Roles of alpha1A- and alpha1B-adrenoceptors in heart: insights from studies of genetically modified mice

Abstract

1. Several mouse strains have been prepared in which different subtypes of the alpha1-adrenoceptor (AR) are overexpressed or deleted. The phenotypes of the animals generated vary depending on whether the receptors are expressed specifically in heart or generally throughout the animal, but some overall conclusions can be drawn. 2. Heightened activity of alpha1B-AR by overexpressing the receptors leads to depressed contractile responses to beta-AR activation, which may be related to activation of the inhibitory G-protein Gi. In contrast, alpha1A-AR cause substantially heightened contractility when overexpressed in heart. 3. Overexpressed alpha1B-AR predispose hearts to hypertrophy and worsen heart failure caused by pressure overload, whereas increased alpha1A-AR expression does not influence hypertrophic responses and, furthermore, improves outcomes after pressure overload or myocardial infarction. 4. Alpha1A-adrenoceptors mediate a preconditioning action to improve functional recovery after acute ischaemic insult, whereas alpha1B-AR are ineffective. Both subtypes appear to protect from inositol 1,4,5-trisphosphate generation and arrhythmogenesis in early postischaemic reperfusion. 5. Although some of the protective effects of heightened alpha1A-AR drive may be related to the enhanced contractility, it is also possible that alpha1A-AR protect from cardiomyocyte apoptotic responses.