Arthur M. Feldman

Background—: [Arg8]-vasopressin (AVP) activates 3 G-protein–coupled receptors: V1A, V2, and V1B. The AVP-V1A receptor is the primary AVP receptor in the heart; however, its role in cardiac homeostasis is controversial. To better understand AVP-mediated signaling in the heart, we created a transgenic mouse with controlled overexpression of the V1A receptor.Methods and Results—: The V1A receptor transgene was placed under the control of the tetracycline-regulated, cardiac-specific α-myosin heavy chain promoter (V1A-TG). V1A-TG mice had a normal cardiac function phenotype at 10 weeks of age; however, by 24 weeks of age, tetracycline-transactivating factor/V1A-TG mouse hearts had reduced cardiac function, cardiac hypertrophy, and dilatation of the ventricular cavity. Contractile dysfunction was also observed in isolated adult cardiac myocytes. When V1A receptor transgene was induced to be expressed in adult mice (V1A-TG_Ind), left ventricular dysfunction and dilatation were also seen, albeit at a later time point. Because the V1A receptor mediates cell signaling through Gα_qprotein, we blocked Gα_qsignaling by crossing tetracycline-transactivating factor/V1A mice with transgenic mice that expressed a small inhibitory peptide against Gα_q. Gα_qblockade abrogated the development of the heart failure phenotype in tetracycline-transactivating factor/V1A-TG mice. The heart failure phenotype could be reversed by administration of doxycycline.Conclusions—: Our results demonstrate a role for V1A-mediated signaling in the development of heart failure and support a role for V1A blockade in the treatment of patients with elevated levels of vasopressin.

Adenosine plays an important role in the pathophysiology of heart failure and in myocardial protection during ischemia and reperfusion. The action of adenosine in the heart is mediated by four G-protein-coupled receptors: A(1)-AR and A(3)-AR, which act via Gα(1), and A(2A)-AR and A(2B)-AR, which act via Gα(s). Understanding of cellular signaling pathways triggered by adenosine has been complicated by the availability of only partially specific adenosine agonists/antagonists. Adenosine signaling appears to be at times redundant in receptor function, and cellular signaling pathways for adenosine are multiple, parallel, and interrelated. Data obtained about the specific role of individual adenosine receptors, through the genetic modulation of receptors in murine hearts have provided important information about the role of adenosine receptors in the heart. Here we review existing data and present new results that clarify the function of individual adenosine receptors in the heart and their role in the development of left ventricular dysfunction, and about the downstream signaling systems that are modified by adenosine receptor activation.