Preserved cardiac function despite marked impairment of cAMP generation.

So many clinical trials of positive inotropes have failed, that it is now axiomatic that agents that increase cAMP are deleterious to the failing heart. An alternative strategy is to alter myocardial Ca(2+) handling or myofilament response to Ca(2+) using agents that do not affect cAMP. Although left ventricular (LV) function is tightly linked to adenylyl cyclase (AC) activity, the beneficial effects of AC may be independent of cAMP and instead stem from effects on Ca(2+) handling. Here we ask whether an AC mutant molecule that reduces LV cAMP production would have favorable effects on LV function through its effects on Ca(2+) handling alone.We generated transgenic mice with cardiac-directed expression of an AC6 mutant (AC6mut). Cardiac myocytes showed impaired cAMP production in response to isoproterenol (74% reduction; p