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Inotropic effects of 2–3 butanedione monoxime (BDM) in intact and skinned frog cardiac fibers
J Mol Cell Cardiol 24 (Supplement VI) (1992) 142
INOTROPIC EFFECTS OF 2-3 BUTANEDIONE MONOXIME (BDM) IN INTACT AND SKINNED FROG CARDIAC FIBERS. J.M. Chesnais and R. Ventura-Clapier. URA-1121 CNRS and U-241 INSERM; Universitk Paris-Sud, 91405 Orsay France. The interest for BDM (a negative inotropic agent), has been increasing in the last years due to its potential protective effect in cardioplegic solutions, but its mechanisms of action remain unclear and controversial. Experiments have been performed on frog atria1 fibers, a tissue where mechanical activation is independent of internal calcium stores (reticulum sarcoplasmic). Simultaneous recordings of calcium currents and contractions of intact fibers have been obtained under voltage clamp using the double sucrose gap technique. To study the direct effects of BDM on mvofibrillar uroteins. atria1 fibers were chemicallv skinned bv Triton X-100 (1%). and mechanical properties of’cross biidges have been studied by thk tension r&ponses to quick‘length changes of 0.5 to 3% muscle length aoolied at maximal activation (pCa 4.5). Up to 5mM, BDM decreased contraction in a dose dep&dent manner without significantly changing’the transsarcoiemmai calcium current, suggesting that intracellular calcium transient is not modified. On skinned fibers. it decreased myotilament calcium sensitivity as well as maximal force and stiffness. Moreover, BDM (1OmM) increased the stiffness to force ratio and increased the cross bridge cycling rate. These effects include a reduction of the number of cycling cross bridges, and of the force generated per each cross bridge. It is concluded that on frog atria1 fibers, BDM acts mostly at the myofibrillar level. It is suggested that BDM interacts with the force producing step of the cross bridge cycle.
143
PHYSIOLOGICAL COMPUTER
DETERMINANTS SIMULATION STUDY.
OF
EARLY
VENTRICULAR
FILLING:
A
K Isaaz, V Baucheron, A Henrot, L Daval. Dept of Cardiology and Dept of Mathematics, Nancy, France. The purpose of this work was to study the physiological determinants of the early transmitrul flow wave (E wave) based on a mathematical modeling. According to the linear momentum e uation, the left atrial (LA)left ventricular (LV) pressure.(P) difference is written: LAP-LVP = A&/& f Bv9 + Cv (1) where v = mitral flow velocity; A, B and C = variables related to LA, LV and mitral orifice geometries; LAP = PoebLAV(t) (2) et LVP = [Po’e-fl+ Po”eaLVV(t)] (3) where a, b = stiffness constants of LV and LA, respectively; T = LV relaxation time constant; LAV, LVV= LA and LV volumes; PO’ = LV pressure at the onset of relaxation; PO, PO” = pressures at zero volume. Equations 1, 2 and 3 were implemented by fourth order Runge-Kutta integration usin,a a personal computer. Output variables were: LAP, LVP, E wave peak velocity (vmax), isovolumic relaxation time (IRT), E wave acceleration time (AT), E wave deceleration time (DT), E wave velocity time integral (VTI). Input variables were: mitral orifice area, LA and LV volume (pre-load), end-systolic LVP (after-load), a, b, T, LV elastance (contractility). Examole: +25% in a (altered LV compliance) resulted in: +9% in IRT, -40% in E wave vmax, -14% in AT, -19% in DT, -50% in VTI; to preserve mitral valve stroke volume (VT1 constant ), a compensatory increase in end-systolic LA volume (+37%) resulting in a + 125% increase in LAP (12 ->27 mmHg) was necessary;this compensatory change resulted in turn in: +55% E wave vmax, -32% in AT, -40% in DT, and -48% in IRT. Conclusion: This mathematical modeling allows to explore the role of physical and physiological determinants of the uansmiual flow velocity, and helps to interpret the Doppler indices of ventricular diastolic function.
144
LEFT VENTRICULAR CONGESTIVE HEART
FILLING FAILURE.
