Inhibition of collateral artery growth by mibefradil: possible role of volume-regulated chloride channels.
Endothelial cell swelling is one of the earliest hallmarks of arteriogenesis, the growth and maturation of collaterals. Mibefradil was found to block endothelial Cl(-) channels that control the volume of endothelial cells. Thus the authors investigated whether the blockade of volume-controlling endothelial cell channels would translate into an inhibition of arteriogenesis. In BALB/c mice, the right femoral artery was ligated and the animals received either mibefradil or solvent (phosphate-buffered saline [PBS]) via osmotic minipumps. Laser Doppler perfusion ratio (R/L) of ligated versus nonligated distal hindlimb increased from 0.06 +/- 0.01 (immediately after ligation) to 0.25 +/- 0.02 (day 7) in the PBS group and only from 0.07 +/- 0.02 to 0.13 +/- 0.02 in the mibefradil group (p <.01). Collateral artery diameters were significantly smaller in the mibefradil group (61 +/- 4.7 microm) versus controls (77.3 +/- 0.9 microm) (p <.05). Relative hemoglobin oxygen saturation measurements confirmed these findings (p <.02). The inhibition of arteriogenesis in the mibefradil group suggests that endothelial Cl(-) channels are involved in the initiation of arteriogenesis.
Ziegelhoeffer
Tibor
T
Department of Experimental Cardiology, Max-Planck Institute, Bad Nauheim, Germany. t.ziegelhoeffer@kerckhoff.mpg.de
Scholz
Dimitri
D
Friedrich
Christian
C
Helisch
Armin
A
Wagner
Shawn
S
Fernandez
Borja
B
Schaper
Wolfgang
W
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D003097:Collateral Circulation / Q000187:drug effects*; D017023:Coronary Angiography; D004730:Endothelium, Vascular / Q000166:cytology; D004909:Erythrocyte Indices; D005263:Femoral Artery / Q000254:growth & development; D020748:Mibefradil / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010101:Oxygen Consumption
D018118:Chloride Channels; D020748:Mibefradil