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

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 (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.

Blood Pressure Variability: Prognostic Value and Therapeutic Implications

“…Acute intravenous administration of a single dose of third-generation beta blockers, carvedilol, and nebivolol, also effectively controls short-term BPV in freely moving spontaneously hypertensive rats and normotensive control animals [14,69]. An interesting finding of this set of experiments is the fact that nebivolol markedly attenuates short-term BPV in spontaneously hypertensive rats and normotensive animals and this beneficial effect is evident at low dose levels associated with limited effects on mean BP values (Figure 2) [69].…”

“…Beat-to-beat BPV has been used for the study of the mechanism of action of antihypertensive drugs and the diagnosis and treatment of patients with cardiovascular diseases [8,9,11]. For instance, in our laboratory, we have shown that carvedilol induced a greater hypotensive response in spontaneously hypertensive rats in comparison with normotensive control animals [14]. The enhanced pharmacological response to carvedilol was partially mediated by a greater vascular sympatholytic activity of the drug in the hypertensive group evidenced by a significant reduction of LF/HF ratio [14].…”

“…For instance, in our laboratory, we have shown that carvedilol induced a greater hypotensive response in spontaneously hypertensive rats in comparison with normotensive control animals [14]. The enhanced pharmacological response to carvedilol was partially mediated by a greater vascular sympatholytic activity of the drug in the hypertensive group evidenced by a significant reduction of LF/HF ratio [14]. More recently, we have compared the effects of different beta blockers on vascular sympathetic activity by means of spectral analysis of blood pressure recording in sinoaortic denervated rats [15].…”

Measurement of blood pressure variability and the clinical value

“…Ebben a formában alkalmas az egyes antihipertenzív gyógyszerek hatásának értékelé-sére is. Ezzel a módszerrel igazolták, hogy a carvedilol hypertoniás patkányoknál erőteljes hipotenzív akciót fejt ki, mert adása hatására jelentősen csökkent az LF/HF arány, ami arra utalt, hogy erős vascularis sympathicolyticus hatás érvényesül [13]. A két 3. generációs béta-blokkoló, a carvedilol és a nebivolol egyaránt erősen csökken-ti az LF/HF arányt, szemben az atenolollal, ahol szignifi kánsan gyengébb hatás van [14].…”

“…Bizonyították, hogy a 3. generációs béta-blokkoló carvedilol és nebivolol egyszeri iv. dózissal hatásosan csökkenti a BPV-t hypertoniás patkányokban és normotoniás egyedekben egyaránt, elsősorban nagyobb dózisok alkalmazásakor [13,14,38].…”