Differential blockade of central effects of angiotensin II by AT2-receptor antagonists

1993 ◽  
Vol 265 (1) ◽  
pp. H226-H231 ◽  
Author(s):  
R. E. Widdop ◽  
S. M. Gardiner ◽  
P. A. Kemp ◽  
T. Bennett
Keyword(s):  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Rapid Onset ◽  
At2 Receptor ◽  
Ang Ii ◽  
Central Administration ◽  
Inhibitory Effects ◽  
Binding Studies ◽  
Receptor Antagonists

In conscious, chronically instrumented, male Long-Evans rats, we showed previously that central administration (intracerebroventricular) of the AT1-receptor antagonist EXP-3174 (1 microgram) caused a rapid-onset marked, but transient, blockade of the regional hemodynamic responses to intracerebroventricular angiotensin II (ANG II). In contrast, the AT2-receptor antagonist PD-123319 (80 micrograms) caused a slow-onset, but marked and persistent, antagonism of the effects of intracerebroventricular ANG II. In the present study we attempted to mimic the actions of PD-123319 by giving a supramaximal dose of EXP-3174 (10 micrograms), and we also assessed the effects of PD-123177 (80 micrograms), an AT2-receptor antagonist that differs from PD-123319 only by a dimethyl group. The higher dose of EXP-3174 did not exert prolonged antagonistic effects against responses to intracerebroventricular ANG II, and PD-123177 was without inhibitory effects in this model. The results indicate important functional differences between putative AT2-receptor antagonists, when assessed in vivo, that are not apparent from binding studies.

scholarly journals Characterisation of angiotensin II receptors in isolated human subcutaneous resistance arteries

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S37-S41 ◽  
Author(s):  
Hoa Ytterberg ◽  
Lars Edvinsson
Keyword(s):  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
At1 Receptor ◽  
Receptor Subtypes ◽  
At2 Receptor ◽  
Ang Ii ◽  
Resistance Arteries ◽  
Receptor Antagonists ◽  
Response Curves ◽  
At1 Receptor Antagonists

Subcutaneous arteries have been used as a model for resistance arteries, which are potentially involved in enhanced blood pressure (BP) regulation in man. Angiotensin II (Ang II) is an important regulator of tone, acting via type 1 (AT1-) and type 2 (AT2-) receptor subtypes. The aim of this study was to characterise the Ang II receptors in isolated human subcutaneous arteries, using pharmacological and molecular methods. Subcutaneous arteries were obtained from patients undergoing elective gut surgery and were carefully dissected from the abdominal wall. Cylindrical segments were mounted on two L-shaped metal prongs, one of which was connected to a force-displacement transducer for continuous recording of isometric tension. Concentration-response curves to Ang II were constructed in the presence and absence of various selective AT1-receptor antagonists, candesartan, EXP3174, irbesartan and losartan, and the AT2-receptor antagonist, PD 123319. Responses to Ang II were measured as increases in force (mN) and expressed as a percentage of the response to 60 mM of KCl. Ang II caused a concentration-dependent contraction (pEC50=9.45±0.48, Emax=120±13%). Candesartan and EXP3174 caused concentration-dependent depression of the Emax of Ang II without any major shift of pEC50. Losartan and irbesartan caused a significant, dose-dependent rightward shift of the Ang II contraction-response curve in human subcutaneous arteries. The results show that contractile responses of human subcutaneous arteries are mediated via the AT1-receptor. The AT1-receptor antagonists, candesartan and EXP3174, acted in an insurmountable manner, while losartan and irbesartan were surmountable AT1-receptor antagonists. The AT2-receptor antagonist, PD 123319, (10, 100 nM) had no effect on Ang II-induced contraction. This is supported by the positive identification of mRNA for the human AT 1-receptor by RT-PCR.

