Therapeutic benefits of calcium channel blockers in cyclosporine-treated organ transplant recipients: blood pressure control and immunosuppression

Abstract

Cyclosporine has dramatically improved the success rates for all forms of organ transplantation. However, its use is complicated by the frequent occurrence of hypertension and reversible nephrotoxicity. The iatrogenic hypertension induced by cyclosporine resembles a low-renin, salt-sensitive form of essential hypertension, which is often controlled with salt restriction and therapies counteracting renal salt acquisition, e.g., diuretics and calcium channel blockers (CCBs). CCBs may also counteract the direct vasoconstrictive effects of cyclosporine, as well as the effects of other vasoconstrictors, such as endothelin or thromboxane, that may be stimulated by cyclosporine. Additionally, CCBs may potentiate the immunosuppression of cyclosporine, yet minimize nephrotoxicity. We demonstrated that the in vitro combination of verapamil and cyclosporine had an additive inhibitory effect on the activation and function of human peripheral blood mononuclear cells in several assays of the afferent and efferent limbs of immunologic responses. This additive immunosuppression was not likely to have been related to these drugs' effects on interleukin-2 (IL-2) circuitry, since no additive inhibition of IL-2 production or IL-2 responsiveness was found. There was some additive inhibition of IL-2 receptor expression at the higher concentrations of verapamil and cyclosporine that were tested. Although the combination of verapamil and cyclosporine additively inhibited mitogen-induced 45Ca uptake, the inhibitory effect of cyclosporine appears to be due to an inhibition of lymphocyte activation rather than direct inhibition of calcium flux through the slow calcium channel, suggesting that the two drugs do not have additive effects in depressing the transmembrane flux of calcium. More recently, we have demonstrated that the inactive enantiomer of verapamil, which does not block the slow calcium channel, has identical immunosuppressive capabilities as the active enantiomer. Thus, the antiproliferative effect of verapamil is probably slow-calcium-channel independent and may represent the ability of the drug to interfere with muscarinic, alpha 1-adrenergic, or even opiate receptors on lymphocytes or to block lymphocyte potassium channels. An even better possibility is that verapamil may diminish necessary precursor molecule uptake into lymphocytes, since both the inactive and active isomeric forms of verapamil are capable of diminishing thymidine, uridine, and leucine incorporation into stimulated lymphocytes--necessary for DNA, RNA, and protein synthesis, respectively. These in vitro observations may have clinical applicability, as early studies demonstrate reduced rejection rates of cyclosporine-treated transplant patients receiving CCBs. Consequently, CCBs are important medications to be considered for use in cyclosporine-treated organ transplant recipients.