title: Substrate dependence of myocardial response to hypoxia in the presence of theophylline.
abstract: 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.
mesh_terms: D000818:Animals; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D013806:Theophylline / Q000494:pharmacology*
chemical_list: D006003:Glycogen; D013806:Theophylline