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Effects of moderate hypertension on function and substrate metabolism of rabbit heart
j Mol Cell Cardiol 19 (Supplement IV) (1987) 1 6 9 SEQUESTRATION OF COENZYME A IMPAIRS CITRIC ACID CYCLE FLUX AND CONTRACTILE PERFORMANCE IN RABBIT HEART. R. R. Russell I I I , H. Taegtmeyer. Department of Internal Medicine University of Texas Medical School, Houston, Texas. In order to assess carbon f l u x through the c i t r i c acid cycle and i t s effects on heart function, we perfused isolated rabbit hearts and incubated broken cell preparations. When GLU u t i l i z a t i o n was i n h i b i t e d by acetoacetate (ACAC, 7.5mM) function declined. In order to define the mechanism of i n h i b i t e d GLU oxidation, we incubated homogenates with [I-14C] GLU and measured 1~C0~ production as well as the content of intermediary metabolites. ACAC i n h i b i t e d COo'production by 51%. With ADAC there was an increase in acetoacetyl-CoA (+191%) ahd acetyl-CoA (+62%), and a decrease in succinyl-CoA (-368%) and free CoASH (-198%). The t o t a l amount of coenzyme A was the same in both groups (7.88 vs. 7.92 ~mol/mg protein for GLU and GLU+ACAC respectively). With ACAC there was also a s i g n i f i c a n t decrease of both succinate and malate. Specific a c t i v i t y in eluent fractions showed a c t i v i t y in the 2-oxoglutarate peak only, i . e . the point of entry of the GLU carbon skeleton in the c i t r i c acid cycle. The results indicate that when heart tissue is flooded with ACAC, f l u x through the c i t r i c acid cycle is impaired due to a block at the level of 2-oxoglutarate dehydrogenase. This block is caused by sequestration of free CoASH in the form of i t s a c y l - d e r i v a t i o n s . In the beating heart the impairment in f l u x of energy is reflected by impaired l e f t v e n t r i c u l a r function.
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LACTATE EXTRACTION BY WORKING RAT HEART IS PRIMARILY WORKDEPENDENT, NOT FLOW DEPENDENT. V.T.B. Nguyen, H. Taegtmeyer. Department of Internal Medicine University of Texas Medical School, Houston, Texas. The importance of flow for determining the rate of substrate u t i l i z a t i o n is not c l e a r l y defined. In order to t e s t whether rates of substrate u t i l i z a t i o n are flow dependent or work dependent, we perfused working r a t hearts at low and high work loads with Krebs-Henseleit bicarbonate saline containing sodium lactate (5mM). We measured rates of coronary flow (CF, ml/min/g dry) and substrate u t i l i z a t i o n (~mol/h/g dry) as they relate to mean a o r t i c pressure (AoP, mmHg) and a o r t i c flow (AoF, ml/min/g dry). Each heart was perfused at low (45 min) and at high work load (45 min). x• n = 4, *P
171 EFFECTS OF MODERATEHYPERTENSIONON FUNCTION AND SUBSTRATEMETABOLISM OF RABBIT HEART. H. Taegtmeyer, M.L. Overturf. Department of Internal Medicine University of Texas Medical School, Houston, Texas. In order to study the early effects of hypertension on the heart we examined isolated hearts from rabbits with slowly developing hypertension of up to 62 weeks duration a f t e r unilateral nephrectomy and renal artery stenosis. Normotensive animals kept under identical conditions served as controls. Mean a r t e r i a l blood pressure rose from 83 to 155 mmHg, but the r a t i o of l e f t v e n t r i c u l a r weight/body weight did not increase. Left v e n t r i c u l a r peak s y s t o l i c pressure of perfused hearts was s i g n i f i c a n t l y higher in hypertensive than in normotensive hearts. These functional changes were accompanied by metabolic changes. Rates of glucose u t i l i z a t i o n were increased and rates of ketone body u t i l i z a t i o n were decreased in hypertensive hearts. A c t i v i t i e s of key enzymes of carbohydrate metabolism (hexokinase, lactate dehydrogenase) were increased, while those of ketone body metabolism (3-oxoacid-CoA transferase, acetoacetyl-CoA synthase) and of the c i t r i c acid cycle ( c i t r a t e synthase, 2-oxoglutarate dehydrogenase) were not d i f f e r e n t between groups. I t is suggested that the mechanism for the structural and functional adaptations which characterize l e f t v e n t r i c u l a r hypertrophy may rest in changes of enzyme a c t i v i t i e s and resultant changes in substrates u t i l i z a t i o n of the heart, which antedate or may even t r i g g e r hypertrophy.
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170
LACTATE EXTRACTION BY WORKING RAT HEART IS PRIMARILY WORKDEPENDENT, NOT FLOW DEPENDENT. V.T.B. Nguyen, H. Taegtmeyer. Department of Internal Medicine University of Texas Medical School, Houston, Texas. The importance of flow for determining the rate of substrate u t i l i z a t i o n is not c l e a r l y defined. In order to t e s t whether rates of substrate u t i l i z a t i o n are flow dependent or work dependent, we perfused working r a t hearts at low and high work loads with Krebs-Henseleit bicarbonate saline containing sodium lactate (5mM). We measured rates of coronary flow (CF, ml/min/g dry) and substrate u t i l i z a t i o n (~mol/h/g dry) as they relate to mean a o r t i c pressure (AoP, mmHg) and a o r t i c flow (AoF, ml/min/g dry). Each heart was perfused at low (45 min) and at high work load (45 min). x• n = 4, *P
171 EFFECTS OF MODERATEHYPERTENSIONON FUNCTION AND SUBSTRATEMETABOLISM OF RABBIT HEART. H. Taegtmeyer, M.L. Overturf. Department of Internal Medicine University of Texas Medical School, Houston, Texas. In order to study the early effects of hypertension on the heart we examined isolated hearts from rabbits with slowly developing hypertension of up to 62 weeks duration a f t e r unilateral nephrectomy and renal artery stenosis. Normotensive animals kept under identical conditions served as controls. Mean a r t e r i a l blood pressure rose from 83 to 155 mmHg, but the r a t i o of l e f t v e n t r i c u l a r weight/body weight did not increase. Left v e n t r i c u l a r peak s y s t o l i c pressure of perfused hearts was s i g n i f i c a n t l y higher in hypertensive than in normotensive hearts. These functional changes were accompanied by metabolic changes. Rates of glucose u t i l i z a t i o n were increased and rates of ketone body u t i l i z a t i o n were decreased in hypertensive hearts. A c t i v i t i e s of key enzymes of carbohydrate metabolism (hexokinase, lactate dehydrogenase) were increased, while those of ketone body metabolism (3-oxoacid-CoA transferase, acetoacetyl-CoA synthase) and of the c i t r i c acid cycle ( c i t r a t e synthase, 2-oxoglutarate dehydrogenase) were not d i f f e r e n t between groups. I t is suggested that the mechanism for the structural and functional adaptations which characterize l e f t v e n t r i c u l a r hypertrophy may rest in changes of enzyme a c t i v i t i e s and resultant changes in substrates u t i l i z a t i o n of the heart, which antedate or may even t r i g g e r hypertrophy.
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