Cyclosporin a Potentiates Receptor-Activated [Ca²⁺]_cIncrease

Abstract

The use of the immunosuppressant cyclosporin A (CsA) is frequently associated with hypertension. Drug-induced local vasoconstriction appears to be responsible for this effect. Using fura-2 and 45Ca2+ efflux techniques, we have examined variations in the cytosolic calcium concentration ([Ca2+]c) in rat aortic smooth muscle cells and have shown that increases in [Ca2+]c after [Arg8]vasopressin, serotonin, endothelin-1 or angiotensin II stimulation were potentiated after preincubation of cells with CsA. This effect was independent of cyclophilin or calcineurin inhibition by CsA. Measurements of inositol phosphates (InsPn) after agonist stimulation showed that CsA also potentiated their formation. As for 45Ca2+ efflux this effect was not related to cyclophilin or calcineurin inhibition. Direct stimulation of G proteins with aluminium tetrafluoride induced an increase in InsPn formation and 45Ca2+ efflux. Neither of these responses was potentiated by CsA. These results indicate that CsA acts on a target upstream of G protein activation, possibly at the receptor level, resulting in a potentiation of InsPn formation and subsequent calcium increase.

Mechanism of enhanced vasoconstrictor hormone action in vascular smooth muscle cells by cyclosporin A

“…It has been shown that an increase in vasoconstriction by CsA is responsible for both side‐effects (Lamb & Webb, 1987; Rego et al , 1990; Sturrock et al , 1993). We have recently demonstrated that CsA potentiates the cytosolic free Ca 2+ ([Ca 2+ ] c ) increase in response to vasoconstrictor hormones in vascular smooth muscle cells (VSMC) (Lo Russo et al , 1996; 1997). The known pharmacological targets of CsA, i.e.…”

Cyclosporine A Amplifies Ca2+ Signaling Pathway in LLC-PK1 Cells through the Inhibition of Plasma Membrane Ca2+ Pump

“…Interestingly, other studies emphasized the potential role of different mediators, prostaglandins, endothelins, nitric oxide, TGF-␤, etc. (13,21,24,29,34). However, despite these efforts, the information gathered at the present from the various experimental approaches cannot be assembled in an unifying view of the CsA-induced nephrotoxicity.…”

“…An early contribution to the recognition of the role of Ca 2ϩ signaling pathway in the generation of toxic effects of CsA came from the demonstration that CsA augmented the receptor stimulated calcium fluxes in isolated hepatocytes (27) and increased [Ca 2ϩ ] i in mesangial cells (39). CsA may also affect the extracellular domain of Ca 2ϩ signaling pathway; the incubation of different cell types with therapeutic doses of CsA is associated with the potentiation of the calcium response upon Ca 2ϩ -coupled receptor engagement (21,24), probably through an upregulation of receptor transcription (2). In addition, CsA may alter the control of intracellular Ca 2ϩ release through ryanodine binding modifications in rat heart (30), and it may stimulate or inhibit the release of Ca 2ϩ from IP 3 -sensitive stores (14,26).…”

The α1-adrenergic receptor not the DA1-dopaminergic receptor mediates cyclosporine–SKF38393 renovascular interaction

“…An increase in vascular a 1 receptor affinity in response to acute CyA treatment has been demonstrated by Tavares et al (2002). Others have shown that CyA acts, via cyclophilin-or calcineurin-independent mechanisms, at a target upstream of G protein, possibly at the receptor level, to increase inositol phosphate formation and cytosolic calcium concentration (Lo Russo et al 1997). Evidence is also available that shows CyA acts by an intracellular mechanism to elevate phosphatidylinositol, which triggers the vascular response to a 1 -adrenoceptor activation (Tavares et al 2002).…”