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 congestive heart failure, resulting in vasoconstriction and reduced cardiac contractility via V(1) vasopressin receptors. V(2) vasopressin receptors (V2Rs), which promote activation of adenylyl cyclase, are physiologically expressed only in the kidney and are absent in the myocardium. Heterologous expression of V2Rs in the myocardium could result in a positive inotropic effect by using the endogenous high concentrations of AVP in heart failure.


RESULTS
We tested gene transfer with a recombinant adenovirus for the human V2R (Ad-V2R) to stimulate contractility of rat or rabbit myocardium in vivo. Ultrasound-guided direct injection or transcoronary delivery of adenovirus in vivo resulted in recombinant receptor expression in the myocardial target area, leading to a substantial increase in [(3)H]AVP binding. In 50% of the cardiomyocytes isolated from the directly injected area, single-cell shortening measurements detected a significant increase in contraction amplitude after exposure to AVP or the V2R-specific desmopressin (DDAVP). Echocardiography of the target myocardial area documented a marked increase in local fractional shortening after systemic administration of DDAVP in V2R-expressing animals but not in control virus-treated hearts. Simultaneous measurement of global contractility (dP/dt(max)) confirmed a positive inotropic effect of DDAVP on left ventricular function in the Ad-V2R-injected animals.


CONCLUSIONS
Adenoviral gene transfer of the V2R into the myocardium increases cardiac contractility in vivo. Heterologous expression of cAMP-forming receptors in the myocardium could lead to novel strategies in the therapy of congestive heart failure by bypassing the desensitized beta-adrenergic receptor-signaling cascade.
Weig
H J
HJ
1. Medizinische Klinik , and Institut für Experimentelle Onkologie/Therapieforschung, Klinikum rechts der Isar, Technische Universität, München, Germany.
Laugwitz
K L
KL
Moretti
A
A
Kronsbein
K
K
Städele
C
C
Brüning
S
S
Seyfarth
M
M
Brill
T
T
Schömig
A
A
Ungerer
M
M
D000256:Adenoviridae / Q000235:genetics; D000257:Adenoviridae Infections / Q000503:physiopathology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D006328:Cardiac Catheterization; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D004452:Echocardiography; D018014:Gene Transfer Techniques; D006321:Heart / Q000503:physiopathology; D006801:Humans; D007267:Injections / Q000379:methods; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000235:genetics* / Q000502:physiology*; D014465:Ultrasonics; D016277:Ventricular Function, Left / Q000187:drug effects
D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D003894:Deamino Arginine Vasopressin