G-protein inwardly rectifying potassium channels are involved in the hypotensive effect of I1-imidazoline receptor selective ligands.
OBJECTIVE
The present study examined the role of G-protein inwardly rectifying potassium (GIRK) channels in the depressor responses elicited by intracisternal injections of imidazoline-like drugs in anesthetized rabbits.


RESULTS
Intracisternal injections of the I1-imidazoline receptor (I1R) selective ligands LNP509 (30 microg/kg) and LNP640 (2 microg/kg) (subthreshold doses), and of the GIRK channel opener flupirtine (30 microg/kg) did not affect mean arterial blood pressure (MAP). LNP509 and LNP640, however, elicited substantial depressor responses in rabbits pretreated with flupirtine (-17 +/- 2 and -18 +/- 1 mmHg, respectively, P < 0.05). Injection of higher doses of LNP509 (200 microg/kg) or LNP640 (10 microg/kg) elicited substantial reductions in MAP (-45 +/- 3 and -39 +/- 2 mmHg, respectively, P < 0.05) in naive rabbits. The depressor responses elicited by the higher doses of LNP509 or LNP640 were markedly diminished by pretreatment with the GIRK channel blocker tertiapin-Q (10 microg/kg) (-23 +/- 3 and -26 +/- 2 mmHg, respectively, P < 0.05 compared with nonpretreated rabbits), whereas tertiapin-Q (10 microg/kg) did not affect MAP by itself. Maximal-specific binding (Bmax) of the I1R ligand [I]LNP911 to PC12 cell membranes (296 +/- 59 fmol/mg protein) was enhanced by flupirtine pretreatment whereas it was reduced by tertiapin-Q pretreatment (687 +/- 122 and 68 +/- 21 fmol/mg protein, respectively, P < 0.05 vs. control binding).


CONCLUSIONS
These findings demonstrate that the modulation of GIRK channels affects I1R's function and raise the possibility that GIRK channels, and I1Rs are parts of a single proteic complex.
Yoro Sy
Guata
G
Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, INSERM U715, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.
Urosevic
Dragan
D
Fellmann
Lyne
L
Greney
Hugues
H
Bousquet
Pascal
P
Feldman
Josiane
J
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002946:Cisterna Magna / Q000187:drug effects*; D003521:Cyclopropanes / Q000008:administration & dosage; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000008:administration & dosage*; D054755:Imidazoline Receptors / Q000502:physiology*; D007278:Injections, Spinal; D008297:Male; D011758:Pyrroles / Q000008:administration & dosage; D011810:Quinoxalines / Q000008:administration & dosage*; D011817:Rabbits
D003521:Cyclopropanes; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007093:Imidazoles; D054755:Imidazoline Receptors; C427228:LNP 509; C529715:LNP640; D011758:Pyrroles; D011810:Quinoxalines; C410887:imidazoline I1 receptors