Cyclosporine A enhances total cell calcium independent of Na-K-ATPase in vascular smooth muscle cells.
The effect of cyclosporine A in enhancing vasconstrictor-induced calcium (Ca2+) mobilization in vascular smooth muscle cells may contribute to important side effects in cyclosporine therapy such as hypertension and nephrotoxicity. As we have previously shown, cyclosporine A stimulates transmembrane Ca2+ influx. Since Ca2+ efflux was not affected by cyclosporine A, we concluded that cyclosporine augments angiotensin II induced Ca2+ mobilization in vascular smooth muscle cells by an increased amount of Ca2+ in angiotensin II sensitive intracellular Ca2+ stores. The present study was therefore designed to examine the effect of cyclosporine A on cellular calcium content and on membrane calcium transport mechanisms. An important mechanism of Ca2+ extrusion from the cell is the Na-Ca exchanger. Its activity is closely related with that of the Na-K-ATPase. By increasing cellular sodium concentration the blockade of Na-K-ATPase would in turn activate cellular calcium uptake bx the Na-Ca exchanger. Therefore, we hypothesized that cyclosporine A might exert its effects in the same manner as a circulating Na-K-ATPase inhibitor. Total cell calcium was measured by atomic absorption and activity of Na-K-ATPase was estimated by an assay measuring phosphate production. Preincubation of the cells with cyclosporine (10 micrograms/ml) for 15 min increased total cell calcium from 31.4 +/- 5.0 to 46.5 +/- 5.3 nmol/mg protein (P < 0.05). Activity of Na-K-ATPase was not affected by cyclosporine A (3.9 +/- 0.2 vs. 4.3 +/- 0.2 mumol Pi h-1 mg-1 protein). Therefore, cyclosporine A induced Ca2+ influx is not mediated by an inhibition of the Na-K-ATPase.(ABSTRACT TRUNCATED AT 250 WORDS)
Bokemeyer
D
D
Medizinische Universitäts-Poliklinik, Bonn, Germany.
Friedrichs
U
U
Bäcker
A
A
Kramer
H J
HJ
Meyer-Lehnert
H
H
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000009:adverse effects*
D014662:Vasoconstrictor Agents; D016572:Cyclosporine; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium