Background-Nebivolol and carvedilol are third-generation ␤-adrenoreceptor antagonists, which unlike classic ␤-blockers, have additional endothelium-dependent vasodilating properties specifically related to microcirculation by a molecular mechanism that still remains unclear. We hypothesized that nebivolol and carvedilol stimulate NO release from microvascular endothelial cells by extracellular ATP, which is a well-established potent autocrine and paracrine signaling factor modulating a variety of cellular functions through the activation of P2-purinoceptors. Methods and Results-Contraction and relaxation of renal glomerular vasculature were measured by determination of intracapillary volume with [ 3 H]-inulin. Biologically active NO was measured with highly sensitive porphyrinic NO microsensors in a single glomerular endothelial cell (GEC). Extracellular ATP was measured by a luciferin-luciferase assay. Enzymatic degradation of extracellular ATP by apyrase and blockade of P2Y-purinoceptors by suramin or reactive blue 2 inhibited both ␤-blocker-induced glomerular vasorelaxations and ␤-blocker-stimulated NO release from GECs. Both ␤-blocker-induced vasorelaxations were in the micromolar concentration range identical to that required for the ␤-blocker stimulation of ATP and NO release from GECs. The maximum of NO release for nebivolol and carvedilol was very similar (188Ϯ14 and 226Ϯ17, respectively). Blockade of ATP release by a mechanosensitive ion channel blocker, Gd 3ϩ , inhibited the ␤-blocker-dependent release of ATP and NO from GECs. Conclusions-These results demonstrate for the first time that nebivolol and carvedilol induce relaxation of renal glomerular microvasculature through ATP efflux with consequent stimulation of P2Y-purinoceptor-mediated NO

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