Effects of different beta adrenoceptor ligands in mice with permanent occlusion of the left anterior descending coronary artery

We have studied the effects of three β AR ligands (carvedilol, alprenolol, and ICI‐118,551) with different pharmacological profiles and negative efficacy at the β 2AR on cardiac in vivo , in vitro , biochemical and gene expression parameters in mice with permanent occlusion of the left anterior descending coronary artery. Cardiac in vivo parameters were determined using Doppler studies. Mitral‐wave E peak velocity (EPV) and aortic peak velocity (AoPV) decreased in the first 2 weeks postocclusion. After 3 weeks of drug treatment, EPV was improved in the carvedilol group to preocclusion values; however, a further reduction in EPV in the alprenolol and control permanent occlusion group was measured and there was no change after ICI‐118,551 treatment. AoPV was unchanged between weeks 2 and 5 in all groups. The left atria were isolated to record isometric tension responses to isoprenaline. Permanent occlusion significantly reduced the maximum isoprenaline response to 30% of control and carvedilol increased the maximum response to isoprenaline significantly to 60%. The biochemical and gene expression studies revealed different effects of the three β AR ligands. Most notably, carvedilol reduced gene expression of myosin heavy chain β . These results indicate that chronic treatment with carvedilol is beneficial in a mouse model of myocardial damage resulting from ischaemia. We hypothesise that these beneficial effects of the drug may be because of the negative efficacy at the β 2AR, combined with β 1AR antagonism.British Journal of Pharmacology (2003) 138 , 1505–1516. doi: 10.1038/sj.bjp.0705205