Étude in vivo de la régulation du flux sanguin post-transplantation par le bloqueur des canaux calciques de type-R l'isradipine
One cause of arterial hypertension is the constriction of blood vessels which is modulated by calcium transport via calcium channels. There exist two main types of calcium channels: voltage operated channels (VOC) and receptor operated channels (ROC). Generally two types of VOC channels are observed in VSMC (vascular smooth muscle cells): The L and T-types. However, these types of calcium channels are not present on vascular endothelial cells (VEC). The L-type calcium channel is sensitive to the calcium channel blocker, nifedipine. Recently, a new type of calcium channel (called R-type) has been identified. This channel can be activated by a sustained depolarization of the cell membrane or a sustained stimulation of some types of receptors such as receptors for insulin and endothelin-1 (ET-1) or some inflammatory mediators. This type of channel exists in both VEC and VSMC and seems to contribute to the regulation of the sustained vascular tone and to the rate of VEC sustained basal secretion. The R-type calcium channel is insensitive to the classical L-type calcium channel blockers such as nifedipine, but is highly sensitive to isradipine (PN200-110). The use of the immunosuppressor cyclosporin A stimulates the production of endogenous ET-1. ET-1, being one of the most important vasoconstrictive peptides, contributes to reduction of blood flow in operated patients and consequently contributes to the arterial hypertension. In order to overcome the side effect of cyclosporin A, we have studied the effect of two drugs, isradipine (R-type calcium channel blocker) and nifedipine (L-type calcium channel blocker), on the reduction of blood flow induced by cyclosporin A. Experiments have been conducted on rabbits having received skin allo_ and autografts. Results show that in allographed animals treated with cyclosporin, there was a decrease in blood flow and an increase in circulating ET-1. Following treatments for 21 days, the blood flow of isradipine-treated rabbits returns to control values, whereas that of nifedipine-treated rabbits remains unchanged. Moreover, the circulating rate of endogenous ET-1 was significantly decreased (p < 0.001) in allographed subjects treated with isradipine whereas these ET-1 values remained high with nifedipine treatment. These data strongly suggest that the undesirable hemodynamic effect of cyclosporin A is caused in part by the stimulation of the R-type vascular calcium channels probably via stimulation of ET-1 receptors and that the combination of the immunosuppressor and an R-type calcium blocker could be beneficial in patients treated with cyclosporin A."--Résumé abrégé par UMI.