Δp85), or by treatment of cells with LY294002, inhibited Ang II-stimulated PAI-1 (plasminogen activator inhibitor-1) mRNA expression. Using a GST (glutathione S-transferase) fusion protein containing the p85 N-terminal SH2 (Src homology 2) domain as ‘bait’ followed by MS/MS (tandem MS), we identified a 70 kDa fragment of the p70 PDGFR-β (platelet-derived growth factor receptor-β) as a signalling adapter that is phosphorylated and recruits the p85 subunit of PI3K after Ang II stimulation of AT1 (Ang II subtype 1) receptors on VSMCs. This fragment of the PDGFR-β, which has a truncation of its extracellular domain, accounted for approx. 15% of the total PDGFR-β detected in VSMCs with an antibody against its cytoplasmic domain. Stimulation of VSMCs with Ang II increased tyrosine-phosphorylation of p70 PDGFR-β at Tyr751 and Tyr1021 and increased its binding to p85. PDGF also induced phosphorylation of p70 PDGFR-β, a response inhibited by the PDGF tyrosine kinase selective inhibitor, AG1296. By contrast, Ang II-induced phosphorylation of the 70 kDa receptor was not affected by AG1296. Ang II-stimulated phosphorylation of the p70 PDGFR-β was blocked by the AT1 receptor antagonist, candesartan (CV 11974) and was partially inhibited by PP2 {4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine}, an Src family kinase inhibitor. Our result suggests that the p70 PDGFR-β functions as an adapter that recruits PI3K to the membrane upon AT1 receptor stimulation.

Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor

Nature ◽  
1995 ◽  
Vol 375 (6528) ◽  
pp. 247-250 ◽  
Author(s):  
Mario B. Marrero ◽  
Bernhard Schieffer ◽  
William G. Paxton ◽  
Lauri Heerdt ◽  
Bradford C. Berk ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
At1 Receptor ◽  
Direct Stimulation ◽  
Stimulation Of ◽  
Stat Pathway

Stimulation of ACTH and GH release by angiotensin II in normal men is mediated by the AT1 receptor subtype

1998 ◽  
Vol 74 (1) ◽  
pp. 27-30 ◽  
Author(s):  
V. Coiro ◽  
R. Volpi ◽  
L. Capretti ◽  
G. Caffarri ◽  
R. Colla ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
At1 Receptor ◽  
Receptor Subtype ◽  
Normal Men ◽  
Stimulation Of

Angiotensin II type 1 receptor-mediated stimulation of c-fos gene expression in astroglial cultures

1993 ◽  
Vol 265 (4) ◽  
pp. C1046-C1049 ◽  
Author(s):  
M. K. Raizada ◽  
B. Rydzewski ◽  
D. Lu ◽  
C. Sumners
Keyword(s):  
Gene Expression ◽  
Angiotensin Ii ◽  
Receptor Activation ◽  
At1 Receptor ◽  
Mrna Levels ◽  
Ang Ii ◽  
Astroglial Cells ◽  
Pai 1 ◽  
Stimulation Of

Angiotensin II (ANG II) stimulates plasminogen activator inhibitor 1 (PAI-1) gene expression in astroglial cells prepared from rat brains. In this study, we investigated whether c-fos gene expression may be involved in this cellular action of ANG II. Incubation of astroglial cultures with ANG II caused a time- and dose-dependent transient stimulation of the steady-state levels of c-fos mRNA, with a maximal stimulation of 50-fold observed with 100 nM ANG II within 30-45 min. This stimulation was completely abolished by the presence of the type 1 ANG II (AT1) receptor antagonist losartan but not by the type 2 ANG II receptor blocker PD-123177. Depolarization of brain cell cultures with 50 mM K+ also caused a 100-fold increase in c-fos mRNA levels, an effect partially blocked by losartan. These observations show that AT1 receptor activation stimulates expression of the c-fos gene, which may act as a third messenger in the regulation of cellular actions of ANG II, including PAI-1 gene expression in astroglial cells.

