Chronic exposure to cyclosporine affects endothelial and smooth muscle reactivity in the rat aorta.
Chronic exposure to cyclosporine affects vascular reactivity. Experiments were designed to characterize the endothelium-dependent and endothelium-independent vascular reactivity of rats exposed to oral cyclosporin A (CyA). Two subsets of rats (n = 6) were treated with CyA (20 mg/kg/day) and olive oil (cyclosporine vehicle), respectively, for a period of 8 weeks. Aortic rings (4-5 mm) were suspended for isometric force measurement in organ chambers containing Krebs Ringer solution (37 degrees C, 95% O2, 5% CO2). The maximal endothelium-dependent relaxation to cumulative doses of acetylcholine was significantly decreased in the CyA-treated aortic rings compared to olive oil-treated ones (data expressed as percent of initial contraction; CyA, 50% +/- 3% versus olive oil, 37% +/- 7%; p < 0.05). However, endothelium-dependent relaxations to histamine and adenosine diphosphate and endothelium-independent relaxation to sodium nitroprusside were not affected in both groups. An endothelium-dependent contraction to serotonin and aggregating platelets were observed in the CyA group, but not in the control group. The endothelium-independent contraction to norepinephrine was enhanced in the CyA group (CyA ED50, log -7.66 +/- 0.18 mol/L versus olive oil ED50, log -7.01 +/- 0.11 mol/L; p < 0.01). These experiments suggest that chronic exposure to cyclosporine A could contribute to augmenting vascular tone by (1) decreased release of endothelial relaxing factor mediated by muscarinic receptors, (2) increased production of endothelium-related constricting factor mediated by serotoninergic receptors, and (3) greater vascular smooth muscle sensitivity to circulating catecholamine.
Cartier
R
R
Department of Cardiovascular Surgery, Montreal Heart Institute, Quebec, Canada.
Dagenais
F
F
Hollmann
C
C
Cambron
H
H
Buluran
J
J
D000109:Acetylcholine / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002784:Cholesterol / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006632:Histamine / Q000494:pharmacology; D007552:Isotonic Solutions; D008077:Lipoproteins, LDL / Q000097:blood / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects*; D009569:Nitric Oxide; D009599:Nitroprusside / Q000494:pharmacology; D000069463:Olive Oil; D010938:Plant Oils / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D013997:Time Factors
D004337:Drug Carriers; D007552:Isotonic Solutions; C051865:Krebs-Ringer solution; D008077:Lipoproteins, LDL; D000069463:Olive Oil; D010938:Plant Oils; D009599:Nitroprusside; D009569:Nitric Oxide; D012701:Serotonin; D000244:Adenosine Diphosphate; D006632:Histamine; D016572:Cyclosporine; D002784:Cholesterol; D000109:Acetylcholine