B-blockers have long been used as the first line of treatment in hypertension. The majority of B-blockers are both B1 and B2-active. Although there are B1 and B2-selective drugs, they are not B1 or B2-specific. We have developed a novel approach to B-blockade using antisense technology to produce a high-specific non-toxic, long-acting inhibitor of B1-adrenoreceptors (B1-AR). The antisense oligonucleotide to B1 mRNA (B1-AS-ODN) reduces cardiac output without a reduction in heart rate. We hypothesize that this difference is due to the specific inhibition of B1-receptors. Since clinical trials have shown improved cardiac function in heart failure patients with B-blockers, we propose to use the B1-AS-ODN in comparison to current B-blockers to study the mechanisms of the beneficial effects.
AIM 1 : To investigate the underlying mechanisms by which 1-AS-ODN decreases cardiac contractility but not heart rate, we will test three alternative hypotheses: 1) that the B1-AR have a higher receptor reserve for controlling heart rate, 2) the B2-receptors play a more important role in heart rate regulation than B1-AR, 3) pacemaker cells in the heart may take up B1-AS less efficiently than cardiomyocytes.
AIM 2 : To elucidate whether a reduction in heart rate is necessary for improving cardiac performance in heart failure by beta-blockade, we will test by comparing B1-AS-ODN to B1-selective blockers on ameliorating cardiac dysfunction induced by aortic banding.
AIM 3 : To study the long-term protective effect of B1-AS-ODN in the prevention and or reversal of LVH and remodeling, we will use transgenic mice over expressing cardiac B1-AR (B1TG4) and test the long-term effects of the AS. Also, we will test rats with aortic banding. In view of the potential use for B-blockers in therapy for heart failure, myocardial infarction and sudden cardiac death, this proposal offer a novel approach, which would have a high impact and low risk.
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