These data suggest that AKAP121 regulates the response to stress in cardiomyocytes, and therefore AKAP121 downregulation might represent an important event contributing to the development of cardiac dysfunction.

Abstract-Nebivolol is a ␤1-adrenergic receptor antagonist that also reduces blood pressure by evoking endothelial NO production and vasodilation. We aimed at assessing whether nebivolol induces NO production also in the heart and delineating the molecular mechanisms involved. Using the fluorescent probe diaminofluorescein, we found that nebivolol induces a dose-dependent NO production in the heart, statistically significant already at 10 Ϫ7 mol/L. It is not an effect because of the blockade of ␤1-adrenergic receptor, because this effect is not shared by another drug of the same class, atenolol. Because nebivolol has been reported to act as an agonist on other ␤-adrenergic receptors, we tested NO production in the presence of receptor antagonists. Nebivolol was not able to induce NO production in presence of the ␤3-antagonist SR59230A, indicating a fundamental role for ␤3-adrenergic receptors in cardiac NO production by nebivolol. Moreover, inducible NO synthase inhibition abolishes NO release in the heart, indicating that nebivolol induces NO production by acting on the inducible isoform of the enzyme. The action of nebivolol on inducible NO synthase was confirmed by real-time PCR experiments, showing cardiac overexpression of inducible NO synthase but not neuronal NO synthase or endothelial NO synthase, after 5 hours of treatment with nebivolol. In conclusion, our study demonstrates that nebivolol also stimulates NO production in the heart. This action of nebivolol is exerted via a signaling pathway starting from the activation of ␤3-adrenergic receptors and leading to overexpression of inducible NO synthase. Cardiac NO production by nebivolol could participate in the cardiovascular effects of nebivolol treatment in patients affected by hypertension and heart failure. Key Words: adrenergic agents Ⅲ adrenergic beta receptors Ⅲ heart Ⅲ NO Ⅲ NO synthase ␤ -Blockers are among the antihypertensive drugs most indicated against heart failure. 1 ␤-Blockers act principally to inhibit the adverse effects of the sympathetic nervous system in patients with heart failure. 2,3 In fact, whereas cardiac adrenergic drive initially supports the performance of the failing heart, long-term activation of the sympathetic nervous system exerts deleterious effects that can be antagonized by the use of ␤-blockers.In addition to the inhibitory effects on ␤1-adrenergic receptors, the novel ␤-blocker nebivolol has additional hemodynamic properties. 4 In particular, nebivolol is able to stimulate endogenous production of NO by inducing phosphorylation of the endothelial enzyme endothelial NO synthase (NOS; eNOS). 5 The particular properties of nebivolol also determine favorable effects on cardiac function in patients with heart failure when compared with classical ␤-blockers, 6 but the mechanisms underlying these beneficial differences have not been well characterized. In this regard, whereas nebivolol action on NO can result in favorable outcomes at vascular levels, the effects of NO on the heart are not so straightforwardly beneficial.In...

Abstract-Hypertension can lead to subarachnoid hemorrhage and eventually to cerebral vasospasm. It has been suggested that the latter could be the result of oxidative stress and an inflammatory response evoked by subarachnoid hemorrhage.Because an unavoidable consequence of hemorrhage is lysis of red blood cells, we first tested the hypothesis on carotid arteries that the proinflammatory cytokine tumor necrosis factor-␣ contributes to vascular oxidative stress evoked by hemolysis. We observed that hemolysis induces a significant increase in tumor necrosis factor-␣ both in blood and in vascular tissues, where it provokes Rac-1/NADPH oxidase-mediated oxidative stress and vasoconstriction. Furthermore, we extended our observations to cerebral vessels, demonstrating that tumor necrosis factor-␣ triggered this mechanism on the basilar artery. Finally, in an in vivo model of subarachnoid hemorrhage obtained by the administration of hemolyzed blood in the cisterna magna, we demonstrated, by high-resolution ultrasound analysis, that tumor necrosis factor-␣ inhibition prevented and resolved acute cerebral vasoconstriction. Moreover, tumor necrosis factor-␣ inhibition rescued the hemolysis-induced brain injury, evaluated with the method of 2,3,5-triphenyltetrazolium chloride and by the histological analysis of pyknotic nuclei. In conclusion, our results demonstrate that tumor necrosis factor-␣ plays a crucial role in the onset of hemolysis-induced vascular injury and can be used as a novel target of the therapeutic strategy against cerebral vasospasm.