[Effect of cyclosporin A dosage on the vascular tone of the thoracic aorta of rats].
Cyclosporine A (CyA) is known to affect the local release of endothelial-derived relaxing factor (EDRF). However, evidence that CyA could specifically alter endothelial signal transduction is not well understood. Experiments were designed to assess dose-dependent effect of CyA on vascular reactivity-specificity of the rat thoracic aorta. Three groups of rats (n = 10) were treated for 4 weeks with oral CyA 15 mg/kg/day (Gr 1), CyA 30 mg/kg/day (Gr 2), and olive oil (Gr 3), the CyA vehicle. At the end of the period, animals were euthanized and the thoracic aorta harvested for isometric assessment of endothelial and smooth muscle function in organ chambers. Maximal endothelial-dependent relaxation (Rmax) to acetylcholine dose-response was similarly affected in rats treated with CyA [Rmax (%): Gr 1: 33 +/- 8, Gr 2: 28 +/- 2, Gr 3:51 +/- 7, *p < 0.05]. At the opposite, response to adenosine diphosphate [Rmax (%): Gr 1: 11 +/- 2, Gr 2:24 +/- 3*, Gr 3:7 +/- 2, *p < 0.01] and histamine [dose-response CE50 (log M): Gr 1: +/- 12 +/- 0.05, Gr 2: +/- 5.45 +/- 0.05*, Gr 3: -4.85 +/- 0.08, *p < 0.05] were significantly enhanced in animals exposed to 30 mg/kg/day. Endothelium-independent relaxation to sodium nitroprusside (SNP) was comparable in all groups and dose-response to depolarizing (KCl) and non-depolarizing (norepinephrine) contractile agents were not affected either. These experiments suggest that CyA does not affect second messenger (cyclic-GMP) activation by an EDRF analogue (SNP) whereas signal transduction coupled to muscarinic, purinergic, and histaminergic receptors are either inhibited or enhanced by CyA in dose-dependent manner in the rat aortic model.
Cartier
R
R
Service de Chirurgie Cardiovasculaire, Institut de Cardiologie de Montréal, Québec, HIT IC8, Canada.
Mathieu
P
P
Bouchard
D
D
Buluran
J
J
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000503:physiopathology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects; D017978:Receptors, Growth Factor / Q000187:drug effects; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D017978:Receptors, Growth Factor; D014662:Vasoconstrictor Agents; D016572:Cyclosporine; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor