Agonistic and antagonistic properties of angiotensin analogs at the AT2 receptor in PC12W cells

Brechler, Véronique; Jones, Phillip W.; Levens, Nigel; Gasparo, Marc de; Bottari, Serge P.

doi:10.1016/0167-0115(93)90244-3

Cited by 112 publications

(49 citation statements)

References 21 publications

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“…6 -10 These current data confirm previous in vitro studies that have demonstrated AT 2 R-mediated vasorelaxation with Ang II in mesenteric arteries, 11-13 and we have now also shown that CGP42112 behaves as a full AT 2 R agonist, as has previously been shown in cell culture. 29 Consistent with this finding, short-term AT 2 R stimulation in vivo with CGP42112, in the presence of candesartan, lowered blood pressure in spontaneously hypertensive rats. 10 More recently, we have also observed widespread regional vasodilator effects of CGP42112 by using identical protocols in a conscious rats instrumented with Doppler flow probes.…”

Section: Discussionsupporting

confidence: 75%

AT ₂ Receptor-Mediated Relaxation Is Preserved After Long-Term AT ₁ Receptor Blockade

Widdop

Matrougui²,

Lévy³

et al. 2002

Hypertension

143

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Abstract-Angiotensin II type 2 receptor (AT 2 R) stimulation may cause vasodilation per se and may contribute to the antihypertensive effect produced by Angiotensin II type 1 receptor (AT 1 R) antagonists, given that AT 1 R blockade increases endogenous levels of Ang II, suggesting a physiological role for the unblocked AT 2 R. Thus, we first directly assessed whether or not there is desensitization to AT 2 R-mediated vasorelaxation because this is an important consideration, given the raised Ang II levels and the marked desensitization that is known to occur after AT 1 R stimulation. Second, we examined if AT 2 R-mediated vasorelaxation is preserved after long-term treatment with the AT 1 R antagonist candesartan cilexetil. Consecutive concentration-response curves to AT 2 R stimulation, with either Ang II (with AT 1 R blockade) or the selective agonist CGP42112, were studied in rat isolated mesenteric resistance arteries mounted in an arteriograph. AT 2 R stimulation with Ang II induced a concentration-dependent relaxation without desensitization. Similarly, CGP42112 evoked highly reproducible relaxation, which, like Ang II, was abolished by the AT 2 R antagonist PD123319. By contrast, AT 1 R-mediated contraction exhibited marked desensitization. In rats treated with candesartan cilexetil (2 mg/kg per day for 2 weeks), AT 1 R-mediated contraction was abolished, whereas AT 2 R-mediated relaxation evoked by either Ang II or CGP42112 was highly reproducible, PD123319-sensitive, and of a magnitude similar to that observed in naïve animals. Therefore, this study has provided unequivocal evidence for the reproducible nature of AT 2 R-mediated vasorelaxation during short-term and long-term AT 1 R blockade. (Ang II), including vasoconstriction, aldosterone release, and trophic effects. The physiological role of the AT 2 receptor (AT 2 R), on the other hand, is more controversial. Increasingly, evidence suggests that AT 2 R stimulation opposes the actions of AT 1 R stimulation. 1 However, recent data with AT 2 R knockout mice have provided conflicting data regarding the trophic effects of AT 2 R, in that AT 2 R in fact mediated Ang II-evoked cardiovascular growth, 2,3 as opposed to conventional dogma of a growth-inhibitory effect of AT 2 R. 4 Interestingly, the former studies are consistent with earlier findings in rats with pharmacological AT 2 R blockade. 5 Although the trophic effects of AT 2 R are open to debate, the potential vasodilator signaling pathways of AT 2 R stimulation are much more accepted. AT 2 R are thought to signal through cGMP/nitric oxide and/or bradykinin, at least in the vasculature and kidney. 6 -9 Indeed, it has recently been shown that short-term in vivo AT 2 R stimulation in spontaneously hypertensive rats will lower blood pressure. 10 In addition, AT 2 R-mediated relaxation of isolated mesenteric resistance arteries has been reported, 11-13 as well as AT 2 receptor mRNA and protein expression in this tissue. 11,[13][14][15] In vivo, AT 1 R antagonists are associated with a rise in plasma ...

