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Effects of inosine on myocardial function and substrate uptake
j M o l C e l l C a r d i o l 19 ( S u p p l e m e n t
III) (1987)
181
~'J:'~--~s OF I N f ~ I N E ON MYOCARDIAL F[3NC-'YION AVID SUBSTRATE UPTAKE. O.D. Mjzs, O. Smiseth, P. Gunnes, Dept. of Physiology, University of Trcms~, Tromso, Norway. The aim of the present study %~s to determine the effect of i.v. inosine on myocardial substrate uptake and function in the in situ dog heart. Inosine was J_nfused i.v. at a rate of 5 mg/kg-min in 8 closed-chest pentobarbital anesthetized dogs. Inosine caused a 46% decrease (p < 0.01 ) in plasma free fatty acids (FFA), a 15% decrease (p < 0.05) in pla~na glycerol, an 18% decrease (p < 0.05) in plasma glucose and a 46% increase (p < 0.01) in blood lactate. This was associated with a 55% decrease (p < 0.01 ) in myocardial FFA uptake and a 72% increase in lactate uptake, while glucose u p t a k e r e m a i n e d u n c h a n g e d . T h e s e metabolic changes oould in part be attributed to a 5-fold increase (p < 0.05) in arterial insulin. Inosine caused an 18% increase (p < 0.01) in myocardial blood flow without changing myocardial oxygen cons~nption. There was a 33% increase (p < 0.01 ) in L V dP/dtmax, a decrease in LVEDP from 4.9 z 0.9 (mean • SHIM) s 0.9 • 0.3 m m H g (p < 0.05) and a 24% decrease (p < 0.01) in systemic vascular resistance. Inosine caused a transient 38% increase in pulmonary vascular resistance. In conclusion, in addition to a positive inotropic effect and vascular effects inosine was found to cause release of insulin and to shift myocardial metabolism towards increased uptake of carbohydrates relative to FFA.
182
IMPAIRED METABOLISM OF NON ISCHEMIC MYOCARDIUM UNDER PUMP FAILURE COMPLICATED IN ACUTE MYOCARDIAL INFARCTION. M. M o c h i z u k i , T. K a t a g i r i , N. Konno, K. l l m e t s u , E. G e s h i , T. K i t s u , T. Y a n a g i s h i t a , F. T a n n o , J . H i r o s h i g e a n d H. N i J t a n i . Third Department of Internal M e d i c i n e , Showa U n i v e r s i t y School of Medicine, Tokyo, Japan. We s t u d i e d metabolism of non-isehemic m y o c a r d i u m t i n d e r pump f a i l u r e complicated in acute myocardial infarction induced by coronary occlusion in dogs. Dogs w e r e separated t o 2 g r o u p s i n w h i c h I,VPs r e d u c e d g r e a t e r t h a n 30% o f t h a t b e f o r e LCX ligation for 2 hrs (D g r o u p ) and did not (ND g r o u p ) . Ca. h T P a s e a c t i v i t y and constituting protein of sarcoplasmic retieu]um (SR) w e r e d e t e r m i n e d i n s u b e n d o ( E n d o ) and subepicardial muscles(Epi) together with tissue levels o f ATP, l a c t a t e and pyruvate. I n i s c h e m i c m y o e a r d i u m Ca ATPase a c t i v i t y a n d m a j o r A T P a s e p r o t e i n o f SR, and tissue l e v e l s o f ATP g r e a t l y d e c r e a s e d a c c o m p a n i e d b y a n i n c r e a s e in lactate, in non-ischemie m y o c a r d i u m o f D g r o u p Ca A T P a s e a c t i v i t y reduced significantly t o 60 a n d 58% o f t h o s e o f i n Endo a n d E p i , r e s p e c t i v e l y , without degradation of major ATPase protein and tissue l e v e l s o f ATP r e d u c e d t o 70% o f t h a t o f i n E n d o . B o t h i n Ende a n d Epi Ca-ATPase activity significantly correlated w i t h LVPs. T i s s u e ATP c o n t e n t also significantly decreased with reduction i n LVPs i n E n d o . These results indicate that metabolism of non ischemic myocardinm is greatly influenced, especially in Endo, under s e v e r e pump f a i l u r e such as cardiogenic shoek and this is conceivable of being caused b y a r e d u c e d c o r o n a r y f l o w in v i c i o u s c i r c l e o f c o n t r a c t i l e failure.
