The β1-adrenoceptor (β1AR) is activated by (-)-noradrenaline and blocked by all clinically used β-blockers. Some β-blockers, typified by (-)-CGP 12177 and (-)-pindolol not only block the β1AR, but also activate it at higher concentrations (∼2-3 orders of magnitude) than those required to block it (Kaumann & Molenaar, 2008). To accommodate these findings, it was hypothesized that β-blockers such as (-)-CGP 12177 and (-)-pindolol bind to the β1AR at two different sites, one that blocks (-)-noradrenaline from activating the receptor, the β1H site, and another that activates the receptor, the β1L site. Acute activation of β1LARs in the heart causes increases in contractile force, hastening of relaxation and increases the probability of arrhythmias (Kaumann & Molenaar, 2008). We have now sought to determine (1) the molecular determinants of the β1LAR and (2) the functional and pathological consequences of chronic activation of β1LAR. β1ARs, β2ARs and mutant β1ARs containing all (β1(β2TMDV)AR) or single amino acids of the fifth transmembrane domain (TMDV) β2AR were prepared and stably expressed in Chinese Hamster Ovary cells. Substitution of heterologous β2AR isoluceine for valine230 in TMDV of the β1AR reduced the ability of the β1AR to form a low affinity binding site of the β1AR. In mice, chronic infusion of (-)-CGP 12177 (0.01 mg 100 mg/kg/24h via osmotic minipump) for 2 or 4 weeks caused a dose-dependent increase in heart rate and cardiac contraction measured as fractional shortening (FS %) which was maintained for 4 weeks. In mice with trans-aortic constriction reducing lumen size by ∼60-65% for a period of 8 weeks, chronic activation of β1LAR with (-)-CGP 12177 during weeks 5-8 caused a more severe cardiac hypertrophy, interstitial fibrosis and inflammation compared to trans-aortic constriction alone, indicating more severe myocardial remodelling. We conclude that chronic activation of β1LAR can be potentially harmful.
Kaumann AJ & Molenaar P (2008) Pharmacology & Therapeutics 118, 303-336.