Intrapericardial delivery enhances cardiac effects of sotalol and atenolol.
Targeting drugs to the heart by intrapericardial (i.p.c.) delivery may be a promising strategy to obtain higher drug efficiencies with lesser side effects. We examined whether i.p.c. delivery of sotalol and atenolol in rats offers advantages over intravenous (i.v.) 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 i.p.c. or i.v. beta-blocker infusions on nitroprusside-induced tachycardia were studied in conscious rats. For both drugs, i.p.c. infusion of 0.03 mg/kg.h produced similar antitachycardiac effects as the 1 mg/kg.h i.v. dose. In a third set of studies, dP/dt max challenged by dobutamine infusion was assessed to study ventricular contractile function after i.v. and i.p.c. sotalol in anesthetized rats. i.p.c. sotalol infusion attenuated the dobutamine response curve to a greater extent than i.v. (P < 0.01). In conclusion, i.p.c. 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 i.v. delivery. Also, depression of ventricular contractility is acquired at a substantially lower i.p.c. sotalol dose. Thus, beta-blocking properties of sotalol and atenolol can be greatly enhanced by applying them i.p.c.
van Brakel
Thomas J
TJ
Cardiovascular Research Institute Maastricht, Department of Cardio-thoracic Surgery, University Hospital and University Maastricht, Maastricht, The Netherlands. t.vanbrakel@ctc.unimaas.nl
Hermans
J J Rob
JJ
Janssen
Ben J
BJ
van Essen
Helma
H
Botterhuis
Nicole
N
Smits
Jos F M
JF
Maessen
Jos G
JG
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001262:Atenolol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D016503:Drug Delivery Systems; D036502:Infusions, Intralesional; D007262:Infusions, Intravenous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010496:Pericardium; D051381:Rats; D017208:Rats, Wistar; D013015:Sotalol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D001262:Atenolol; D013015:Sotalol