183
REPERFUSION INDUCED VENTRICULAR FIBRILLATION IN ISOLATED PERFUSED RAT HEART : ANTIARRHYTHMIC EVALUATION OF MEXILETINE AND DISOPYRAMIDE. S.Mochizuki, M.Ishiki & M.Nagano. Department of Medieine,Aoto Hospital, Jikei University School of Medicine, Tokyo, Japan Myocardial metabolic changes and effect of mexiletine and disopyramide were evalu ated in the reperfusion-induced ventrieular fibrillation ( VF ). The hearts were perfused by Neely-Morgan working rat heart mode with Krebs Henseleit bicarbonate(KHB) buffer for 5 min followed by 25 min of global ischemia with pacing and subsequent reperfusion of 30 min without pacing ( Control:C ). After the onset of VF, the buffer was switched to KHB containing 5 mg/L mexiletine ( M ) or disopyramide ( D ) respectively. Coronary effluent was collected through pulmonary artery eannulation and P02, PC02, HC03- , electrolytes were measured. VF developed in all of the hearts in C and sustained for 28 min (mean), whereas it was terminated within 7 min in M and ii min in D respectively after the onset of VF. However, the recovery rate of ventricular function during reperfusion in D (71% of the preisehemie level) was significantly higher than in M (35%). There was no significant difference in coronary flow rate among the 3 groups. Venous PC02 levels demonstrated the increase of 8 and 29% of the preischemic level at 5 and 15 min after reperfusion respectively in C, whereas they were significantly reduced in either M or D when compared with C. There was no significant difference in HCO 3- and electrolyte balance among the 3 groups. These results indicated that the reperfusion-induced VF might be associated with the reduced CO 2 washout and both M and D dramatically terminated the development of VF which related to the acceleration of CO 2 washout. -
S.61
III) (1987)
181
~'J:'~--~s OF I N f ~ I N E ON MYOCARDIAL F[3NC-'YION AVID SUBSTRATE UPTAKE. O.D. Mjzs, O. Smiseth, P. Gunnes, Dept. of Physiology, University of Trcms~, Tromso, Norway. The aim of the present study %~s to determine the effect of i.v. inosine on myocardial substrate uptake and function in the in situ dog heart. Inosine was J_nfused i.v. at a rate of 5 mg/kg-min in 8 closed-chest pentobarbital anesthetized dogs. Inosine caused a 46% decrease (p < 0.01 ) in plasma free fatty acids (FFA), a 15% decrease (p < 0.05) in pla~na glycerol, an 18% decrease (p < 0.05) in plasma glucose and a 46% increase (p < 0.01) in blood lactate. This was associated with a 55% decrease (p < 0.01 ) in myocardial FFA uptake and a 72% increase in lactate uptake, while glucose u p t a k e r e m a i n e d u n c h a n g e d . T h e s e metabolic changes oould in part be attributed to a 5-fold increase (p < 0.05) in arterial insulin. Inosine caused an 18% increase (p < 0.01) in myocardial blood flow without changing myocardial oxygen cons~nption. There was a 33% increase (p < 0.01 ) in L V dP/dtmax, a decrease in LVEDP from 4.9 z 0.9 (mean • SHIM) s 0.9 • 0.3 m m H g (p < 0.05) and a 24% decrease (p < 0.01) in systemic vascular resistance. Inosine caused a transient 38% increase in pulmonary vascular resistance. In conclusion, in addition to a positive inotropic effect and vascular effects inosine was found to cause release of insulin and to shift myocardial metabolism towards increased uptake of carbohydrates relative to FFA.
