Mitochondrial oxidative phosphorylation: tissue oxygen sensor for regulation of coronary flow.
The observation that mitochondrial oxidative phosphorylation in vivo is dependent on oxygen tension throughout the physiological range (Wilson et al., 1979a , 1979b ) has made this metabolic pathway the most probable candidate for the tissue oxygen sensor in the regulation of local blood flow. We have utilized the oxygen dependent regulatory system for coronary blood flow to examine this possibility. Alterations in coronary flow were induced by: 1. Varied work load; 2. Infusion of Amytal (an inhibitor of mitochondrial respiration); 3. Infusion of DNP; 4. Hypoxia. Increased work load caused increased coronary flow with no decrease in effluent oxygen tension while Amytal infusion and hypoxia caused vasodilation with increased and decreased O2 tension respectively. This indicates that oxygen tension per se cannot be responsible for the observed vasodilation. Tissue energy metabolism was evaluated by measuring metabolite levels in hearts which were freeze-clamped in each state of perfusion. In all four methods of vasodilation, a decrease in cellular energy state ratio ([ATP]f/[ADP]f[Pi]) expressed as the calculated ratio of free adenine nucleotides, was observed for conditions which increased flow. Systematic variation of work load, Amytal or DNP concentration resulted in quantitatively the same correlation between tissue [ATP]f/[ADP]f[Pi] and coronary flow. It is concluded that mitochondrial oxidative phosphorylation is the oxygen sensor for the regulation of coronary blood flow by tissue oxygen tension. Infusion of adenosine, a known coronary vasodilator, induced vasodilation which was completely blocked by theophylline.(ABSTRACT TRUNCATED AT 250 WORDS)
D019297:2,4-Dinitrophenol; D000241:Adenosine / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000654:Amobarbital / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation; D003401:Creatine / Q000378:metabolism; D004140:Dinitrophenols / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D051381:Rats; D011919:Rats, Inbred Strains; D013806:Theophylline / Q000494:pharmacology
D004140:Dinitrophenols; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D013806:Theophylline; D000654:Amobarbital; D000241:Adenosine; D003401:Creatine; D019297:2,4-Dinitrophenol