Upregulation of angiotensin II type 2 receptor expression in estrogen-induced pituitary hyperplasia

2004 ◽  
Vol 286 (5) ◽  
pp. E786-E794 ◽  
Author(s):  
Cecilia Suarez ◽  
Graciela Díaz-Torga ◽  
Arturo González-Iglesias ◽  
Carolina Cristina ◽  
Damasia Becu-Villalobos
Keyword(s):  
Angiotensin Ii ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
At2 Receptor ◽  
Ang Ii ◽  
Pituitary Hyperplasia ◽  
Releasing Effect ◽  
At2 Receptors

Recent evidence shows that reexpression and upregulation of angiotensin II (ANG II) type 2 (AT2) receptor in adult tissues occur during pathological conditions such as tissue hyperplasia, inflammation, and remodeling. In particular, expression of functional AT2 receptors in the pituitary and their physiological significance and regulation have not been described. In this study, we demonstrate that chronic in vivo estrogen treatment, which induces pituitary hyperplasia, enhances local AT2 expression (measured by Western blot and RT-PCR) concomitantly with downregulation of ANG II type 1 (AT1) receptors. In vivo progesterone treatment of estrogen-induced pituitary hyperplasia did not modify either the ANG II receptor subtype expression pattern or octapeptide-induced and AT1-mediated calcium signaling. Nevertheless, an unexpected potentiation of the ANG II prolactin-releasing effect was observed in this group, and this response was sensitive to both AT1 and AT2 receptor antagonists. These data are the first to document that ANG II can act at the pituitary level through the AT2 receptor subtype and that estrogens display a differential regulation of AT1 and AT2 receptors at this level.

scholarly journals The Angiotensin II Type 2 (AT2) Receptor Promotes Axonal Regeneration in the Optic Nerve of Adult Rats

1998 ◽  
Vol 188 (4) ◽  
pp. 661-670 ◽  
Author(s):  
Ralph Lucius ◽  
Stefan Gallinat ◽  
Philip Rosenstiel ◽  
Thomas Herdegen ◽  
Jobst Sievers ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Receptor Antagonist ◽  
Axonal Regeneration ◽  
At1 Receptor ◽  
At2 Receptor ◽  
Ang Ii ◽  
Adult Rats ◽  
Nerve Crush ◽  
Retinal Explants

The renin-angiotensin system (RAS) has been traditionally linked to blood pressure and volume regulation mediated through the angiotensin II (ANG II) type 1 (AT1) receptor. Here we report that ANG II via its ANG II type 2 (AT2) receptor promotes the axonal elongation of postnatal rat retinal explants (postnatal day 11) and dorsal root ganglia neurons in vitro, and, moreover, axonal regeneration of retinal ganglion cells after optic nerve crush in vivo. In retinal explants, ANG II (10−7–10−5 M) induced neurite elongation via its AT2 receptor, since the effects were mimicked by the AT2 receptor agonist CGP 42112 (10−5 M) and were entirely abolished by costimulation with the AT2 receptor antagonist PD 123177 (10−5 M), but not by the AT1 receptor antagonist losartan (10−5 M). To investigate whether ANG II is able to promote axonal regeneration in vivo, we performed optic nerve crush experiments in the adult rats. After ANG II treatment (0.6 nmol), an increased number of growth-associated protein (GAP)-43–positive fibers was detected and the regenerating fibers regularly crossed the lesion site (1.6 mm). Cotreatment with the AT2 receptor antagonist PD 123177 (6 nmol), but not with the AT1 receptor antagonist losartan (6 nmol), completely abolished the ANG II–induced axonal regeneration, providing for the first time direct evidence for receptor-specific neurotrophic action of ANG II in the central nervous system of adult mammals and revealing a hitherto unknown function of the RAS.

scholarly journals Angiotensin II Type 2 Receptor Stimulation Increases the Rate of NG108–15 Cell Migration via Actin Depolymerization

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2923-2933 ◽  
Author(s):  
Peter Kilian ◽  
Shirley Campbell ◽  
Lyne Bilodeau ◽  
Marie-Odile Guimond ◽  
Claude Roberge ◽  
...  
Keyword(s):  
Cell Migration ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Neuronal Cell ◽  
Cellular Migration ◽  
At2 Receptor ◽  
Migration Speed ◽  
Ang Ii ◽  
Filamentous Actin ◽  
Actin Depolymerization