182
IMPAIRED METABOLISM OF NON ISCHEMIC MYOCARDIUM UNDER PUMP FAILURE COMPLICATED IN ACUTE MYOCARDIAL INFARCTION. M. M o c h i z u k i , T. K a t a g i r i , N. Konno, K. l l m e t s u , E. G e s h i , T. K i t s u , T. Y a n a g i s h i t a , F. T a n n o , J . H i r o s h i g e a n d H. N i J t a n i . Third Department of Internal M e d i c i n e , Showa U n i v e r s i t y School of Medicine, Tokyo, Japan. We s t u d i e d metabolism of non-isehemic m y o c a r d i u m t i n d e r pump f a i l u r e complicated in acute myocardial infarction induced by coronary occlusion in dogs. Dogs w e r e separated t o 2 g r o u p s i n w h i c h I,VPs r e d u c e d g r e a t e r t h a n 30% o f t h a t b e f o r e LCX ligation for 2 hrs (D g r o u p ) and did not (ND g r o u p ) . Ca. h T P a s e a c t i v i t y and constituting protein of sarcoplasmic retieu]um (SR) w e r e d e t e r m i n e d i n s u b e n d o ( E n d o ) and subepicardial muscles(Epi) together with tissue levels o f ATP, l a c t a t e and pyruvate. I n i s c h e m i c m y o e a r d i u m Ca ATPase a c t i v i t y a n d m a j o r A T P a s e p r o t e i n o f SR, and tissue l e v e l s o f ATP g r e a t l y d e c r e a s e d a c c o m p a n i e d b y a n i n c r e a s e in lactate, in non-ischemie m y o c a r d i u m o f D g r o u p Ca A T P a s e a c t i v i t y reduced significantly t o 60 a n d 58% o f t h o s e o f i n Endo a n d E p i , r e s p e c t i v e l y , without degradation of major ATPase protein and tissue l e v e l s o f ATP r e d u c e d t o 70% o f t h a t o f i n E n d o . B o t h i n Ende a n d Epi Ca-ATPase activity significantly correlated w i t h LVPs. T i s s u e ATP c o n t e n t also significantly decreased with reduction i n LVPs i n E n d o . These results indicate that metabolism of non ischemic myocardinm is greatly influenced, especially in Endo, under s e v e r e pump f a i l u r e such as cardiogenic shoek and this is conceivable of being caused b y a r e d u c e d c o r o n a r y f l o w in v i c i o u s c i r c l e o f c o n t r a c t i l e failure.
183
REPERFUSION INDUCED VENTRICULAR FIBRILLATION IN ISOLATED PERFUSED RAT HEART : ANTIARRHYTHMIC EVALUATION OF MEXILETINE AND DISOPYRAMIDE. S.Mochizuki, M.Ishiki & M.Nagano. Department of Medieine,Aoto Hospital, Jikei University School of Medicine, Tokyo, Japan Myocardial metabolic changes and effect of mexiletine and disopyramide were evalu ated in the reperfusion-induced ventrieular fibrillation ( VF ). The hearts were perfused by Neely-Morgan working rat heart mode with Krebs Henseleit bicarbonate(KHB) buffer for 5 min followed by 25 min of global ischemia with pacing and subsequent reperfusion of 30 min without pacing ( Control:C ). After the onset of VF, the buffer was switched to KHB containing 5 mg/L mexiletine ( M ) or disopyramide ( D ) respectively. Coronary effluent was collected through pulmonary artery eannulation and P02, PC02, HC03- , electrolytes were measured. VF developed in all of the hearts in C and sustained for 28 min (mean), whereas it was terminated within 7 min in M and ii min in D respectively after the onset of VF. However, the recovery rate of ventricular function during reperfusion in D (71% of the preisehemie level) was significantly higher than in M (35%). There was no significant difference in coronary flow rate among the 3 groups. Venous PC02 levels demonstrated the increase of 8 and 29% of the preischemic level at 5 and 15 min after reperfusion respectively in C, whereas they were significantly reduced in either M or D when compared with C. There was no significant difference in HCO 3- and electrolyte balance among the 3 groups. These results indicated that the reperfusion-induced VF might be associated with the reduced CO 2 washout and both M and D dramatically terminated the development of VF which related to the acceleration of CO 2 washout. -
S.61