Targeting drugs to the heart by intrapericardial (IPC) delivery may be a promising strategy to obtain higher drug efficiencies with lesser side effects. We examined whether IPC delivery of sotalol and atenolol in rats offers advantages over intravenous (IV) application. Following sustained IPC infusion of sotalol or atenolol, pericardial fluid levels exceeded plasma levels 97 and 134 times respectively (P < 0.01) resulting in 3.8 and 4.7 times higher overall left ventricular tissue drug levels (P < 0.05). In a second experiment, the effects of the IPC or IV β-blocker infusions on nitroprusside-induced tachycardia were studied in conscious rats. For both drugs, IPC infusion of 0.03 mg/kg·h produced similar antitachycardiac effects as the 1 mg/kg·h IV dose. In a third set of studies, dP/dt max challenged by dobutamine infusion was assessed to study ventricular contractile function after IV and IPC sotalol in anesthetized rats. IPC sotalol infusion attenuated the dobutamine response curve to a greater extent than IV (P < 0.01). In conclusion, IPC infusion of sotalol and atenolol results in high cardiac tissue concentrations with low systemic drug levels. Similar antitachycardiac effects can be obtained at a 10- to 30-fold lower dose compared with IV delivery. Also, depression of ventricular contractility is acquired at a substantially lower IPC sotalol dose. Thus, β-blocking properties of sotalol and atenolol can be greatly enhanced by applying them IPC.