Clinical studies conducted with
carvedilol suggest that beta-
adrenoceptor antagonism is an effective therapeutic approach to the treatment of
heart failure. However, many
beta-adrenoceptor antagonists are weak partial agonists and possess significant intrinsic
sympathomimetic activity (ISA), which may be problematic in the treatment of
heart failure. In the present study, the ISAs of
bucindolol,
xamoterol,
bisoprolol, and
carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed
heart failure [spontaneously hypertensive
heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes. At equieffective beta1-adrenolytic doses, the administration of
xamoterol and
bucindolol produced a prolonged, equieffective, and dose-related increase in heart rate in both pithed SD rats (ED50 = 5 and 40 microgram/kg, respectively) and SHHF rats (ED50 = 6 and 30 microgram/kg, respectively). The maximum effect of both compounds in SHHF rats was approximately 50% of that observed in SD rats. In contrast,
carvedilol and
bisoprolol had no significant effect on resting heart rate in the pithed SD or SHHF rat. The maximum increase in heart rate elicited by
xamoterol and
bucindolol was inhibited by treatment with
propranolol,
carvedilol, and
betaxolol (beta1-adrenoceptor antagonist) but not by
ICI 118551 (beta2-adrenoceptor antagonist) in neonatal rat. When the beta-
adrenoceptor-mediated cAMP response was examined in cardiomyocytes, an identical partial agonist/antagonist response profile was observed for all compounds, demonstrating a strong correlation with the in vivo results. In contrast,
GTP-sensitive
ligand binding and tissue
adenylate cyclase activity were not sensitive methods for detecting beta-
adrenoceptor partial agonist activity in the heart. In summary,
xamoterol and
bucindolol, but not
carvedilol and
bisoprolol, exhibited direct beta1-adrenoceptor-mediated ISA in normal and
heart failure rats.