Differential Cardiovascular Regulatory Activities of the α_1B- and α_1D-Adrenoceptor Subtypes

Abstract

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 α₁-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.