Differential cardiovascular regulatory activities of the α1B- and α1D-adrenoceptor subtypes

The regulation of cardiac and vascular function by the α 1B - and α 1D -adrenoceptors (ARs) has been assessed in two lines of transgenic mice, one over-expressing a constitutively active α 1B -AR mutation (α 1B -AR C128F ) and the other an α 1D -AR knockout line. The advantage of using mice expressing a constitutively active α 1B -AR is that the receptor is tonically active, thus avoiding the use of nonselective agonists that can activate all subtypes. In hearts from animals expressing α 1B -AR C128F , the activities of the mitogen-activated protein kinases, extracellular signal-regulated kinase, and c-Jun N-terminal kinase were significantly elevated compared with nontransgenic control animals. Mice over-expressing the α 1B -AR C128F had echocardiographic evidence of contractile dysfunction and increases in chamber dimensions. In isolated-perfused hearts or left ventricular slices from α 1B -AR C128F -expressing animals, the ability of isoproterenol to increase contractile force or increase cAMP levels was significantly decreased. In contrast to the prominent effects on the heart, constitutive activation of the α 1B -AR had little effect on the ability of phenylephrine to induce vascular smooth muscle contraction in the isolated aorta. The ability of phenylephrine to stimulate coronary vasoconstriction was diminished in α 1D -AR knockout mice. In α 1D -AR knockout animals, no negative effects on cardiac contractile function were noted. These results show that the α 1 -ARs regulate distinctly different physiologic processes. The α 1B -AR appears to be involved in the regulation of cardiac growth and contractile function, whereas the α 1D -AR is coupled to smooth muscle contraction and the regulation of systemic arterial blood pressure.