Article

Differential regulation by AT 1 and AT 2 receptors of angiotensin II-stimulated cyclic GMP production in rat uterine artery and aorta

Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
British Journal of Pharmacology (Impact Factor: 4.84). 04/2004; 141(6):1024-31. DOI: 10.1038/sj.bjp.0705694
Source: PubMed

ABSTRACT

In the present study we determined whether angiotensin II (Ang II) could increase cyclic GMP levels in two blood vessels that exhibit markedly different angiotensin II receptor subtype expression: rat uterine artery (UA; AT2 receptor-predominant) and aorta (AT1 receptor-predominant), and investigated the receptor subtype(s) and intracellular pathways involved.
UA and aorta were treated with Ang II in the absence and presence of losartan (AT1 antagonist; 0.1 μM), PD 123319 (AT2 antagonist; 1 μM), NOLA (NOS inhibitor; 30 μM), and HOE 140 (B2 antagonist; 0.1 μM), or in combination.
Ang II (10 nM) induced a 60% increase in UA cyclic GMP content; an effect that was augmented with PD 123319 and HOE 140 pretreatment, and abolished by cotreatment with losartan, as well as by NOLA.
In aorta, Ang II produced concentration-dependent increases in cyclic GMP levels. Unlike effects in UA, these responses were abolished by PD 123319 and by NOLA, whereas losartan and HOE 140 caused partial inhibition.
Thus, in rat UA, Ang II stimulates cyclic GMP production through AT1 and, to a less extent, AT2 receptors. In rat aorta, the Ang II-mediated increase in cyclic GMP production is predominantly AT2 receptor-mediated. In both preparations, NO plays a critical role in mediating the effect of Ang II, whereas bradykinin has differential roles in the two vessels. In UA, B2 receptor blockade may result in a compensatory increase in cyclic GMP production, whilst in aorta, bradykinin accounts for approximately half of the cyclic GMP produced in response to Ang II.
British Journal of Pharmacology (2004) 141, 1024–1031. doi:10.1038/sj.bjp.0705694

Download full-text

Full-text

Available from: Robert E Widdop
  • Source
    • "It demonstrated that (1) lower angiotensin AT 2 receptors (AT 2 R) mRNA and protein expression can contribute to vasoconstriction in untreated SHR; (2) acute and chronic AT 1 -blockade restored AT 2 R expression and its vasodilator function in mesenteric resistance arteries and contributes to blood pressure control in SHR treated (You et al., 2005; Badzynska et al., 2014). Vasodilation induced by AT 2 R stimulation has been associated with NO production by endothelial cells and cGMP production by smooth muscle cells (Hannan et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: This work investigated the effects of the ethanolic extract (EEJg) of aerial parts of Jatropha gossypiifolia L. and its aqueous (AFJg) and chloroformic (CFJg) fractions on the blood pressure and vascular reactivity (VR) in normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR). In anaesthetized NWR, the EEJg and its fractions reduced mean blood pressure (MAP). The oral administration of EEJg (100 mg/kg/bw), for 8 weeks, did not alter MAP and heart rate in the non-anesthetized SHR. VR was determined in mesenteric artery rings, with the EEJg and fractions inhibiting the contractile responses to noradrenaline (NA, 10-9 to 10-4 M) in NWR, but not in SHR. In addition, the CFJg inhibited the contractile response to calcium (CaCl 2 , 10-6 to 10-2 M). These results suggest that J. gossypiifolia L. has no effect on the hypertensive factors in SHR, which is a model of polygenic hypertension, but indicate the presence of substances with hypotensive activity, which act directly on the adrenoceptor and/or decrease calcium mobilization in NWR.
    Full-text · Article · Apr 2014 · African journal of pharmacy and pharmacology
  • Source
    • "AGTR1 is a ubiquitously expressed protein with significant effects in renal, cardiovascular, hepatic, and neural physiology. However, AGTR1 protein expression is tissue and cell specific primarily due to differential transcription of the Agtr1 gene (Hannan et al. 2004, Tower et al. 2010, Braga 2011). Changes in Agtr1 transcription also occur under pathophysiological conditions , such as damaged cardiac tissue after myocardial infarction (Sun & Weber 1994), atrial tissue and the rostral ventrolateral medulla in chronic heart failure (Kaprielian et al. 1997, Gao et al. 2008), and in cardiac, renal, and neural tissue in cases of spontaneous hypertension (Esler 1993, Raizada et al. 1993, Lenkey et al. 1997). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently, we have demonstrated that 13-cis retinoic acid (13cRA) down-regulates rat angiotensin type 1A receptor (AT1AR) gene transcription through a MAP Kinase (ERK1/2) dependent mechanism in rat liver epithelial and aortic smooth muscle cells. However, the exact mechanism remained unknown. In this study, we determined the signaling intermediates activated by ERK1/2 involved in 13cRA mediated AT1AR down-regulation. Serially deleted rat AT1AR promoter CAT constructs indicate fragments containing a region -2541 and -1836 bp upstream of the 5 prime possess an Sp1 consensus sequence (5'-TGGGGCGGGGCGGGG-3') have reduced CAT activity. Mobility shift analysis using untreated nuclear extracts in the presence of mithramycin A suggest the trans-acting factor binding to this cis-acting element is Sp1. 13cRA significantly reduced specific binding without any change in Sp1 protein expression. Studies showed 13cRA maximally phosphorylates and tranlocates to the nucleus ERK1/2 within 5-10 minutes, activating Egr-1 mRNA expression at 20 minutes followed by de novo protein synthesis, leading to an Egr-1/Sp1 interaction. siRNA silencing of Egr-1 restored AT1AR mRNA and protein expression in 13cRA treated cells, and Sp1 silencing results in complete loss of AT1AR expression. Our study suggests that 13cRA mediated activation of ERK1/2, through Egr-1, is capable of disrupting Sp1, the requisite transactivator for AT1AR expression, providing a novel paradigm in AT1AR gene transcription.
    Preview · Article · Mar 2013 · Journal of Molecular Endocrinology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: British Journal of Pharmacology (2003) 140, 809–824. doi:10.1038/sj.bjp.0705448
    Full-text · Article · Dec 2003 · British Journal of Pharmacology
Show more