Augmentation of cardiac contractility with no change in L-type Ca2+ current in transgenic mice with a cardiac-directed expression of the human adenylyl cyclase type 8 (AC8)

SPECIFIC AIMSThe β-adrenergic cascade is severely impaired in virtually every form of experimental heart failure (HF) and in the human syndrome. Several studies have shown that AC5 and/or AC6 protein levels, the dominant adenylyl cyclase (AC) isoforms expressed in heart, are reduced in HF, leading to a decrease in total AC activity and a reduction in cAMP-dependent protein kinase (PKA) activity and cardiac contraction. 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 neuronal AC8 in the transgenic mouse line AC8TG.PRINCIPAL FINDINGS1. Influence of AC8 expression on the spontaneous contractility of the heartAnatomical examination of 4- to 5-month-old AC8TG and nontransgenic (NTG) mice and their hearts showed no obvious difference between the two groups. Left ventricular systolic pressure (LVSP), heart rate (HR), and rate pressure product (RPP=LVSPxH...