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

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 (E (max), -27.6 ± 3.9%; p < 0.05) compared with WKY group (E (max), -13.4 ± 2.5%). SH rats showed a greater hypotensive effect of racemic carvedilol (E (max), -45.5 ± 5.0%; p < 0.05) with regard to WKY group (E (max), -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.