Inhibition of PI3K improves contractility in alpha1-adrenergically stimulated myocardium.
Recent studies have demonstrated that phosphoinositide 3-kinases (PI3Ks) play a fundamental role in regulating myocardial contractility. However, even though alpha1-adrenergic receptor stimulation is known to activate PI3Ks, the impact of this pathway on the inotropic effects of alpha1-stimulation is unclear. Isolated rabbit ventricular myocytes were preincubated with the PI3K inhibitor wortmannin (WM, 0.1 micromol/L). The alpha1 agonist phenylephrine (PE, 10 micromol/L) induced a significantly stronger increase in contractility in WM-treated versus control myocytes (Fractional shortening in percent of resting cell length: 6.14+/-0.33 percent; n=26 versus 4.85+/-0.33 percent; n=26, P less than 0.05). Furthermore, pretreatment with WM significantly increased the positive inotropic effect of PE in intact muscle strips from rabbit hearts. Mechanistically, we demonstrate that in WM-treated myocytes PE increased phospholamban (PLN) phosphorylation and intracellular Ca2+ transients to a significantly greater extent than in control myocytes. In summary, this is the first study to demonstrate that inhibition of PI3K by increasing PLN phosphorylation and Ca2+ transients significantly improves contractility in alpha1-adrenergically stimulated myocardium. This may have clinical implications for the treatment of decreased cardiac function in acute heart failure.
Department of Cardiology and Pneumology, Heart Center,Georg-August-University Goettingen, Robert-Koch-Strasse 40, 37075 Goettingen, Germany.
Claudius
C
Jacobshagen
Swantje
S
Kortlepel
Bernhard W
BW
Unsoeld
Thomas
T
Sowa
Harald
H
Koegler
Gerd
G
Hasenfuss
Lars S
LS
Maier
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011817:Rabbits; D016276:Ventricular Function
D000316:Adrenergic alpha-Agonists; D000081082:Phosphoinositide-3 Kinase Inhibitors; D002118:Calcium