Summary
Chronic treatment with cyclosporine A (Cx) seems to produce a decreased ability of the endothelium to secrete nitric oxide. However, its effect on the coronary arterial system remains controversial. Therefore, coronary arteries isolated from piglets treated by intramuscular injections of Cx 10 mg/kg day, IM, for 22 days were studied in organ baths and compared with those isolated from control animals (IM injections of the Cx solvent). Depolarization-induced contractions (KCl 120 mM) were similar in both groups, whereas the acetylcholine-induced contractions (percent of 120 mM KCl) were enhanced: The area under the curve (AUC) was 245±51 in the Cx group versus 110±15 in the control group (p<0.05). Removal of the endothelium did not significantly modify the acetylcholine-induced contractions in both groups and, therefore, did not attenuate the enhanced responsiveness to acetylcholine in the Cx group. On unrubbed rings contracted with prostaglandin F2α, the endothelium-dependent relaxations from serotonin (in the presence of 1 μM ketanserin) were reduced: The AUC was 479±24 in the Cx group versus 385±22 in the control group (p<0.02). Larger AUC values were also found for bradykinin and substance P in the Cx group: 158±18 versus 55±17 (in the control group, p<0.01) and 198±8 versus 145±12 (p<0.01), respectively. Nevertheless, no alteration in calcium ionophore-induced relaxations was observed: The AUC was 217±10 in the Cx group and 224±18 in the control group (NS). Indomethacin incubation (10 μM) did not prevent the impairment in endothelium-dependent relaxations and did not attenuate the cyclosporine-induced augmentation of acetylcholine-induced contractions. Thus, chronic administration of cyclosporine to piglets impairs the coronary endothelial function and produces functional changes in smooth muscle cells. These alterations may play a role in the occurrence of cardiac graft vasculopathy.
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References
Myers BD. Cyclosporine-associated hypertension. Am J Med 1988;85:131–133.
Schachter M. Cyclosporine A and hypertension. J Hypertens 1988;5:511–516.
Ausch-Schwelk W, Bossaller C, Götze S, Thelen J, Fleck E. Endothelial and vascular smooth muscle function after chronic treatment with cyclosporine A. J Cardiovasc Pharmacol 1993;21:435–440.
Berkenboom G, Unger P, Goldman M, Fang ZY, Fontaine J. Prevention of cyclosporine A-induced vascular toxicity by pentoxifylline. J Cardiovasc Pharmacol 1991;18:761–768.
Bossaller C, Försterman U, Hertel R, Obricht C, Reschke V, Fleck E. Cyclosporine A inhibits endothelium-dependent vasodilation and vascular prostacyclin production. Eur J Pharmacol 1989;165:165–169.
Gallego MJ, Lopez Farré A, Riesco A, et al. Blockade of endothelium-dependent responses in conscious rats by cyclosporine A: Effect of L-arginine. Am J Physiol 1993; 264:H708-H714.
O'Neil GS, Chester AH, Kushwaha S, Rose M, Tadjkarimi S, Yacoub MH. Cyclosporin treatment does not impair the release of nitric oxide in human coronary arteries. Br Heart J 1991;66:212–216.
Okumara K, Yasue H, Ishizaka H, Ogawa H, Fujii H. Endothelium-dependent dilator response to substance P in patients with coronary spastic angina. J Am Coll Cardiol 1992;20:838–844.
Kalsner S. Coronary reactivity in human vessels: Some questions and some answers. Fred Proc 1985;44:321–325.
Cohen RA, Zitnay KM, Haudenschild CC, Cunningham LD. Loss of selective endothelial cell vasoactive functions caused by hypercholesterolemia in pig coronary arteries. Circ Res 1988;63:903–910.
Shimokawa H, Flavahan NA, Vanhoutte PM. Loss of endothelial pertussis toxin-sensitive G protein function in atherosclerotic porcine coronary arteries. Circulation 1991;83: 652–660.
Christie MI, Griffith TM, Lewis MJ. A comparison of basal and agonist-stimulated release of endothelium-derived relaxing factor from different arteries. Br J Pharmacol 1989; 98:397–406.
Gräser J, Leisner A, Tiedt N. Absence of role of endothelium in the response of isolated porcine coronary arteries to acetylcholine. Cardiovasc Res 1986;20:299–302.
Chan BBK, Kern JA, Flanagan TL, Kron IL, Tribble CG. Effects of in vivo cyclosporine administration on endothelium-dependent responses in isolated vascular rings. Circulation 1991;86(Suppl II):II295-II299.
Berkenboom G, Unger P, Fang ZY, Degré S, Fontaine J. Comparison of responses to acetylcholine and serotonin on isolated canine and human coronary arteries. Cardiovasc Res 1989;23:780–787.
Toda N, Okamura T. Endothelium-dependent and independent responses to vasoactive substances of isolated human coronary arteries. Am J Physiol 1989;257:H988-H995.
Berkenboom G, Brékine D, Unger P, Gulbis B, Fontaine J. Attenuation of cyclosporine A-induced vascular toxicity by ramipril. J Cardiovasc Pharmacol 1994;24:17–21.
Lamb FS, Webb RC. Cyclosporin augments reactivity of isolated blood vessels. Life Sci 1987;40:2571–2578.
Meyer-Lehnert HM, Schrier RW. Potential mechanism of cyclosporine A-induced vascular smooth muscle contraction. Hypertension 1989;13:352–360.
Pfeilschifter J, Rüegg UT. Cyclosporin A augments angiotensin II-stimulated rise in intracellular free calcium in vascular smooth muscle cells. Biochem J 1987;24:883–887.
Gallego MJ, Villalon ALG, Lopez Farré AJ, et al. Mechanisms of the endothelial toxicity of cyclosporin A. Role of nitric oxide, cGMP, and Ca2+ Circ Res 1994;74:477–484.
Sudhir K, MacGregor JS, DeMarco T, et al. Cyclosporine impairs release of endothelium-derived relaxing factors in epicardial and resistance coronary arteries. Circulation 1994;90:3018–3023.
Rego A, Vargas R, Wroblewska B, Foegh ML, Ramwell PW. Attenuation of vascular relaxation and cyclic GMP responses by cyclosporin A. J Pharmacol Exp Ther 1990;252: 165–170.
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Berkenboom, G., Brékine, D., Unger, P. et al. Coronary vasomotor responses in cyclosporine-treated piglets. Cardiovasc Drug Ther 10, 17–22 (1996). https://doi.org/10.1007/BF00051126
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DOI: https://doi.org/10.1007/BF00051126