Substrate dependence of myocardial response to hypoxia in the presence of theophylline

The experiments reported here were designed to determine whether stimulating glycogenolysis with theophylline affects the ability of isolated rabbit papillary muscles to sustain and recover from a transient hypoxic episode (15 min). Different substrates [glucose (Glc), pyruvate (Pyr), and butyrate (BA)] were used to either support the glycogen levels or permit their depletion. To evaluate the metabolic consequences, the dynamic relation (coupling coefficient) between the oxidation-reduction level of the intramitochondrial pyridine nucleotide NADH and the mechanical power was determined using a microfluorometer. In the absence of theophylline, the presence of Glc was associated with a smaller decrease in developed tension (tau) during the hypoxic period (Glc 53 +/- 5%) when compared with the nonglycolytic substrates (Pyr 33 +/- 5% or BA 31 +/- 6%). The extent of the recovery was not dependent on the available substrate. The addition of theophylline was accompanied by a substrate-dependent increase in tau: Glc 153 +/- 9%, Pyr 134 +/- 9%, and BA 116 +/- 7%. Theophylline increased the impact of the hypoxic episode on mechanical performance: Glc 17 +/- 4%, Pyr 4 +/- 4%, and BA 6 +/- 5%. With Glc, recovery was comparable to control. For the nonglycolytic substrates, recovery of mechanical function was depressed (Pyr 69 +/- 7%, BA 71 +/- 6%), and there was a significant loss of metabolic sensitivity. These data show that the inotropic response to theophylline is in part determined by the available substrate; theophylline exacerbates the impact of a hypoxic episode, and this effect may be due to the metabolic consequences of its presence.