Enhanced cardiac contractility after gene transfer of V2 vasopressin receptors in vivo by ultrasound-guided injection or transcoronary delivery

Background-Systemic levels of arginine vasopressin (AVP) are increased in c ongestive heart failure, resulting in vasoconstriction and reduced cardiac contractility via V-1 vasopressin receptors. V-2 vasopressin receptors (V2R s), which promote activation of adenylyl cyclase, are physiologically expre ssed only in the kidney and are absent in the myocardium. Heterologous expr ession of V2Rs in the myocardium could result in a positive inotropic effec t by using the endogenous high concentrations of AVP in heart failure. Methods and Results-We tested gene transfer with a recombinant adenovirus f or the human V2R (Ad-V2R) to stimulate contractility of rat or rabbit myoca rdium in vivo. Ultrasound-guided direct injection or transcoronary delivery of adenovirus in vivo resulted in recombinant receptor expression in the m yocardial target area, leading to a substantial increase in [H-3]AVP bindin g. In 50% of the cardiomyocytes isolated from the directly injected area, s ingle-cell shortening measurements detected a significant increase in contr action amplitude after exposure to AVP or the V2R-specific desmopressin (DD AVP), Echocardiography of the target myocardial area documented a marked in crease in local fractional shortening after systemic administration of DDAV P in V2R-expressing animals but not in control virus-treated hearts. Simult aneous measurement of global contractility (dP/dt(max)) confirmed a positiv e inotropic effect of DDAVP on left ventricular function in the Ad-V2R-inje cted animals. Conclusions-Adenoviral gene transfer of the V2R into the myocardium increas es cardiac contractility in vivo. Heterologous expression of cAMP-forming r eceptors in the myocardium could lead to novel strategies in the therapy of congestive heart failure by bypassing the desensitized beta-adrenergic rec eptor-signaling cascade.