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

The regulation of cardiac and vascular function by the alpha(1B)- and alpha(1D)-adrenoceptors (ARs) has been assessed in two lines of transgenic mice, one over-expressing a constitutively active alpha(1B)-AR mutation (alpha(1B)- AR(C128F)) and the other an alpha(1D)-AR knockout line. The advantage of using mice expressing a constitutively active alpha(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 alpha(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 alpha(1B)-AR(C128F) had echocardiographic evidence of contractile dysfunction and increases in chamber dimensions. In isolated-perfused hearts or left ventricular slices from alpha(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 alpha(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 alpha(1D)-AR knockout mice. In alpha(1D)-AR knockout animals, no negative effects on cardiac contractile function were noted. These results show that the alpha(1)-ARs regulate distinctly different physiologic processes. The alpha(1B)-AR appears to be involved in the regulation of cardiac growth and contractile function, whereas the alpha(1D)-AR is coupled to smooth muscle contraction and the regulation of systemic arterial blood pressure.