Abstract

We have recently identified imidazoline I₁-receptors in the heart. In the present study, we tested regulation of cardiac I₁-receptors versus α₂ -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 μg/kg/h s.c.) for 1 and 4 weeks. Autoradiographic binding of ¹²⁵I-paraiodoclonidine (0.5 nM, 1 h, 22°C) and inhibition of binding with epinephrine (10^–10–10^–5 M) demonstrated the presence of α₂-adrenoceptors in heart atria and ventricles. Immunoblotting and reverse transcription-polymerase chain reaction identified α_2A-α_2B-, and α_2C, and -adrenoceptor proteins and mRNA, respectively. However, compared with normotensive controls, cardiac α₂ -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 I₁-receptors in SHR are dose-dependently normalized by 1 week, with no additional effect after 4 weeks of treatment. Moxonidine (120 μg/kg/h) decreased B_max in right (40.0 ± 2.9–7.0 ± 0.6 fmol/unit area; p < 0.01) and left (27.7 ± 2.8–7.1 ± 0.4 fmol/unit area; p < 0.01) atria, and decreased the 85- and 29-kDa imidazoline receptor protein bands, in right atria, to 51.8 ± 3.0% (p < 0.01) and 82.7 ± 5.2% (p < 0.03) of vehicle-treated SHR, respectively. Moxonidine-associated percentage of decrease in B_max only correlated with the 85-kDa protein (R² = 0.57; p < 0.006), suggesting that this protein may represent I₂-receptors. The weak but significant correlation between the two imidazoline receptor proteins (R² = 0.28; p < 0.03) implies that they arise from the same gene. In conclusion, the heart possesses I₁-receptors and α₂-adrenoceptors, but only I₁-receptors are responsive to hypertension and to chronic in vivo treatment with a selective I₁-receptor agonist.