Summary
4 Groups of 2 month-old male Wistar rats were treated with a) cyclosporin A (CyA) 30 mg/kg/day alone, b) CyA plus cicletanine (Cic) 60 mg/kg/day, c) vehicle (vegetable oil) 1 ml/100 g rat/day and d) no treatment for 8 weeks. The reactivity of isolated papillary muscle to isoprenaline and Ca 2+ was not altered in any of the treated groups. Endothelium-dependent relaxation induced by acetylcholine was inhibited in aorta ring segments from CyA treated rats as compared to that of control and CyA+Cic-treated rats. The relaxation induced by acetylcholine in rat aortas was similar in all groups in the presence of 10 μM indomethacin. Noradrenaline sensitivity of aortic segments was not affected by any treatments applied. The Ca2+-concentration response curves of aorta segments from CyA-treated and CyA+Cic-treated rats were shifted to the right as compared to control rats. In interlobar renal arteries the endothelium-dependent relaxation induced by acetylcholine was not affected by any form of treatment. In renal arteries 10 μM indomethacin increased the maximal relaxation induced by acetylcholine about 50%. In these vessels noradrenaline sensitivity in CyA and CyA+Cic treated rats was higher than in controls. Cocaine, 3 μM, shifted the noradrenaline concentration response curve to the left about 0.4 log units in all renal vessel groups, thus renal vascular smooth muscle sensitivity to noradrenaline was significantly greater in vessels from rats receiving CyA than in vessels from control rats. Administration of CyA induced only slight renal morphological changes. Cic was without effect on CyA induced morphological abnormalities. The results indicate that Cic is able to reverse the inhibitory effect of CyA on endothelium-dependent relaxations in aorta but does not affect the increased noradrenaline sensitivity of renal arteries associated with CyA treatment and was without effect on CyA induced changes in renal morphology. Treatment with CyA alone or in combination with Cic had no effect on the contractile force of the papillary muscle, indicating that CyA only affects function of vascular but not cardiac tissue.
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References
Bertani T, Perico N, Abbate M, Battaglia C, Remuzzi G (1987) Renal injury induced by long-term administration of cyclosporine A to rats. Am J Pathol 127:569–579
Blinks JR (1966) Field stimulation as a means of effecting the graded release of autonomic transmitters in isolated heart muscle. J Pharmacol Exp Ther 151:221–235
Borel JF, Padova FD, Mason J, Quesniaux V, Ryffel B, Wenger R (1989) Pharmacology of cyclosporine (Sandimmune). Pharm Rev 42:239–242
Bourgain RH, Deby C (1988) Enhancement of prostacyclin generation by cicletanine (an in vitro investigation). Drug Exp Clin Res XIV:135–139
Clostre F, Etienne A (1988) General pharmacology of cicletanine. Drugs Exp Clin Res XIV:73–82
Copur MS, Tasdemir I, Turgan C, Yasavul U, Caglar S (1989) Effects of nitrendipine on bloodpressure and blood ciclosporin A level in patients with posttransplant hypertension. Nephron 52:227–230
Dieperink H, Leyssac PP, Starklint H, Jørgensen KA, Kemp E (1986) Antagonist capacities of nifedipine, captopril, phenoxybenzamine, prostacyclin and indomethacin on cyclosporin A induced impairment of rat renal function. Eur J Clin Invest 16:540–548
English J, Evan A, Houghton DC, Bennett WM (1987) Cyclosporine induced acute renal dysfunction in the rat. Transplant 44:135–141
Frei U, Harms A, Bakovic-Alt R, Pichlmayr R, Koch M (1990) Calcium channel blockers for kidney protection. J Cardiovasc Pharmacol 16:811–815
Gibbs CL (1978) Cardiac energetics. Physiol Rev 52:174–254
Gillum DM, Truong L, Tasby J, Migliore P, Suki WN (1988) Chronic cyclosporine nephrotoxicity. A rodent model. Transplant 46:285–292
Gisbert MP, Mery PF, Fischmeister R (1988) A patch-clamp study of the effects of cicletanine on whole-cell calcium current in ventricular myocytes. Drugs Exp Clin Res XIV:109–115
Hess ML, Hastillo A, Thompson JA, Sansonetti DJ, Szentpery S, Barrhart G, Lower RR (1987) Lipid mediators in organ transplantation: Does cyclosporin A accelerate coronary atherosclerosis. Transplant Proc 19:71–73
Lamb FS, Webb RC (1987) Cyclosporine augments reactivity of isolated blood vessels. Life Sci 40:2571–2578
Mason J (1989) Pharmacology of Cyclosporine (Sandimmune). Pharm Rev 42:423–434
Mason J, Müller-Schweinitzer E, Dupont M, Casellas D, Mihatsch M, Moore L, Kaskel F (1991) Cyclosporine and the renin-angiotensin system. Kidney Int 39 [Suppl 32]:528–532
Mikkelsen EO, Poulsen SH, Nyborg NCB, Sehested J (1991) Cyclosporin A treatment affects endothelium-dependent relaxation of large (aorta) but not small intrarenal arteries in rats. Blood Vessels 23:318 (abstr)
Mulvany MJ, Halpern W (1977) Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Rec 41:19–26
Patil PN, Fudge K, Jacobowitz D (1972) Steric aspects of adrenergic drugs. XVIII. α-adrenergic receptors of mammalian aorta. Eur J Pharmacol 19:79–87
Propper DJ, Whiting PH, Power DJ, Edward N, Catto GRD (1989) The effect of nifedipine on graft function in renal allograft recipients treated with cyclosporin A. Clin Nephrol 32:62–67
Rego A, Vargas R, Foegh ML, Ramwell PW (1988) Effect of cyclosporine A treatment on vascular reactivity of the rat thoracic aorta. Transplant Proc XX:572–577
Schachter M (1988) Cyclosporine A and hypertension. J Hypert 6:511–516
Tejani A, Lancman I, Pomrantz A, Khawar M, Chen C (1988) Nephrotoxicity of cyclosporine A and cyclosporine G in a rat model. Transplant 45:184–187
Weir MR, Peppler R, Gomolka D, Handwerger BS (1989) Additive inhibitory effect of cyclosporine and verapamil may occur through different mechanisms that may be dependent or independent of the slow calcium channel. Transplant Proc 21:866–870
Xue H, Bukoski RD, McCarron DA, Bennett WM (1987) Induction of contraction in isolated rat aorta by cyclosporine. Transplantation 43:715–718
Zoja C, Fursi L, Zilio P, Benigni A, Remuzzi G (1986) Cyclopsporin-induced endothelial cell injury. Lab Invest 55:455–462
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Mikkelsen, E.O., Poulsen, S.H., Nyborg, N.C.B. et al. Difference between aortic and renal vascular reactivity in cyclosporin A treated rats and the effect of cicletanine. Naunyn-Schmiedeberg's Arch Pharmacol 345, 356–361 (1992). https://doi.org/10.1007/BF00168698
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DOI: https://doi.org/10.1007/BF00168698