(—)‐CGP 12177‐induced increase of human atrial contraction through a putative third β‐adrenoceptor

Abstract

The inotropic effects of (−)−4‐(3‐t‐butylamino‐2‐hydroxypropoxy)benzimidazol‐2‐one ((−)−CGP 12177), an antagonist for β1‐ and β2‐adrenoceptors as well as an agonist for β3‐adrenoceptors, were investigated on paced preparations of isolated right atrial appendages obtained from patients without advanced heart failure undergoing open heart surgery. In the presence of (−)−propranolol (200 nM), (−)−CGP 12177 increased contractile force with a ‐log EC50, M, of 7.3. The maximum effects of (−)−CGP 12177 amounted to 15% and 11% of the effects of (−)−isoprenaline (400 μm) and of CaCl2 (6.75 mM) respectively. (—)‐Bupranolol 1 μm, an antagonist with a pKB of ∼7.5 for β3‐adrenoceptors, antagonized surmountably the positive inotropic effects of (—)‐CGP 12177 (in the presence of 200 nM (−)−propranolol) with an apparent pKB of 7.3. The potent positive inotropic effects of (−)−CGP 12177 and their resistance to blockade by (−)−propranolol but antagonism by (−)−bupranolol are consistent with the existence in human atrial myocardium of a minor third β‐adrenoceptor population, possibly related to β3‐adrenoceptors.

Tools to study β3-adrenoceptors

“…Bupranolol is a clinically used β-adrenoceptor antagonist, which also has been used to demonstrate the involvement of β 3 -adrenoceptor in functional responses (Horinouchi and Koike 2001;Igawa et al 1998;Kaumann 1996;Takeda et al 2002a). However, in competition binding studies with human β-adrenoceptor subtypes, bupranolol has lower affinity for β 3 -adrenoceptors than for β 1 -and β 2 -adrenoceptors (Baker 2005;Candelore et al 1999).…”

Markedly reduced effects of (−)‐isoprenaline but not of (−)‐CGP12177 and unchanged affinity of β‐blockers at Gly389‐β1‐adrenoceptors compared to Arg389‐β1‐adrenoceptors

“…b 1 -Adrenoceptors also mediate the cardiac effects of nonconventional partial agonists (NCPA) (e.g. (À)-CGP12177) that are partially resistant to b-blockers in mammalian heart (Kaumann, 1989;Lowe et al, 2002), including man (Kaumann, 1996;Joseph et al, 2003;Sarsero et al, 2003). Two binding sites for (À)-( 3 H)-CGP12177) have been detected in rat left atrium (Sarsero et al, 1999) and human right atrium (Sarsero et al, 2003).…”

Overexpression of β1‐adrenoceptors in adult rat ventricular myocytes enhances CGP 12177A cardiostimulation: implications for ‘putative’β4‐adrenoceptor pharmacology

“…pindolol and CGP 12177A) that block the effects of catecholamines in human heart with high affinity at b 1 -and b 2 -adrenoceptors, and produce cardiostimulant effects (positive inotropy, lusitropy and chronotropy) at B100-fold higher concentrations (Kaumann, 1989;Kaumann & Molenaar, 1997). The cardiostimulant effects of the nonconventional partial agonists are relatively resistant to antagonism by classical b 1 -adrenoceptor antagonists, including propranolol, but blocked with moderate affinity by bupranolol and carvedilol (Kaumann 1989;1996;Lowe et al, 2002). A pharmacologically distinct Gs-protein (stimulatory guanine nucleotide binding protein)/Adenylyl cyclase/adenosine 3 0 ,5 0 -cyclic monophosphate (cAMP)-coupled receptor, the 'putative' b 4 -adrenoceptor, was proposed to mediate these effects (Kaumann, 1997;Kaumann & Lynham, 1997).…”