Mediation of the positive chronotropic effect of CGP 12177 and cyanopindolol in the pithed rat by atypical β‐adrenoceptors, different from β₃‐adrenoceptors

Abstract

1 The influence of ,I-, /2-, and f3-adrenoceptor agonists and of CGP 12177 and cyanopindolol on heart rate and diastolic blood pressure was studied in the pithed rat.2 The /3-adrenoceptor agonist, prenalterol, increased heart rate and the #2-adrenoceptor agonist, fenoterol, caused a fall in blood pressure. The effect of prenalterol was antagonized by the /,Badrenoceptor antagonist, CGP 20712 0.1 Mmol kg-' and the action of fenoterol was attenuated by the /32-adrenoceptor antagonist, ICI 118551 0.1 jimol kg-'. Both effects were markedly diminished by the non-selective f-adrenoceptor antagonist, bupranolol 0.1 umol kg-'.3 The non-selective ,B-adrenoceptor agonist, isoprenaline, three /3-agonists as well as CGP 12177 and cyanopindolol elicited a positive chronotropic effect, exhibiting the following pEDA60 values (negative log values of the doses increasing heart rate by 60 beats min-'): isoprenaline 10.4, CGP 12177 8.3, cyanopindolol 7.2, BRL 37344 6.9, ZD 2079 5.2 and CL 316243<5. Ih-, /2-, P3-, a,-adrenoceptors or 5-HT2A receptors. This effect may involve atypical P-adrenoceptors, similar or identical to those described by Kaumann (1989) in isolated heart preparations.

Identification of Key Residues in Transmembrane 4 Responsible for the Secondary, Low-Affinity Conformation of the Humanβ1-Adrenoceptor

“…The high-affinity component (readily blocked by b-blockers) is thought to occur via the high-affinity catecholamine conformation, while the lowaffinity component (resistant to b-blockade) occurs via the secondary low-affinity conformation (Walter et al, 1984;Baker et al, 2003). These two b 1 -adrenoceptor conformations have also been demonstrated in rat, mouse, ferret, and human heart (e.g., Kompa and Summers, 1999;Kaumann et al, 2001;Lowe et al, 2002;Joseph et al, 2003;Sarsero et al, 2003;Molenaar et al, 2007), human blood vessels (e.g., Mallem et al, 2004;Kozlowska et al, 2003Kozlowska et al, , 2006, and in whole animals (e.g., Malinowska and Schlicker, 1996;Zakrzeska et al, 2005). However, the physiologic or clinical relevance of this conformation remains unknown, even though the plasma concentration of carvedilol (100 ng/ml 5 300 nM) used in human cardiovascular diseases is sufficient to occupy this secondary conformation (Sawangkoon et al, 2000;Baker et al, 2003).…”

α1‐Adrenoceptor antagonist properties of CGP 12177A and other β‐adrenoceptor ligands: evidence against β3‐ or atypical β‐adrenoceptors in rat aorta

“…b 3 -Adrenoceptors are pharmacologically characterised by (i) low affinity of classical b-adrenoceptor antagonists, (ii) activation by selective agonists, such as BRL 37344 (Arch et al, 1984), (iii) activation by 'nonconventional partial agonists' (potent b 1 -/b 2 -adrenoceptor antagonists with b 3 -agonist activity at higher concentrations (Kaumann, 1989) such as cyanopindolol (Engel et al, 1981) and CGP 12177A (Mohell & Dicker, 1989)) and (iv) blockade by selective b 3 -adrenoceptor antagonists such as SR 59230A (Manara et al, 1996). A further atypical b-adrenoceptor, designated the putative b 4 -adrenoceptor, was also characterised in the heart (Kaumann, 1989;Kaumann & Molenaar, 1996;Malinowska & Schlicker, 1996) and in adipose tissue (Galitzky et al, 1997), which shared properties (i) and (iii) above but not (ii) and (iv).…”

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

“…The b 4 -adrenoceptor is not activated by selective b 3 -adrenoceptor agonists (Kaumann & Molenaar, 1996;Malinowska & Schlicker, 1996;Oostendorp & Kaumann, 2000;Sarsero et al, 1999), SR 59230 (3-(2-Ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate) (selective b 3 -adrenoceptor antagonist) fails to shift the concentration-response curve to CGP 121777A (Kaumann & Molenaar, 1996) and the cardiostimulant effects of CGP 12177A are still observed in hearts of knockout mice with disruption of the b 3 -adrenoceptor gene .…”