Third-Generation β-Blockers Stimulate Nitric Oxide Release From Endothelial Cells Through ATP Efflux

Abstract

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

Celiprolol, A Vasodilatory β-Blocker, Inhibits Pressure Overload–Induced Cardiac Hypertrophy and Prevents the Transition to Heart Failure via Nitric Oxide–Dependent Mechanisms in Mice

“…Intriguingly, ␤-blockers with vasodilating properties, such as nebivolol and carvedilol, have also been reported to augment NO release from endothelial cells. 10 Recent studies in our laboratory demonstrated that celiprolol, a selective ␤ 1 -blocker with vasodilating properties, increased NO production in canine myocardial ischemia, 11 and we also reported that inhibition of eNOS can induce myocardial hypertrophy in rats. 12 However, very few studies were designed to explore the relation between eNOS signaling pathway and the inhibitory effect of ␤-blockers on cardiac remodeling.…”

“…31 The mechanisms for the linkage of ␤ 1 -blockade to eNOS upregulation have been clarified by other investigators. Kalinowski et al 10 demonstrated that some ␤-blockers augment NO production via activation of ATP efflux, with consequent stimulation of P 2 Y purinoceptor. Celiprolol was also reported to activate eNOS through the PI3K-Akt signaling pathway.…”

Purinergic signalling in the kidney in health and disease

“…Tubular sodium transport systems are more sensitive to diadenosine tetraphosphate (Ap 4 A) than systems involved in glomerular filtration rates [167]. β-Blockers induce relaxation of the glomerular microvasculature by releasing ATP, which acts via P2Y receptors on endothelial cells to produce NO, resulting in vasodilation [180]. Connexin (Cx) 40 hemichannels and extracellular ATP are the key molecular elements of the glomerular endothelial calcium wave [371].…”

Modulation of Oxidant and Antioxidant Enzyme Expression and Function in Vascular Cells

“…Third-generation ␤-blockers like carvedilol and nebivolol may enhance NO release in EC, increase vascular glutathione content, inhibit ROS formation, and reduce lipid peroxidation. 39 Several calcium channel blockers were shown to inhibit oxidation of LDL and other lipids in animals and humans. For example, nifedipine increases NO bioavailability by decreased ROS formation in EC and enhances MnSOD expression in VSMC.…”