Roles of α1A- and α1B-adrenoceptors in heart:: Insights from studies of genetically modified mice

Several mouse strains have been prepared in which different subtypes of the alpha(1)-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. Heightened activity of alpha(1B)-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 G(i). In contrast, alpha(1A)-AR cause substantially heightened contractility when overexpressed in heart. Overexpressed alpha(1B)-AR predispose hearts to hypertrophy and worsen heart failure caused by pressure overload, whereas increased alpha(1A)-AR expression does not influence hypertrophic responses and, furthermore, improves outcomes after pressure overload or myocardial infarction. alpha(1A)-Adrenoceptors mediate a preconditioning action to improve functional recovery after acute ischaemic insult, whereas alpha(1B)-AR are ineffective. Both subtypes appear to protect from inositol 1,4,5-trisphosphate generation and arrhythmogenesis in early postischaemic reperfusion. Although some of the protective effects of heightened alpha(1A)-AR drive may be related to the enhanced contractility, it is also possible that alpha(1A)-AR protect from cardiomyocyte apoptotic responses.