Angiotensin II (Ang II) has been reported to induce migration in neuronal cell types. Using time-lapse microscopy, we show here that Ang II induces acceleration in NG108–15 cell migration. This effect was antagonized by PD123319, a selective AT2 receptor antagonist, but not by DUP753, a selective AT1 receptor antagonist, and was mimicked by the specific AT2 receptor agonist CGP42112. This Ang II-induced acceleration was not sensitive to the inhibition of previously described signaling pathways of the AT2 receptor, guanylyl cyclase/cyclic GMP or p42/p44mapk cascades, but was abolished by pertussis toxin treatment and involved PP2A activation. Immunofluorescence studies indicate that Ang II or CGP42112 decreased the amount of filamentous actin at the leading edge of the cells. This decrease was accompanied by a concomitant increase in globular actin levels. Regulation of actin turnover in actin-based motile systems is known to be mainly under the control of the actin depolymerizing factor and cofilin. Basal migration speed decreased by 77.2% in cofilin-1 small interfering RNA-transfected NG108–15 cells, along with suppression of the effect of Ang II. In addition, the Ang II-induced increase in cell velocity was abrogated in serum-free medium as well as by genistein or okadaic acid treatment in a serum-containing medium. Such results indicate that the AT2 receptor increases the migration speed of NG108–15 cells and involves a tyrosine kinase activity, followed by phosphatase activation, which may be of the PP2A type. Therefore, the present study identifies actin depolymerization and cofilin as new targets of AT2 receptor action, in the context of cellular migration.

Angiotensin II receptors are expressed and functional in human esophageal mucosa

2009 ◽  
Vol 297 (5) ◽  
pp. G1019-G1027 ◽  
Author(s):  
Anna Casselbrant ◽  
Anders Edebo ◽  
Peter Hallersund ◽  
Emma Spak ◽  
Herbert F. Helander ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ion Transport ◽  
Receptor Antagonist ◽  
Ussing Chamber ◽  
Renin Angiotensin System ◽  
Esophageal Mucosa ◽  
Ang Ii

Only few studies have been devoted to the actions of the renin-angiotensin system (RAS) in the human gastrointestinal tract. The present study was undertaken to elucidate the expression and action of RAS in the human esophageal mucosa. Mucosal specimens with normal histological appearance were obtained from healthy subjects undergoing endoscopy and from patients undergoing esophagectomy due to neoplasm. Gene and protein expressions of angiotensin II (Ang II) receptor type 1 (AT1) and type 2 (AT2) and angiotensin-converting enzyme (ACE) were analyzed. In vivo functionality in healthy volunteers was reflected by assessing transmucosal potential difference (PD). Ussing chamber technique was used to analyze the different effects of Ang II on its AT1 and AT2 receptors. Immunoreactivity to AT1 and AT2 was localized to stratum superficiale and spinosum in the epithelium. ACE, AT1, and AT2 were found in blood vessel walls. Transmucosal PD in vivo increased following administration of the AT1 receptor antagonist candesartan. In Ussing preparations mean basal transmural PD was −6.4 mV, epithelial current ( Iep) 34 μA/cm2, and epithelial resistance ( Rep) 321 Ω·cm2. Serosal exposure to Ang II increased PD as a result of increased Iep, whereas Rep was constant. Ang II given together with the selective AT1-receptor antagonist losartan, or AT2 agonist C21 given alone, resulted in a similar effect. Ang II given in presence of the AT2-receptor antagonist PD123319 did not influence PD, but Iep decreased and Rep increased. In conclusion, Ang II receptors and ACE are expressed in the human esophageal epithelium. The results suggest that AT2-receptor stimulation increases epithelial ion transport, whereas the AT1 receptor inhibits ion transport and increases Rep.

Neuronal actions of oxytocin on the subfornical organ of male rats

1999 ◽  
Vol 276 (6) ◽  
pp. E1004-E1008 ◽  
Author(s):  
Takayoshi Hosono ◽  
Herbert A. Schmid ◽  
Kazuyuki Kanosue ◽  
Eckhart Simon
Keyword(s):  
Receptor Antagonist ◽  
Subfornical Organ ◽  
Male Rats ◽  
Vasopressin Receptor ◽  
Ang Ii ◽  
Inhibitory Effects ◽  
Extracellular Recordings ◽  
Similar Threshold ◽  
Dose Dependent

