Synthesis and structure-activity relationships of a novel series of non-peptide angiotensin II receptor binding inhibitors specific for the AT2 subtype

Blankley, C. John; Hodges, John C.; Klutchko, S.; Himmelsbach, Richard J.; Chucholowski, Alexander; Connolly, Cleo J.; Neergaard, Sandra J.; Nieuwenhze, Michael S. Van; Sebastian, Alan

doi:10.1021/jm00115a014

Cited by 157 publications

(126 citation statements)

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“…As in murine myotubes, Ang II directly induced protein degradation in soleus muscle, as determined by tyrosine release, and was more effective at lower concentrations than in murine myotubes. To confirm that the effect was direct and to determine the receptor involved, the protein degradation assay was performed in the presence of ZD7155, a selective competitive antagonist for the Ang II type 1 (AT 1 ) receptor (Junggren et al, 1996) or PD123319, a selective AT 2 receptor antagonist (Blankley et al, 1991), or saralasin, a competitive nonselective Ang II antagonist (Steinhausen et al, 1986). The results in Figure 7A show attenuation of the increased protein degradation by both PD123319 and saralasin, while ZD7155 had no effect.…”

Section: Resultsmentioning

confidence: 98%

Angiotensin II directly induces muscle protein catabolism through the ubiquitin–proteasome proteolytic pathway and may play a role in cancer cachexia

2005

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The ability of angiotensin I (Ang I) and II (Ang II) to induce directly protein degradation in skeletal muscle has been studied in murine myotubes. Angiotensin I stimulated protein degradation with a parabolic dose -response curve and with a maximal effect between 0.05 and 0.1 mM. The effect was attenuated by coincubation with the angiotensin-converting enzyme (ACE) inhibitor imidaprilat, suggesting that angiotensin I stimulated protein degradation through conversion to Ang II. Angiotensin II also stimulated protein breakdown with a similar dose -response curve, and with a maximal effect between 1 and 2.5 mM. Total protein degradation, induced by both Ang I and Ang II, was attenuated by the proteasome inhibitors lactacystin (5 mM) and MG132 (10 mM), suggesting that the effect was mediated through upregulation of the ubiquitin -proteasome proteolytic pathway. Both Ang I and Ang II stimulated an increased proteasome 'chymotrypsin-like' enzyme activity as well as an increase in protein expression of 20S proteasome a-subunits, the 19S subunits MSS1 and p42, at the same concentrations as those inducing protein degradation. The effect of Ang I was attenuated by imidaprilat, confirming that it arose from conversion to Ang II. These results suggest that Ang II stimulates protein degradation in myotubes through induction of the ubiquitin -proteasome pathway. Protein degradation induced by Ang II was inhibited by insulin-like growth factor and by the polyunsaturated fatty acid, eicosapentaenoic acid. These results suggest that Ang II has the potential to cause muscle atrophy through an increase in protein degradation. The highly lipophilic ACE inhibitor imidapril (Vitort) (30 mg kg À1 ) attenuated the development of weight loss in mice bearing the MAC16 tumour, suggesting that Ang II may play a role in the development of cachexia in this model.

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Section: Resultsmentioning

confidence: 98%

Angiotensin II directly induces muscle protein catabolism through the ubiquitin–proteasome proteolytic pathway and may play a role in cancer cachexia

2005

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“…Cardiovascular responses to microinjections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) into the ARCN. The ARCN (ϳ2 mm long in the rostrocaudal direction) was arbitrarily divided into the following three equal segments (the coordinates mentioned for each segment indicate the level caudal to the bregma): the rostral segment (2.1-2.9 mm), middle segment (2.9 -3.7 mm), and caudal segment (3.7-4.5 mm).…”

Section: Resultsmentioning

confidence: 99%

“…High concentrations of ANG-(1-12) have been reported in the rat brain, and cells immunoreactive for ANG-(1-12) have been identified in the nucleus tractus solitarius (NTS) of the rat (1,30). Bilateral microinjections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) into the NTS have been reported to elicit transient depressor responses and an attenuation of baroreflex sensitivity (1). Chronic immunoneutralization of endogenous brain ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) by intracerebroventricular injections of anti-ANG-(1-12) IgG in hypertensive rats have been reported to elicit antihypertensive effects (21).…”

