Atrial natriuretic peptide blunts the cellular effects of cyclosporine in smooth muscle.
The effect of cyclosporine A to enhance vasoconstrictor-induced calcium (Ca2+) mobilization in vascular smooth muscle cells may contribute to important side effects in cyclosporine therapy such as hypertension and nephrotoxicity. On the other hand, atrial natriuretic peptide (ANP) is known to diminish vasoconstrictor-stimulated Ca2+ mobilization. The present study, therefore, examined the interaction of cyclosporine and ANP on Ca2+ kinetics in cultured rat vascular smooth muscle cells. Intracellular free calcium concentrations ([Ca2+]i) were measured using fura-2. 45Ca2+ was used to estimate Ca2+ efflux and cellular Ca2+ influx. Preincubation of the cells with cyclosporine (10 micrograms/ml) for 12 minutes lowered basal [Ca2+]i from 48 +/- 4 to 28 +/- 3 nM (p < 0.01). However, in the presence of cyclosporine, the angiotensin II (10(-8) M)-stimulated rise of [Ca2+]i was increased from 296 +/- 22 to 460 +/- 47 nM (p < 0.001). ANP (5 x 10(-9) M) blocked the Ca2+ mobilization by angiotensin II (71 +/- 7 versus 69 +/- 7 nM, NS) and also completely inhibited the effect of angiotensin II in the presence of cyclosporine (77 +/- 5 versus 78 +/- 5 nM, NS). Basal efflux as well as angiotensin II-stimulated 45Ca2+ efflux were not altered by preincubation with cyclosporine, indicating that the effect of cyclosporine on [Ca2+]i was not due to an inhibition of 45Ca2+ efflux.(ABSTRACT TRUNCATED AT 250 WORDS)
Bokemeyer
D
D
Medizinische Poliklinik, Department of Medicine, University of Bonn, Germany.
Kramer
H J
HJ
Meyer-Lehnert
H
H
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes; D002478:Cells, Cultured; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D007425:Intracellular Membranes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
D002132:Calcium Radioisotopes; D016572:Cyclosporine; D009320:Atrial Natriuretic Factor; D002118:Calcium