The aim of this study was to investigate effects of oxytocin (OT) on electrical neuronal activities in rat subfornical organ (SFO) and compare its action with the well-described excitatory effects of blood-borne angiotensin II (ANG II) on the same SFO neurons. With the use of extracellular recordings from spontaneously active neurons in slice preparations of the SFO of male rats, 11.7% of tested neurons ( n = 206) were excited and 9.7% were inhibited by superfusion with 10−6 M OT. Both excitatory and inhibitory effects of OT were dose dependent with similar threshold concentrations and were blocked by a specific OT-receptor antagonist but not by a vasopressin receptor antagonist. Blocking synaptic transmission with low calcium medium suppressed only inhibitory effects of OT. All but one of the OT-sensitive neurons were also excited by superfusion with ANG II at a concentration much lower than required for OT, suggesting that synaptically released OT rather than blood-borne OT alters the activity of SFO neurons in vivo. The results support the hypothesis that neurally released OT may modulate SFO-mediated functions by acting on OT-sensitive neurons.

Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation

2007 ◽  
Vol 293 (2) ◽  
pp. H1291-H1299 ◽  
Author(s):  
Amy K. L. Banes-Berceli ◽  
Pimonrat Ketsawatsomkron ◽  
Safia Ogbi ◽  
Bela Patel ◽  
David M. Pollock ◽  
...  
Keyword(s):  
Drinking Water ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Vascular Complications ◽  
Diabetic Rats ◽  
Ang Ii ◽  
Endothelin 1 ◽  
Endothelium Dependent Relaxation ◽  
Stat Pathway

The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats, we performed a time course study [ days 7, 14, and 28 after streptozotocin (STZ) injection] to determine changes in phosphorylation of JAK2, STAT1, and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1, and STAT3. Phosphorylation of JAK2, STAT1, and STAT3 was significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT1 receptor antagonist, 10 mg·kg−1·day−1 orally in drinking water), atrasentan (ETA receptor antagonist, 10 mg·kg−1·day−1 orally in drinking water), and AG-490 (JAK2 inhibitor, 5 mg·kg−1·day−1 intraperitoneally). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (SBP; tail cuff) of STZ-induced diabetic rats (SBP: 157 ± 9.0, 130 ± 3.3, 128 ± 6.8, and 131 ± 10.4 mmHg in STZ, STZ-candesartan, STZ-atrasentan, and STZ-AG-490 rats, respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3 ± 3.0, 92.6 ± 7.4, 76.9 ± 12.1, and 38.3 ± 13.1% in sham, sham + AG-490, STZ + AG-490, and STZ rats, respectively). Treatment of rats with AG-490 restored endothelium-dependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZ-induced diabetes.

Central administration of PD 123319 or EXP-3174 inhibits effects of angiotensin II

1993 ◽  
Vol 264 (1) ◽  
pp. H117-H125 ◽  
Author(s):  
R. E. Widdop ◽  
S. M. Gardiner ◽  
P. A. Kemp ◽  
T. Bennett
Keyword(s):  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Cardiovascular Response ◽  
Cardiovascular Responses ◽  
At1 Receptor ◽  
Ang Ii ◽  
Central Administration ◽  
Antagonist Activity ◽  
Renal Vasoconstriction ◽  
Regional Hemodynamics

Cardiovascular responses to intracerebroventricular angiotensin II (ANG II) were measured in conscious rats, chronically instrumented for the measurement of regional hemodynamics, over 4 consecutive days in the absence and presence of either the AT2 receptor antagonist, PD 123319 (experiment 1), or the AT1 receptor antagonist, EXP-3174 (experiment 2). Intracerebroventricular ANG II had pressor and bradycardic effects, which were associated with marked mesenteric and hindquarters vasoconstriction, and a small transient renal vasoconstriction. Both PD 123319 and EXP-3174, given intracerebroventricularly, abolished the cardiovascular response to intracerebroventricular ANG II, although the profiles of activity of the compounds were different. PD 123319 caused a slowly developing, but remarkably prolonged (1-2 days) inhibition of the effects of ANG II, whereas EXP-3174 caused an immediate inhibition of the effects of ANG II, although responses to ANG II had returned to control levels by the following day. These data suggest that the hemodynamic effects of ANG II may involve concurrent, and interdependent, activation of AT1 and AT2 receptors or that PD 123319 undergoes a unique biotransformation in the brain to some product(s) with AT1 receptor antagonist activity.

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