Blockade of cyclosporine-induced vasoconstriction by the calcium channel blocker diltiazem in dogs.
The calcium channel blocker diltiazem has been shown to reduce cyclosporine toxicity both in clinical and in experimental studies. To determine the effect of diltiazem administration on cyclosporine vasoconstriction and on renal release of endothelin, we administered cyclosporine in models of renal and hind limb autoperfusion in the dog. Infusion of cyclosporine in the hind limb (20 mg) during diltiazem perfusion caused an average increase of 6 +/- 2 mm Hg in hind limb perfusion pressure compared with 17 +/- 2 mm Hg before diltiazem, a significant difference (p < 0.05). Similarly, injections of cyclosporine (10 mg) in the kidney during diltiazem infusion caused an average increase of 26 +/- 4 mm Hg in renal perfusion pressure compared with 83 +/- 13 mm Hg before diltiazem infusion, a significant decrease in the renal vascular response (p < 0.05). On the other hand, sodium nitroprusside did not change the renal vasoconstriction to cyclosporine, which suggests a specific effect of diltiazem. Serum levels of endothelin in renal venous blood increased from 0.5 +/- 0.4 pg/ml to 3.8 +/- 0.6 pg/ml with cyclosporine, despite diltiazem infusion. Therefore, although the calcium channel blocker diltiazem effectively decreases cyclosporine-induced renal and hind limb vasoconstriction, it does not act by preventing endothelin release induced by cyclosporine stimulation.
Carrier
M
M
Department of Cardiovascular Surgery, Montreal Heart Institute, Quebec, Canada.
Tronc
F
F
Stewart
D
D
Nattel
S
S
Pelletier
L C
LC
D000818:Animals; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004110:Diltiazem / Q000494:pharmacology*; D004285:Dogs; D016232:Endothelins / Q000097:blood; D006614:Hindlimb / Q000098:blood supply; D009599:Nitroprusside / Q000494:pharmacology; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D016232:Endothelins; D009599:Nitroprusside; D016572:Cyclosporine; D004110:Diltiazem