Abnormal contraction caused by expression of G(i)-coupled receptor in transgenic model of dilated cardiomyopathy

Although increased G(i) signaling has been associated with dilated cardiomy opathy in humans, its role is not clear. Our goal was to determine the effe cts of chronically increased G(i) signaling on myocardial function. We stud ied transgenic mice that expressed a G(i)-coupled receptor (Ro1) that was t argeted to the heart and regulated by a tetracycline-controlled expression system. Ro1 expression for 8 wk resulted in abnormal contractions of right ventricular muscle strips in vitro. Ro1 expression reduced myocardial force by >60% (from 35 +/- 3 to 13 +/- 2 mN/mm(2), P< 0.001). Nevertheless, sens itivity to extracellular Ca2+ was enhanced. The extracellular [Ca2+] result ing in half-maximal force was lower with Ro1 expression compared with contr ol (0.41 +/- 0.05 vs. 0.88 +/- 0.05 mM, P< 0.001). Ro1 expression slowed bo th contraction and relaxation kinetics, increasing the twitch time to peak (143 +/- 6 vs. 100 +/- 4 ms in control, P< 0.001) and the time to half rela xation (124 +/- 6 vs. 75 +/- 6 ms in control, P< 0.001). Increased pacing f requency increased contractile force threefold in control myocardium (P< 0. 001) but caused no increase of force in Ro1-expressing myocardium. When sti mulation was interrupted with rests, postrest force increased in control my ocardium, but there was postrest decay of force in Ro1-expressing myocardiu m. These results suggest that defects in contractility mediated by G(i) sig naling may contribute to the development of dilated cardiomyopathy.