Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 385, Issue 3, pp 325–335

Enantioselective pharmacokinetic and pharmacodynamic properties of carvedilol in spontaneously hypertensive rats: focus on blood pressure variability

  • Facundo Martín Bertera
  • Julieta Sofía Del Mauro
  • Diego Chiappetta
  • Ariel Héctor Polizio
  • Fabián Buontempo
  • Carlos Alberto Taira
  • Christian Höcht
ORIGINAL ARTICLE

DOI: 10.1007/s00210-011-0698-7

Cite this article as:
Bertera, F.M., Del Mauro, J.S., Chiappetta, D. et al. Naunyn-Schmiedeberg's Arch Pharmacol (2012) 385: 325. doi:10.1007/s00210-011-0698-7

Abstract

The cardiovascular effects and pharmacokinetics of carvedilol were assessed in spontaneously hypertensive (SH) and Wistar Kyoto (WKY) animals with special focus on short-term blood pressure variability (BPV). Male SH and WKY rats were acutely treated with vehicle or carvedilol 1 or 5 mg kg−1 (i.v.), and effects on blood pressure (BP), heart rate (HR) and BPV were recorded. Plasma pharmacokinetics of R- and S-carvedilol was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by pharmacokinetic–pharmacodynamic (PK–PD) modelling. Short-term BPV was assessed by standard deviation of BP recording. Vascular sympatholytic activity of carvedilol was studied by estimation of drug effects on ratio between low frequency (LF) and high frequency (HF) BPV (LF/HF ratio). Although pharmacokinetic properties of carvedilol remained mainly unaffected in SH rats with regard to WKY rats, hypertensive animals showed a reduction in drug clearance of R- and S-carvedilol after administration of 1 mg kg−1 compared with WKY rats. PK–PD analysis of HR changes induced by S-carvedilol showed a greater maximal bradycardic response to carvedilol in SH rats (Emax, −27.6 ± 3.9%; p < 0.05) compared with WKY group (Emax, −13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (Emax, −45.5 ± 5.0%; p < 0.05) with regard to WKY group (Emax, −17.9 ± 4.5%). Carvedilol induced a greater reduction of LF/HF ratio in SH rats compared with WKY rats. Short-term BPV was markedly reduced by carvedilol in WKY and SH rats. In conclusion, as a consequence of an enhanced bradycardic response and a greater vascular sympatholytic activity, carvedilol exerts a greater hypotensive response in SH rats compared with WKY animals and dramatically reduces short-term BPV.

Keywords

Carvedilol Spontaneously hypertensive rats Pharmacokinetics Pharmacokinetic–pharmacodynamic modelling Sympathetic vascular activity Blood pressure variability 

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Facundo Martín Bertera
    • 1
    • 2
  • Julieta Sofía Del Mauro
    • 1
  • Diego Chiappetta
    • 3
  • Ariel Héctor Polizio
    • 1
  • Fabián Buontempo
    • 4
  • Carlos Alberto Taira
    • 1
    • 2
  • Christian Höcht
    • 1
    • 2
    • 5
  1. 1.Department of Pharmacology, School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos AiresArgentina
  2. 2.Institute of Physiopathology and Clinical Biochemistry, School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos AiresArgentina
  3. 3.Department of Pharmaceutical Technology, School of Pharmacy and BiochemistryUniversity of Buenos AiresBuenos AiresArgentina
  4. 4.Department of PharmacyJuan P Garrahan Pediatric HospitalBuenos AiresArgentina
  5. 5.Facultad de Farmacia y BioquímicaUniversidad de Buenos AiresBuenos AiresArgentina

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