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confidence: 99%

The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II

Arakawa

Chitravanshi

Sapru

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Arakawa H, Chitravanshi VC, Sapru HN. The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1-12) and angiotensin II. Am J Physiol Heart Circ Physiol 300: H951-H960, 2011. First published December 24, 2010 doi:10.1152/ajpheart.01144.2010.-The hypothalamic arcuate nucleus (ARCN) has been reported to play a significant role in cardiovascular regulation. It has been hypothesized that the ARCN may be one of the sites of cardiovascular actions of angiotensins (ANGs). Experiments were carried out in urethaneanesthetized, artificially ventilated, adult male Wistar rats. The ARCN was identified by microinjections of N-methyl-D-aspartic acid (NMDA; 10 mM). Microinjections (50 nl) of ANG-(1-12) (1 mM) into the ARCN elicited increases in mean arterial pressure (MAP), heart rate (HR), and greater splanchnic nerve activity (GSNA). The tachycardic responses to ANG-(1-12) were attenuated by bilateral vagotomy. The cardiovascular responses elicited by ANG-(1-12) were attenuated by microinjections of ANG II type 1 receptor (AT1R) antagonists but not ANG type 2 receptor (AT2R) antagonist. Combined inhibition of ANG-converting enzyme (ACE) and chymase in the ARCN abolished ANG-(1-12)-induced responses. Microinjections of ANG II (1 mM) into the ARCN also increased MAP and HR. Inhibition of ARCN by microinjections of muscimol (1 mM) attenuated the pressor and tachycardic responses to intravenously administered ANG-(1-12) and ANG II (300 pmol/kg each). These results indicated that 1) microinjections of ANG-(1-12) into the ARCN elicited increases in MAP, HR, and GSNA; 2) HR responses were mediated via both sympathetic and vagus nerves; 3) AT1Rs, but not AT2Rs, in the ARCN mediated ANG-(1-12)-induced responses; 4) both ACE and chymase were needed to convert ANG-(1-12) to ANG II in the ARCN; and 5) ARCN plays a role in mediating the cardiovascular responses to circulating ANGs. blood pressure; heart rate; microinjection; N-methyl-D-aspartic acid; sympathetic nerve activity THE HYPOTHALAMIC ARCUATE NUCLEUS (ARCN) may play a significant role in cardiovascular regulation (10, 38). Consistent with this notion, we (31) have recently reported that chemical stimulation of the ARCN elicited increases in mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). These reports have provided a basis for investigations on different neurotransmitters and neuromodulators in the ARCN that may play a role in the regulation of cardiovascular function in normal and pathological states.A new endogenous angiotensin (ANG), ANG-(1-12), has recently been identified (30,44). Intravenous administration of this peptide has been reported to elicit an immediate pressor response in the rat, and this effect was blocked by prior administration of an ANG-converting enzyme (ACE) inhibitor or an ANG II type 1 receptor (AT 1 R) antagonist (30). These data indicated that in the periphery, ANG-(1-12) exerts its actions via a rapid conversion to ANG II (30). High concentrations of ANG-(1-12) have been reported in th...

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“…1) suggested that the AT2R plays an important role in the regulation of satellite cell differentiation and muscle regeneration. To investigate the role of the AT2R during muscle regeneration in vivo, we infused mice with the AT2R antagonist PD123319 (28) in a setting of CTX-induced injury ( Fig. 2A).…”

Section: At2r Expression Increases During Muscle Regeneration-mentioning

confidence: 99%

Angiotensin Type 2 Receptor Signaling in Satellite Cells Potentiates Skeletal Muscle Regeneration

Yoshida

Huq

Delafontaine

2014

Journal of Biological Chemistry

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Background: Angiotensin II induces skeletal muscle atrophy, but the function of other renin-angiotensin system components in skeletal muscle physiology is understood poorly. Results: Angiotensin II type 2 receptor (AT2R) blockade inhibits skeletal muscle regeneration and myoblast differentiation. Conclusion: AT2R positively regulates skeletal muscle regeneration. Significance: Stimulation of AT2R signaling may be beneficial in muscle wasting conditions.

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Synthesis and structure-activity relationships of a novel series of non-peptide angiotensin II receptor binding inhibitors specific for the AT2 subtype

Cited by 157 publications

References 6 publications

Angiotensin II directly induces muscle protein catabolism through the ubiquitin–proteasome proteolytic pathway and may play a role in cancer cachexia

Angiotensin II directly induces muscle protein catabolism through the ubiquitin–proteasome proteolytic pathway and may play a role in cancer cachexia

The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II

Angiotensin Type 2 Receptor Signaling in Satellite Cells Potentiates Skeletal Muscle Regeneration

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