Acute effects of third generation β-blockers on short-term and beat-to-beat blood pressure variability in sinoaortic-denervated rats

An increase in blood pressure variability (BPV) contributes to the development of target organ damage associated with hypertension. Treatment with conventional b-blockers, such as atenolol, has been associated with an increase in BPV; however, the extrapolation of these results to third generation b-blockers with pleiotropic effects seems to be inappropriate. The cardiovascular effects of third generation b-blockers, carvedilol and nebivolol, were assessed in sinoaortic-denervated rats (SAD) and compared with the second generation b-blocker atenolol and the calcium channel blocker verapamil, with a special focus on short-term BPV. Male SAD rats were acutely treated with carvedilol, nebivolol, atenolol or verapamil at two different doses, and the effects on blood pressure and BPV were recorded. Short-term BPV was assessed by the s.d. of BP recordings. Beat-tobeat BPV was studied using spectral analysis to assess the vascular sympatholytic activity of carvedilol and nebivolol by estimating the effects of these drugs on the ratio of low frequency (LF) to high frequency (HF) BPV (LF/HF ratio). Nebivolol, carvedilol and the calcium channel blocker verapamil significantly attenuated short-term BPV at both doses in SAD animals, and there were no differences between the drugs. Conversely, atenolol did not modify baseline s.d. values at either dose. Carvedilol and nebivolol significantly reduced the LF/HF ratio in SAD rats compared with the effects of atenolol and verapamil, suggesting the ability of the third generation b-blockers to reduce vascular sympathetic activity. In conclusion, third generation b-blockers induce a marked reduction in short-term BPV in SAD rats compared to atenolol. Moreover, the ability of carvedilol and nebivolol to reduce short-term BPV in SAD rats is equivalent to that of verapamil, suggesting that these b-blockers may have an additional beneficial effect through their control of short-term variability to a similar extent to calcium channel blockers.Fil: Bertera, Facundo Martín. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina;Fil: del Mauro, Julieta Sofía. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina;Fil: Lovera, Valeria. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina;Fil: Chiappetta, Diego Andrés. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina;Fil: Polizio, Ariel Héctor. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina;Fil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina;Fil: Höcht, Chistian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina

Enantioselective pharmacokinetics and cardiovascular effects of nebivolol in L-NAME hypertensive rats

The cardiovascular effects and pharmacokinetics of nebivolol were assessed in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive and normotensive control rats. Male Wistar rats were randomly divided to drink tap water (control) or L-NAME solution for 2 weeks. The effects of nebivolol (3 or 10 mg kg−1 i.v.) on blood pressure (BP), heart rate and BP variability (BPV) were recorded in awake L-NAME and control rats. Short-term and beat-to-beat BPV was assessed by the s.d. and spectral analysis of the BP recordings. Nebivolol pharmacokinetics was studied by means of traditional blood sampling. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; the clearance and the volume of distribution of l-nebivolol were significantly greater than those of the d-enantiomer. The hypotensive response to nebivolol was significantly enhanced in L-NAME rats (Δmean arterial pressure (MAP): −16.1±1.1%, P<0.05 vs. control rats) compared with normotensive animals (ΔMAP: −1.4±2.1%). An analysis of the beat-to-beat BPV showed a greater reduction in VLF BPV in the L-NAME compare with the control rats. Nebivolol significantly reduced the low-frequency/high-frequency ratio in hypertensive L-NAME animals compared with normotensive rats. Short-term BPV was markedly reduced by nebivolol in both experimental groups, although the attenuation of the s.d. of BP recording was greater in L-NAME rats. In conclusion, the hypotensive efficacy of nebivolol is significantly enhanced in L-NAME rats compared with normotensive animals, which is most likely due to a greater reduction in vascular sympathetic activity. Nebivolol markedly attenuated short-term BPV in both experimental groups, suggesting that β-blockers with additional pharmacological actions provide beneficial cardiovascular effects by controlling high BP and its short-term variability.Fil: Bertera, Facundo Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: del Mauro, Julieta Sofía. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Lovera, Valeria. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Chiappetta, Diego Andrés. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Polizio, Ariel Héctor. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentin