Abstract 1871: Nebivolol Decreases Human Ventricular Contractility by Activating Beta 3-Adrenoceptors
Background. Nebivolol is a β-blocker of third generation used in the treatment of heart failure. It associates selective β1-adrenergic antagonist properties with vasodilating endothelial effects mediated by NO. Only few studies suggested that this vasodilatation could result from a putative activation of β3-adrenergic receptors (β3-ARs). The aim of the present study was to assess whether nebivolol could activate β3-ARs in human heart.
Method. The effect of nebivolol (0.1 nM-10 μM) upon the developed peak tension was tested in endomyocardial biopsies from human non-rejecting transplanted hearts. Samples were stimulated at 0.6 Hz in organ baths superfused with oxygenated Tyrode (37±0.5°C). Tension was recorded at steady-state using a mechanoelectric force transducer.
Results. Nebivolol induced a concentration-dependent decrease in peak tension (Emax obtained at 10 μM=−55±4%, n=6) which was similar to that obtained with a preferential β3-AR agonist, BRL37344 (BRL, Emax at 1 μM=−45±2%, n=12). As obtained for BRL effects, the pre-treatment with 10 μM nadolol, a β1,2-AR antagonist, did not modify nebivolol-induced negative inotropic effect. Conversely, the nebivolol effect was significantly reduced by 64% (n=6, p<0,05) in the presence of 1 μM L-748,337, a selective β3-AR antagonist, and by 60% (n=6, p<0,05) after pre-treatment with 100 μM L-NMMA, a NOS inhibitor, as for the BRL effect which was reduced by 56% (n=7, p<0,05) and by 51% (n=10, p<0,05) in the presence of L-748,337 and L-NMMA respectively.
Conclusion. Our study demonstrated that nebivolol-induced negative inotropic effect result from a β3-AR and NO pathway activation in human heart. The vasodilating properties of nebivolol previously described in human microcoronary arteries associated with its negative inotropic effect could improve the energetic balance in heart. Those effects could explain the amelioration of hemodynamic parameters obtained in patients with heart failure after nebivolol administration as described in clinical trials.