Abolition of (-)-CGP 12177-evoked cardiostimulation in double beta1/beta2-adrenoceptor knockout mice. Obligatory role of beta1-adrenoceptors for putative beta4-adrenoceptor pharmacology.
Some beta1- and beta2-adrenoceptor-blocking agents, such as (-)-CGP 12177, cause cardiostimulant effects at concentrations considerably higher than those that antagonise the effects of catecholamines. The cardiostimulant effects of these non-conventional partial agonists are relatively resistant to blockade by (-)-propranolol and have been proposed to be mediated through putative beta4-adrenoceptors or through atypical states of either beta1- or beta2-adrenoceptors. We investigated the effects of (-)-CGP 12177 on sinoatrial rate and left atrial contractile force as well as the ventricular binding of (-)-[3H]CGP 12177 in tissues from wild-type, beta2-adrenoceptor knockout and beta1/beta2-adrenoceptor double knockout mice. The cardiostimulant effects of (-)-CGP 12177 were present in wild-type and beta2-adrenoceptor knockout mice but were absent in beta1/beta2-adrenoceptor double knockout mice. Thus, the presence of beta1-adrenoceptors is obligatory for the cardiostimulant effects of (-)-CGP 12177. It appears therefore that an atypical state of the beta1-adrenoceptor contributes to the mediation of the cardiostimulant effects induced by non-conventional partial agonists. Ventricular beta1- and beta2-adrenoceptors, labelled in wild-type with a K(D) approximately 0.5 nmol/l (approximately 16 fmol/mg protein), were absent in beta1/beta2-adrenoceptor double knockout mice. However, a high density binding site (approximately 154-391 fmol/mg protein) that did not saturate completely (K(D) approximately 80-200 nM) was labelled by (-)-[3H]CGP 12177 in the three groups of mice, being distinct from beta1- and beta2-adrenoceptors, as well as from the site mediating the agonist effects of (-)-CGP 12177.
Kaumann
A J
AJ
Babraham Institute, and Department of Physiology, University of Cambridge, UK. ajk41@hermes.cam.ac.uk
Engelhardt
S
S
Hein
L
L
Molenaar
P
P
Lohse
M
M
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D016275:Atrial Function; D001667:Binding, Competitive / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D010869:Pindolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D011412:Propanolamines / Q000378:metabolism / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000502:physiology; D012849:Sinoatrial Node / Q000187:drug effects / Q000502:physiology; D014316:Tritium
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D014316:Tritium; C047975:cyanopindolol; D003994:Bucladesine; D010869:Pindolol; D007545:Isoproterenol; C033394:CGP 12177; D015056:1-Methyl-3-isobutylxanthine