Cyclosporine treatment preserves coronary resistance artery function in rat cardiac allografts.
BACKGROUND
A marked decline in vascular myogenic response occurs during the course of rat cardiac allograft rejection. Two important contributory features are an inducible nitrous oxide synthase (iNOS)-catalyzed, NO-mediated vasodilation and a loss of smooth muscle function. In this study, we examine the effect of cyclosporine immunosuppressive therapy on the alleviation of arterial dysfunction of coronary resistance arteries in allografts using pressure myography.


METHODS
Rats receiving heterotopic abdominal cardiac transplantation were treated with cyclosporine (5 mg/kg), Cremophore or distilled water. Coronary septal arteries (internal diameter 200 microm) were dissected from isograft (Lewis to Lewis) and allograft (Fisher to Lewis) rat hearts at Day 21 post-transplantation and mounted on a pressure myograph. Pressure-induced vasoconstriction was measured before and after iNOS inhibition with aminoguanidine (AG; 100 micromol/liter). Both endothelium-based (ACh-induced) and endothelium-independent (sodium nitroprusside-induced) vasorelaxation were also recorded in each group.


RESULTS
Pressure-induced myogenic contraction was reduced in allograft coronary arteries at Day 21 post-transplantation compared with matched isografts (p < 0.05). AG potentiated myogenic tone in allograft arteries, but had no effect on untreated Day 21 isograft vessels, indicating the presence of iNOS-based relaxation only in allograft vessels. Depolarization-induced vasoconstriction was lower in allograft compared with isograft arteries (p < 0.05). Cyclosporine therapy also improved depolarization-induced constriction in allograft vessels compared with untreated groups (p < 0.05). Furthermore, cyclosporine therapy preserved endothelium-based and endothelium-independent vasorelaxation in allograft arteries at Day 21 post-transplantation.


CONCLUSIONS
Cyclosporine immunosuppressive therapy has a significant effect on the alleviation of early endothelial and smooth muscle dysfunction in coronary allograft arteries.
Moien-Afshari
Farzad
F
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Choy
Jonathan C
JC
McManus
Bruce M
BM
Laher
Ismail
I
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000503:physiopathology; D016572:Cyclosporine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D016027:Heart Transplantation / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014661:Vasoconstriction / Q000187:drug effects
D004791:Enzyme Inhibitors; D006146:Guanidines; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine