s-adenosylhomocysteine and Myocardial-Ischemia

To investigate the relationship between flow and energy metabolism during coronary underperfusion, regional myocardial ATP content, cytosolic adenosine concentrations, and blood flow were measured during segmental coronary artery occlusion (complete ligation, n = 10) and demand ischemia (catecholamines plus atrial pacing with subtotal stenosis, n = 6) in halothane anesthetized open-chest dogs. During coronary occlusion or demand ischemia, L-homocysteine thiolactone was infused for 20 min, after which left ventricular tissue was rapidly frozen and analyzed for regional blood flow (microspheres) and content of ATP and S-adenosylhomocysteine (SAH), an index of cytosolic adenosine. In nonischemic regions, ATP and SAH contents in both groups were the same as in unstimulated control animals with intact coronary circulation (n = 7), indicating that adrenergic stimulation during unrestricted flow had no effect on ATP or cytosolic adenosine. In the ischemic regions of both groups, there were decreases in regional flow, ATP content, and systolic wall thickening, and increases in SAH content. To compare the indexes of energy metabolism in tissue regions receiving equal blood flow, tissue samples were grouped into intervals of equal blood flow (ml.min-1.g-1). At every level of flow, ATP content in demand ischemia was 25-39% higher than in coronary occlusion. Estimates of cytosolic adenosine concentrations (using a mathematical model) in the lowest flow interval averaged 5 microM in demand ischemia, approximately twice as high as in coronary occlusion. It is concluded that in tissue regions receiving equal blood flow, ATP was better maintained and cytosolic adenosine was higher in demand ischemia than in coronary occlusion. The differences in ATP content and cytosolic adenosine were not due to different blood flows but rather to more favorable energy metabolism in demand ischemia.

Topics: Adenosine; Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Cytosol; Dogs; Female; Hemodynamics; Male; Myocardial Ischemia; Myocardium; S-Adenosylhomocysteine

Myocardial adenosine production increases transiently during the onset of catecholamine stimulation; however, there is conflicting evidence regarding whether cytosolic adenosine concentrations are increased during sustained steady-state stimulation. If cytosolic adenosine is not elevated during steady-state stimulation, then adenosine produced in the cytosol does not play a role in mediating the sustained increase in myocardial blood flow. The purpose of the present study was to determine whether cytosolic adenosine concentrations in the anesthetized dog heart are increased during steady-state stimulation with norepinephrine, epinephrine, and atrial pacing. Regional cytosolic adenosine concentrations were assessed by measuring myocardial content of S-adenosyl-L-homocysteine (SAH) after 20 min of intravenous administration of L-homocysteine thiolactone. Excess homocysteine causes myocardial accumulation of SAH at a rate dependent on the cytosolic concentration of adenosine. Steady-state metabolic stimulation caused more than twofold increases in myocardial blood flow and oxygen consumption, but there was no increase in left ventricular content of SAH in the stimulation group [6.3 +/- 0.9 nmol/g (SE); n = 6] relative to a parallel unstimulated control group (6.4 +/- 0.9 nmol/g; n = 6). The transmural distribution of SAH was nearly uniform, and there was no correlation between regional measurements of blood flow and myocardial content of SAH or ATP either during metabolic stimulation or under control conditions. In separate experiments, myocardial ischemia caused fivefold increases in SAH content, confirming the sensitivity of the SAH method for increased cytosolic adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Adenosine Triphosphate; Animals; Blood Pressure; Cardiac Pacing, Artificial; Catecholamines; Coronary Circulation; Cytosol; Dogs; Heart; Heart Rate; Hemodynamics; Homocysteine; Homocystine; Myocardial Ischemia; Myocardium; Oxygen Consumption; Reference Values; S-Adenosylhomocysteine