EFFECTS OF CYCLOSPORINE-A DOSAGE ON VASCU LAR TONE OF THE RAT THORACIC AORTA

Cyclosporine A (CyA) is known to affect the local release of endotheli al-derived relaxing factor (EDRF). However, evidence that CyA could sp ecifically alter endothelial signal transduction is not well understoo d. Experiments were designed to assess dose-dependent effect of CyA on vascular reactivity-specificity of the rat thoracic aorta. Three grou ps of rats (n = 10) were treated for 4 weeks with oral CyA 15 mg/kg/da y (Gr 1), CyA 30 mg/kg/day (Gr 2), and olive oil (Gr 3), the CyA vehic le. At the end of the period, animals were euthanized and the thoracic aorta harvested for isometric assessment of endothelial and smooth mu scle function in organ chambers. Maximal endothelial-dependent relaxat ion (Rmax) to acetylcholine dose-response was similarly affected in ra ts treated with CyA [Rmax (%): Gr 1: 33 +/- 8, Gr 2: 28 +/- 2, Gr 3: 5 1 +/- 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 CE(50) (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 (norepine phrine) contractile agents were not affected either. These experiments suggest that CyA does not affect second messenger (cyclic-GMP) activa tion by an EDRF analogue (SNP) whereas signal transduction coupled to muscarinic, purinergic, and histaminergic receptors are either inhibit ed or enhanced by CyA in dose-dependent manner in the rat aortic model .