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Section: Discussionsupporting

confidence: 75%

AT ₂ Receptor-Mediated Relaxation Is Preserved After Long-Term AT ₁ Receptor Blockade

Widdop

Matrougui²,

Lévy³

et al. 2002

Hypertension

143

View full text Add to dashboard Cite

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“…110,111 Most of the studies have described CGP42112A as a selective peptide AT 2 receptor agonist. [112][113][114] However, a few studies have also considered it as an AT 2 receptor antagonist and employed it to abolish the effects of angiotensin neuropeptides. 115 It has been described as acting as a selective AT 2 receptor ligand (may act as agonist as well as antagonist) depending upon the dose.…”

Section: At 2 Receptorsmentioning

confidence: 99%

Renin–angiotensin system in pain: Existing in a double life?

Bali

Singh

Jaggi

2014

J Renin Angiotensin Aldosterone Syst

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Apart from the well-documented role of the renin-angiotensin-aldosterone system (RAAS) in regulating the blood pressure and other related parameters, its role in modulating different physiological/pathological functions, including pain, has also been described. Like its dual role in regulating stress-related anxiety and cognitive functions, its dual role has also been documented in pain modulation in different disease states. Drugs blocking the RAAS activation, viz., renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, AT 1 receptor antagonists and aldosterone antagonists, have been shown to produce beneficial effects in migraine and neuropathic and nociceptive pain. Their beneficial effects have been mainly attributed to inhibition of the inflammatory cascade of reactions by inhibiting the generation of key cytokines, including tumor necrosis factor (TNF)-α. On the contrary, clinical as well as preclinical studies have also shown the paininducing actions of renin-angiotensin system (RAS) blocking drugs. Furthermore, the pain-relieving actions of angiotensin II (AngII) and pain-inducing actions of AT 1 blockers have also been described. The pain-inducing actions of ACE inhibitors have been mainly attributed to interference with metabolism of bradykinin and substance P, while the analgesic actions of AngII have been mainly related to activation of brain localized AT 2 receptors and release of endogenous opioids. The present review describes the dual role of the RAAS in different states of pain.

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“…Therapeutic circulating concentrations of irbesartan are reported to be between ~1-10 mmol/L 25,37) . Pharmacokinetic studies suggest that the effective inhibitory dose of PD123319 for use in in vitro culture is 0.1-1 µmol/L 38) . The MKK1/2 inhibitor, PD98059, binds directly to MKK1/2 blocking it's capacity to phosphorylate ERK1/2, consequently blocking ERK1/2 activation 39) .…”

Section: Zymographymentioning

confidence: 99%

Involvement of Angiotensin II Type 1 and 2 Receptors in Gelatinase Regulation in Human Carotid Atheroma <i>in vitro </i>

Clancy

Koblar

Golledge

2016

JAT

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Agonistic and antagonistic properties of angiotensin analogs at the AT2 receptor in PC12W cells

Cited by 112 publications

References 21 publications

AT ₂ Receptor-Mediated Relaxation Is Preserved After Long-Term AT ₁ Receptor Blockade

AT ₂ Receptor-Mediated Relaxation Is Preserved After Long-Term AT ₁ Receptor Blockade

Renin–angiotensin system in pain: Existing in a double life?

Involvement of Angiotensin II Type 1 and 2 Receptors in Gelatinase Regulation in Human Carotid Atheroma <i>in vitro </i>

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Agonistic and antagonistic properties of angiotensin analogs at the AT2 receptor in PC12W cells

Cited by 112 publications

References 21 publications

AT 2 Receptor-Mediated Relaxation Is Preserved After Long-Term AT 1 Receptor Blockade

AT 2 Receptor-Mediated Relaxation Is Preserved After Long-Term AT 1 Receptor Blockade

Renin–angiotensin system in pain: Existing in a double life?

Involvement of Angiotensin II Type 1 and 2 Receptors in Gelatinase Regulation in Human Carotid Atheroma <i>in vitro </i>

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AT ₂ Receptor-Mediated Relaxation Is Preserved After Long-Term AT ₁ Receptor Blockade

AT ₂ Receptor-Mediated Relaxation Is Preserved After Long-Term AT ₁ Receptor Blockade