Imidazoline Receptors but Not α₂-Adrenoceptors Are Regulated in Spontaneously Hypertensive Rat Heart by Chronic Moxonidine Treatment

Abstract

We have recently identified imidazoline I 1 -receptors in the heart. In the present study, we tested regulation of cardiac I 1 -receptors versus ␣ 2 -adrenoceptors in response to hypertension and to chronic exposure to agonist. Spontaneously hypertensive rats (SHR, 12-14 weeks old) received moxonidine (10, 60, and 120 g/kg/h s.c.) for 1 and 4 weeks. Autoradiographic binding of 125 I-paraiodoclonidine (0.5 nM, 1 h, 22°C) and inhibition of binding with epinephrine (10 Ϫ10 -10 Ϫ5 M) demonstrated the presence of ␣ 2 -adrenoceptors in heart atria and ventricles. Immunoblotting and reverse transcription-polymerase chain reaction identified ␣ 2A -, ␣ 2B -, and ␣ 2C -adrenoceptor proteins and mRNA, respectively. However, compared with normotensive controls, cardiac ␣ 2 -adrenoceptor kinetic parameters, receptor proteins, and mRNAs were not altered in SHR with or without moxonidine treatment. In contrast, autoradiography showed that up-regulated atrial I 1 -receptors in SHR are dose-dependently normalized by 1 week, with no additional effect after 4 weeks of treatment. Moxonidine (120 g/kg/h) decreased B max in right (40.0 Ϯ 2.9 -7.0 Ϯ 0.6 fmol/unit area; p Ͻ 0.01) and left (27.7 Ϯ 2.8 -7.1 Ϯ 0.4 fmol/unit area; p Ͻ 0.01) atria, and decreased the 85-and 29-kDa imidazoline receptor protein bands, in right atria, to 51.8 Ϯ 3.0% (p Ͻ 0.01) and 82.7 Ϯ 5.2% (p Ͻ 0.03) of vehicle-treated SHR, respectively. Moxonidine-associated percentage of decrease in B max only correlated with the 85-kDa protein (R 2 ϭ 0.57; p Ͻ 0.006), suggesting that this protein may represent I 1 -receptors. The weak but significant correlation between the two imidazoline receptor proteins (R 2 ϭ 0.28; p Ͻ 0.03) implies that they arise from the same gene. In conclusion, the heart possesses I 1 -receptors and ␣ 2 -adrenoceptors, but only I 1 -receptors are responsive to hypertension and to chronic in vivo treatment with a selective I 1 -receptor agonist.

Cystathionine-γ lyase-derived hydrogen sulfide mediates the cardiovascular protective effects of moxonidine in diabetic rats

“…3A). These findings in STZ rats are supported by similar responses caused by chronic moxonidine administration in other model systems including SHRs and cardiomyocytes (Aceros et al, 2011; El-Ayoubi et al, 2004; Ernsberger et al, 1999; Hamilton et al, 1993; Mukaddam-Daher, 2012). Second, we present a novel molecular mechanism for the favorable cardiovascular and redox effects of moxonidine in diabetes based on recent evidence that identified DAPK3 as an upstream activator of MAPKs, and as a mediator of oxidative stress and hypertension (Usui et al, 2012).…”

Imidazoline receptors in the heart: a novel target and a novel mechanism of action that involves atrial natriuretic peptides

“…Moxonidine (120 µg kg -1 h -1 ) decreased (P < 0.01) I 1 -receptor Bmax in right and left atria to normal levels (Figure 2), without altering α2-adrenoceptor Bmax. These results showed for the first time that imidazoline I 1 -receptors and α2-adrenoceptors are present in heart atria and ventricles, and that only imidazoline I 1 -receptors are responsive to changes in the cardiovascular environment and to chronic exposure to the I 1 -selective agonist, moxonidine (15,16). These results implicate heart imidazoline I 1 -receptors in cardiovascular regulation.…”

Immunodetection and subcellular distribution of imidazoline receptor proteins with three antibodies in mouse and human brains: Effects of treatments with I1- and I2-imidazoline drugs

“…↓or↑: modest decrease or increase (<20 %); ↓↓or↑↑: marked decrease or increase (>30 %); ≈: no significant change. Abbreviations. corr: correlation between Bmax and IR protein; Mox: moxonidine; Efa: efaroxan; Ida: idazoxan Selected references: 1 (Ruiz et al, 1993), 2 (Escribá et al, 1994), 3 (García-Sevilla et al, 1995a,b), 4 (Escribá et al, 1995), 5 (Sastre et al, 1996), 6 (Escribá et al, 1996), 7 (García-Sevilla et al, 1996a,b), 8 (Ivanov et al, 1998a,b), 9 (Boronat et al, 1998), 10 (García-Sevilla et al, 1998), 11 (García-Sevilla et al, 1999), 12 (Piletz et al, 1999), 13 (Barturen et al, 1999), 14 (Halaris et al, 1999), 15 (Olmos et al, 1999a), 16 (Piletz et al, 2000a,b), 17 (Alahari et al, 2000), 18 (El-Ayoubi et al, 2002), 19 (Tyacke et al, 2002), 20 (Sano et al, 2002), 21 (García-Sevilla and Ferrer-Alcón, 2003), 22 (Piletz et al, 2003), 23 (Ma et al, 2003), 24 (El-Ayoubi et al, 2003), 25 (Dontenwill et al, 2003a,b), 26 (Chen et al, 2003), 27 (El-Ayoubi et al, 2004), 28 (Lim and Hong, 2004), 29 (Zhang and Abdel-Rahman, 2006), 30 (Sun et al, 2007), 31 (Zhang and Abdel-Rahman, 2008), 32 (Wang et al, 2009), 33 (Li and Zhang, 2011), 34 (Ding et al, 2013), 35 (Wang et al, 2013), 36 (Mar et al, 2013), 37 (Aceros et al, 2014), 38 (Chen et al, 2014). …”