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Cyclosporine, but not FK506, selectively induces renal and coronary artery smooth muscle contraction

      Abstract

      Background: Cyclosporine immunosuppression for organ transplantation is associated with hypertension and nephrotoxicity. Because the effects of cyclosporine as an immunosuppressant are mediated by the effect of cyclosporine as a phosphatase inhibitor, and phosphatase inhibitors are potent vascular smooth muscle contractile agents, we hypothesized that cyclosporine might induce contraction of the renal artery vascular smooth muscle directly. Methods: Strips of bovine renal, carotid, superior mesenteric, or coronary arteries were obtained fresh from an abattoir. The strips were equilibrated in a muscle bath, and the contractile responses to cyclosporine and FK506 were determined. Results: Cyclosporine (50 to 5000 μg/ml), but not FK506, induced rapidly developing, sustained contractions of renal and coronary artery smooth muscle. The magnitude of the cyclosporine-induced contractions of carotid and superior mesenteric artery smooth muscles was significantly less. The magnitude of renal artery smooth muscle contractions induced by cyclosporine was enhanced in the presence of an intact endothelium. Conclusions: Although these effects occurred in vitro to relatively high doses of cyclosporine, these data suggest that cyclosporine may selectively induce renal artery smooth muscle contraction through activation of the Ca2+-dependent phosphatase (calcineurin) in the smooth muscle, and these contractions may be enhanced by the release of endothelial-derived contracting factors. (Surgery 1998;123:456-60.)
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      References

        • Hamilton DV
        • Carmichael DJS
        • Evans DB
        • Calne RY
        Hypertension in renal transplant recipients on cyclosporin A and corticosteroids and azathioprine.
        Transplant Proc. 1982; 14: 597-600
        • Myers BD
        • Ross J
        • Newton L
        • Luetscher L
        • Perlroth M
        Cyclosporine-associated chronic nephropathy.
        N Engl J Med. 1984; 311: 699-705
        • Curtis JJ
        • Laskow DA
        Cyclosporine-induced nephrotoxicity: pathophysiology of decreased blood flow.
        Transplant Proc. 1988; 20: 540-543
        • Takeda Y
        • Miyamori I
        • Yoneda T
        • Takeda R
        Endothelin-1 release from the mesenteric arteries of cylcosporine-treated rats.
        Eur J Pharmacol. 1992; 213: 445-447
        • Voss BL
        • Hamilton KK
        • Samara EN
        • McKee PA
        Cyclosporine suppression of endothelial prostacyclin generation.
        Transplantation. 1988; 45: 793-798
        • Cartier R
        • Dagenais F
        • Hollmann C
        • Cambron H
        • Buluran J
        Chronic exposure to cyclosporine affects endothelial and smooth muscle reactivity in the rat aorta.
        Ann Thorac Surg. 1994; 58: 789-794
        • Rego A
        • Vargas R
        • Wroblewska B
        • Foegh M
        • Ramwell PW
        Attenuation of vascular relaxation and cGMP responses by cyclosporin A.
        J Pharmacol Exp Ther. 1990; 252: 165-170
        • Huang HC
        • Rego A
        • Vargas R
        • Foegh ML
        • Ramwell PW
        Nitroprusside-induced vascular relaxation is attenuated in organ-transplanted animals treated with cyclosporine.
        Transplant Proc. 1987; 19: 126-130
        • Xue H
        • Bukoski RD
        • McCarron DA
        • Bennet WM
        Induction of contraction in isolated rat aorta by cyclosporine.
        Transplantation. 1987; 43: 715-718
        • Liu J
        • Farmer JD
        • Lane WS
        • Friedman J
        • Weissman I
        • Schreiber SL
        Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.
        Cell. 1991; 66: 807-815
        • Fruman DA
        • Klee CB
        • Bierer BE
        • Burakoff SJ
        Calcineurin phosphatase activity in T-lymphocytes is inhibited by FK506 and cyclosporin A.
        Proc Natl Acad Sci USA. 1992; 89: 3686-3690
        • Suzuki A
        • Itoh R
        Effects of calyculin A on tension and myosin phosphorylation in skinned smooth muscle of the rabbit mesenteric artery.
        Br J Pharmacol. 1993; 109: 703-712
        • Takai A
        • Bialojan C
        • Troschka M
        • Ruegg JC
        Smooth muscle myosin phosphatase inhibition and force enhancement by black sponge toxin.
        FEBS Lett. 1987; 217: 81-84
        • Yeh JL
        • Whitney EG
        • Brophy CM
        Nitric oxide (NO) is an autocrine feedback regulator of vascular smooth muscle contraction.
        Surgery. 1996; 119: 104-109
        • Grobelwski GE
        • Andreas C
        • Wagner C
        • Williams JA
        Cyclosporin A inhibits Ca2+/calmodulin-dependent protein phosphatase and secretion in pancreatic acinar cells.
        J Biol Chem. 1994; 269: 15111-15117
        • Swenson JM
        • Fricker FJ
        • Armitage JM
        Immunosuppression switch in pediatric heart transplant recipients: cyclosporine to FK506.
        J Am Coll Cardiol. 1995; 25: 1183-1188
        • Sturrock ND
        • Lang CC.
        • Coutie WJ
        • Sruthers AD
        Cyclosporin-induced renal vasoconstriction is augmented by furosemide and by antiotensin II in humans.
        J Hypertens. 1995; 13: 987-991
        • Hoffman A
        • Grossman E
        • Ohman P
        The initial vasodilation and the later vasoconstriction of endothelin-1 are selective to specific vascular beds.
        Am J Hypertens. 1990; 3: 789-794
        • Whitney EG
        • Menice CB
        • Yeh J
        • Bagwell C
        • Jerius H
        • Brophy CM
        Renal artery smooth muscle is refractory to contraction by angiotensin II.
        J Surg Res. 1996; 61: 307-310
        • Furchgott RF
        • Vanhoutte PM
        Endothelium derived relaxing and contracting factors.
        FASEB J. 1989; 3: 2007-2017
        • Lanese DM
        • Conger JD
        Effects of endothelin receptor antagonist on cyclosporine-induced vasoconstriction in isolated rat renal arterioles.
        J Clin Invest. 1993; 91: 2144-2149
        • Rossman P
        • Jirka J
        • Chadimova M
        • Reneltova I
        • Saudek F
        Arteriolosclerosis of the human renal allograft: morphology, origin, life history, and relationship to cyclosporine therapy.
        Virchows Arch. 1991; 418: 129-141