Augmentation of cardiac contractility with no change in L‐type Ca 2+ current in transgenic mice with a cardiac‐directed expression of the human adenylyl cyclase type 8 (AC8)

The β‐adrenergic cascade is severely impaired in heart failure (HF), in part because of a reduction in the activity of the two dominant cardiac adenylyl cyclase (AC) isoforms, AC5 and AC6. Hence, cardiac‐directed AC overexpression is a conceivable therapeutic strategy in HF. In this study, we explored the consequences at the cellular and organ level of a cardiac‐directed expression of the human AC8 in the transgenic mouse line AC8TG. Unlike AC5 and AC6, which are inhibited by intracellular Ca 2+ , AC8 is stimulated by Ca 2+ ‐calmodulin. Langendorff perfused hearts from AC8TG mice had a twofold higher left ventricular systolic pressure, a 40% faster heart rate, a 37% faster relaxation, and a 30% higher sensitivity to external Ca 2+ than nontransgenic control mice (NTG). Cell shortening measured in isolated ventricular myocytes developed 22% faster and relaxed 43% faster in AC8TG than in NTG mice. Likewise, Ca 2+ transients measured in fluo‐3 AM‐loaded myocytes were 30% higher and relaxed 24% faster in AC8TG compared with NTG mice. In spite of the large increase in Ca 2+ transients and contraction, expression of AC8 had no effect on the whole‐cell L‐type Ca 2+ current (I Ca,L ) amplitude. Moreover, I Ca,L was unchanged even when AC8 was activated by raising intracellular Ca 2+ . Thus, cardiac expression of AC8 leads to an increase in cAMP that activates specifically Ca 2+ uptake into the sarcoplasmic reticulum but not Ca 2+ influx at the sarcolemma, suggesting a strong compartmentation of the cAMP signal.