Rapamycin modifies the vascular tone of rat isolated aortas

Background

Post-PTCA restenosis has been almost completely prevented by rapamycin (RP)-eluting stents. High costs, however, preclude a broader utilization of these devices. In a pilot study, we have obtained promising data with the administration of oral RP to patients presenting high risk for restenosis, reducing costs considerably.

Aim

As inhibitory effects on endothelial cell proliferation potentially deleterious to the cardiovascular system have been reported during oral administration of RP in animal models, the present study addresses the in vitro effects of this drug on endothelial function.

Methods

Rat aortic rings with or without endothelium were prepared for isometric recordings. Contractile responses (to norepinephrine, 0.3 μM) and relaxant responses (to acetylcholine [1 μM] or to sodium nitroprusside [0.001–1000 μM]) were obtained in the absence or presence of increasing concentrations of RP, incubated to the preparations for different periods of time.

Results

RP (1 hour, 100 ng/ml) produced slight but significant increments in contractions of aortas without endothelium to norepinephrine (74 ± 4% to 101 ± 7%, n = 16, P < 0.001). This difference was no longer present at higher RP concentrations (1000 ng/ml, n = 8). Under the same conditions, RP did not modify endothelium-dependent relaxations induced by acetylcholine at any concentration tested (n = 6). Contractile responses elicited by norepinephrine in aortas without endothelium were not significantly affected by RP (1000 ng/ml, n = 6). However, concentration–response relaxant curves to sodium nitroprusside (endothelium independent) were significantly shifted to the right (n = 6, P < 0.05).

Conclusions

Our preliminary results indicate that acute administration of RP promotes significant modifications in rat isolated aorta vascular tone, mainly by reducing endothelium-independent relaxation. Ex vivo experiments with chronic RP oral administration to rats are underway in order to define possible implications of these findings in the vasculature.