Imidazoline receptors but not alpha 2-adrenoceptors are regulated in spontaneously hypertensive rat heart by chronic moxonidine treatment.
We have recently identified imidazoline I(1)-receptors in the heart. In the present study, we tested regulation of cardiac I(1)-receptors versus alpha(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 microg/kg/h s.c.) for 1 and 4 weeks. Autoradiographic binding of (125)I-paraiodoclonidine (0.5 nM, 1 h, 22 degrees C) and inhibition of binding with epinephrine (10(-10)-10(-5) M) demonstrated the presence of alpha(2)-adrenoceptors in heart atria and ventricles. Immunoblotting and reverse transcription-polymerase chain reaction identified alpha(2A)-alpha(2B)-, and alpha(2C), and -adrenoceptor proteins and mRNA, respectively. However, compared with normotensive controls, cardiac alpha(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 microg/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 (R(2) = 0.57; p < 0.006), suggesting that this protein may represent I(2)-receptors. The weak but significant correlation between the two imidazoline receptor proteins (R(2) = 0.28; p < 0.03) implies that they arise from the same gene. In conclusion, the heart possesses I(1)-receptors and alpha(2)-adrenoceptors, but only I(1)-receptors are responsive to hypertension and to chronic in vivo treatment with a selective I(1)-receptor agonist.
El-Ayoubi
Rouwayda
R
Laboratory of Cardiovascular Biochemistry, CHUM Research Center, 3840 St-Urbain St. (6-816), Montréal, Quebec, Canada, H2W 1T8.
Menaouar
Ahmed
A
Gutkowska
Jolanta
J
Mukaddam-Daher
Suhayla
S
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D007093:Imidazoles / Q000008:administration & dosage*; D054755:Imidazoline Receptors; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000096:biosynthesis* / Q000235:genetics; D011955:Receptors, Drug / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D007093:Imidazoles; D054755:Imidazoline Receptors; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; C043482:moxonidine