In the present study, we hypothesized that differences in b-adrenoceptor binding and regulation between Metoprolol (MET) and Carvedilol (CAR) may influence positive inotropic responsiveness after abrupt b-blocker withdrawal.

In vitro experiments were performed on isolated, electrically stimulated human atrial muscle strips. Before application of b-blockers (baseline), isoprenaline (ISO) potency and efficacy was identical in all groups (n=8-10). In the presence of both MET (1 μM) and CAR (10 nM), ISO potency was reduced compared to control (C) muscles (logEC₅₀ [M]: C, - 8.7±0.4; MET, -6.5±0.2; CAR, -7.0±0.2; p<0.001 vs C). After wash-out of ß-blockers, in MET-treated muscles, ISO potency returned to baseline values, whereas in CAR-treated preparations, ISO potency remained decreased (logEC₅₀ [M]: C,- 8.3±0.3; MET, -8.2±0.4; CAR, -6.6±0.2; p<0.001 CAR vs C).

In vivo experiments were performed in 7 healthy volunteers who received 190 mg of MET succinate and 50 mg of CAR for 10 days in a randomized cross-over design with a wash-out period of 4 weeks. Dobutamine stress-echocardiography (5-40 μg/kg/min) was performed before, during and 44 hours after application of study medication. Under either ß-blocker medication, heart rate (HR), HR-corrected velocity of circumferential fiber shortening (V_cfc), and cardiac output (CO) was significantly (p<0,005) reduced compared to baseline. In contrast, 44 hours after abrupt ß-blocker withdrawal, all parameters returned to baseline values in the MET group, whereas in CAR-treated volunteers, all parameters remained significantly reduced (HR, p<0.005; V_cfc, p<0.02; CO, p<0.0007).

Conclusion: Neither Metoprololsuccinat nor Carvedilol led to a significant rebound effect after abrupt withdrawal in healthy volunteers. The ß-blocking effect of carvedilol is prolonged far beyond its elimination in plasma, which may be due to persistent receptor binding or allosteric inhibition from nonspecific lipophilic binding sites.