Regulation of intracellular pH in the perfused heart by external HCO3- and Na(+)-H+ exchange

1993 ◽  
Vol 265 (1) ◽  
pp. H289-H298 ◽  
Author(s):  
A. A. Grace ◽  
H. L. Kirschenlohr ◽  
J. C. Metcalfe ◽  
G. A. Smith ◽  
P. L. Weissberg ◽  
...  
Keyword(s):  
Intracellular Ph ◽  
Cardiac Tissue ◽  
Intracellular Acidosis ◽  
Proton Efflux ◽  
Efflux Rate ◽  
Perfused Heart ◽  
Acid Load ◽  
Ethanesulfonic Acid ◽  
Intracellular Buffering Capacity ◽  
Ferret Heart

Both Na(+)-dependent HCO3- influx and the Na(+)-H+ antiport have been shown to contribute to recovery from intracellular acidosis in avian and mammalian cardiac tissue. We have investigated the participation of these mechanisms in the recovery of intracellular pH (pHi) after an acid load in the Langendorff-perfused ferret heart. pHi was measured from the phosphorus-31 nuclear magnetic resonance chemical shift of 2-deoxy-D-glucose 6-phosphate. Basal pHi was higher in HCO(3-)-buffered solution (7.05 +/- 0.01; n = 8) than in nominally HCO(3-)-free N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) solution (6.98 +/- 0.02; n = 9). Addition of 5-(N-ethyl-N-isopropyl)amiloride (EIPA) caused a significant fall in pHi in HEPES solution (6.91 +/- 0.02; n = 5) but not in HCO3- solution (7.02 +/- 0.02; n = 5). Intrinsic intracellular buffering capacity in 0 Na(+)-HEPES solution was 37 +/- 2 mmol/l (n = 4), and additional buffering due to HCO(3-)-CO2 was approximately 13 mmol/l in HCO3- solution. After an intracellular acidosis induced by an NH4Cl prepulse, the proton efflux rate (JH) at pHi 6.90 was 0.5 +/- 0.2 nmol.l-1.min-1 (n = 14) in HEPES solution and 1.2 +/- 0.4 mmol.l-1.min-1 (n = 13) in HCO3- solution. The addition of 1 microM EIPA effectively blocked proton efflux in HEPES solution (JH < 0.1 mmol.l-1.min-1; n = 8), whereas it slowed pHi recovery in HCO3- solution (JH = 0.6 +/- 0.2 mmol.l-1.min-1; n = 9). There was no recovery of pHi in Na(+)-free HCO3- solution (JH < 0.1 mmol.l-1.min-1; n = 3). The Na(+)-H+ antiport and a mechanism requiring both external Na+ and HCO3- each contribute approximately 50% to proton efflux at pHi 6.90 during the recovery from intracellular acidosis in the isolated perfused mammalian heart.

Intracellular pH recovery during respiratory acidosis in perfused hearts

1994 ◽  
Vol 266 (2) ◽  
pp. C489-C497 ◽  
Author(s):  
J. I. Vandenberg ◽  
J. C. Metcalfe ◽  
A. A. Grace
Keyword(s):  
Intracellular Ph ◽  
Cardiac Tissue ◽  
Respiratory Acidosis ◽  
Ph Indicator ◽  
Ethanesulfonic Acid ◽  
Intracellular Buffering Capacity ◽  
Acid Extrusion ◽  
Acid Loading ◽  
Perfused Hearts ◽  
Ferret Heart

Na(+)-H+ exchange and Na(+)-dependent HCO3- influx both contribute to recovery of intracellular pH (pHi) after an acidosis induced by using the NH4Cl prepulse technique in mammalian and avian cardiac tissue. We have investigated the relative contributions of these mechanisms to pHi recovery during respiratory acidosis in the Langendorff-perfused ferret heart with and without correction of extracellular pH (pHo). pHi was measured from the chemical shift of the exogenous 31P nuclear magnetic resonance pH indicator 2-deoxy-D-glucose 6-phosphate. Intrinsic intracellular buffering capacity, calculated from the change in intracellular HCO3- concentration after a change in CO2, was reduced from approximately 33 (no inhibitors of acid extrusion present) to 19 +/- 5 mM when H+ extrusion during the acid loading phase was inhibited. During respiratory acidosis (pHo approximately 6.95), the proton efflux rate (JH) calculated at pHi 6.85 was 0.30 +/- 0.04 mmol.l-1.min-1 (n = 9). When pHo was corrected by increasing external HCO3- concentration to 60 mM during respiratory acidosis (pHo approximately 7.33), JH was 1.11 +/- 0.11 mmol.l-1.min-1 (n = 7), and when pHo was partially corrected by the addition of 50 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid to the perfusion solution (pHo approximately 7.1), JH was 0.64 +/- 0.08 mmol.l-1.min-1 (n = 6). In all three groups Na(+)-H+ exchange and HCO3- influx each contributed approximately 50% to acid-equivalent efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

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