IS A DETERMINANT
Z. Chatti, F. Zannad, K. Isaaz, M. Ismail, I. F. Bruntz, E. Aliot - Cardiology
OF EXERCISE
dcpartement
CAPACITY
IN
HBpital Central - Nancy, France
Resting left vcnuicular (LV) systolic [unction is usually poorly correlated to excrcicecapacity in patients (pts) with ~ongestivc heart failurc (CHF). We studied the possible role of LV filling paramctcrs by measuring pressure half time (PHT), E/A ratio and isovolumctric relaxation time (IRT) using echo dopplcr mitral flow analysis (HP, 7702 OA), as well as s;mptom limited (C&UC and/or dyspnca) peak oxygen consumption (pVO2) and anaerobic threshold (AT graphical dctcrmination ; 30 w/3 min cyclocrgometcr, CPX mcd~cal graphics respiratory gas analysis). 31 pts aged 56 f9 years with CHF were studied ; NYHA grade II and III. radionuclidc LV cjcction Craction (El!) was 27 f 6 % and pVO2 = 15+ 6 ml / min / kg. All pts had a sinus rhythm ; 23 had ischcmic heart discasc and 8 had dilated cardiomyopathy. pVO2 (expressed ils Ihc nercentaze OC thcrorethical V02 max) and AT wcrc significantly rclatcd to PHT (r = 0.46 and 0.46 ; p < 0.01) Lo E/A ( r = i)$. and-- 0.35 ; p < 0.01) but not td IRT ncithcr LOKF. Pts will, pVO2 > 50 u/o( 69 ? 17 %) had a-significantlyklwcr E/A (1.36 + 0.69) than pts with pVO2 < 50% (34 k 7 % E/A = 2.35 ? 1.30 ; p < 0.02) despite a similar EF ( 27 f 4 % vs 28 17 % ; NS). 23 pts with secondary mitral rcgurgiiat~o~~ grade II and Ill jlcft atriai Uopplcr) had IowerpVOZ as compared to thi: remaining 8 pts with no regurgitation ( 12.5 + 3.1 vs 19.9 + 7.4 ml/min/kg ; p < 0.01). Step by step multivariate correlation analysis showed that the severity of mitral regurgitation was indcpcndcntly rclatcd to pVO2 (p < 0.01). In conclusion, WC suggest that alteration of LV filling paramctcrs and mitral regurgitation may contribute more than EF to exercise limitation in pts with CHF. S.52
INOTROPIC EFFECTS OF 2-3 BUTANEDIONE MONOXIME (BDM) IN INTACT AND SKINNED FROG CARDIAC FIBERS. J.M. Chesnais and R. Ventura-Clapier. URA-1121 CNRS and U-241 INSERM; Universitk Paris-Sud, 91405 Orsay France. The interest for BDM (a negative inotropic agent), has been increasing in the last years due to its potential protective effect in cardioplegic solutions, but its mechanisms of action remain unclear and controversial. Experiments have been performed on frog atria1 fibers, a tissue where mechanical activation is independent of internal calcium stores (reticulum sarcoplasmic). Simultaneous recordings of calcium currents and contractions of intact fibers have been obtained under voltage clamp using the double sucrose gap technique. To study the direct effects of BDM on mvofibrillar uroteins. atria1 fibers were chemicallv skinned bv Triton X-100 (1%). and mechanical properties of’cross biidges have been studied by thk tension r&ponses to quick‘length changes of 0.5 to 3% muscle length aoolied at maximal activation (pCa 4.5). Up to 5mM, BDM decreased contraction in a dose dep&dent manner without significantly changing’the transsarcoiemmai calcium current, suggesting that intracellular calcium transient is not modified. On skinned fibers. it decreased myotilament calcium sensitivity as well as maximal force and stiffness. Moreover, BDM (1OmM) increased the stiffness to force ratio and increased the cross bridge cycling rate. These effects include a reduction of the number of cycling cross bridges, and of the force generated per each cross bridge. It is concluded that on frog atria1 fibers, BDM acts mostly at the myofibrillar level. It is suggested that BDM interacts with the force producing step of the cross bridge cycle.
143
PHYSIOLOGICAL COMPUTER
DETERMINANTS SIMULATION STUDY.
OF
EARLY
VENTRICULAR
FILLING:
A
K Isaaz, V Baucheron, A Henrot, L Daval. Dept of Cardiology and Dept of Mathematics, Nancy, France. The purpose of this work was to study the physiological determinants of the early transmitrul flow wave (E wave) based on a mathematical modeling. According to the linear momentum e uation, the left atrial (LA)left ventricular (LV) pressure.(P) difference is written: LAP-LVP = A&/& f Bv9 + Cv (1) where v = mitral flow velocity; A, B and C = variables related to LA, LV and mitral orifice geometries; LAP = PoebLAV(t) (2) et LVP = [Po’e-fl+ Po”eaLVV(t)] (3) where a, b = stiffness constants of LV and LA, respectively; T = LV relaxation time constant; LAV, LVV= LA and LV volumes; PO’ = LV pressure at the onset of relaxation; PO, PO” = pressures at zero volume. Equations 1, 2 and 3 were implemented by fourth order Runge-Kutta integration usin,a a personal computer. Output variables were: LAP, LVP, E wave peak velocity (vmax), isovolumic relaxation time (IRT), E wave acceleration time (AT), E wave deceleration time (DT), E wave velocity time integral (VTI). Input variables were: mitral orifice area, LA and LV volume (pre-load), end-systolic LVP (after-load), a, b, T, LV elastance (contractility). Examole: +25% in a (altered LV compliance) resulted in: +9% in IRT, -40% in E wave vmax, -14% in AT, -19% in DT, -50% in VTI; to preserve mitral valve stroke volume (VT1 constant ), a compensatory increase in end-systolic LA volume (+37%) resulting in a + 125% increase in LAP (12 ->27 mmHg) was necessary;this compensatory change resulted in turn in: +55% E wave vmax, -32% in AT, -40% in DT, and -48% in IRT. Conclusion: This mathematical modeling allows to explore the role of physical and physiological determinants of the uansmiual flow velocity, and helps to interpret the Doppler indices of ventricular diastolic function.
144
LEFT VENTRICULAR CONGESTIVE HEART
FILLING FAILURE.
IS A DETERMINANT
Z. Chatti, F. Zannad, K. Isaaz, M. Ismail, I. F. Bruntz, E. Aliot - Cardiology
OF EXERCISE
dcpartement
CAPACITY
IN
HBpital Central - Nancy, France
Resting left vcnuicular (LV) systolic [unction is usually poorly correlated to excrcicecapacity in patients (pts) with ~ongestivc heart failurc (CHF). We studied the possible role of LV filling paramctcrs by measuring pressure half time (PHT), E/A ratio and isovolumctric relaxation time (IRT) using echo dopplcr mitral flow analysis (HP, 7702 OA), as well as s;mptom limited (C&UC and/or dyspnca) peak oxygen consumption (pVO2) and anaerobic threshold (AT graphical dctcrmination ; 30 w/3 min cyclocrgometcr, CPX mcd~cal graphics respiratory gas analysis). 31 pts aged 56 f9 years with CHF were studied ; NYHA grade II and III. radionuclidc LV cjcction Craction (El!) was 27 f 6 % and pVO2 = 15+ 6 ml / min / kg. All pts had a sinus rhythm ; 23 had ischcmic heart discasc and 8 had dilated cardiomyopathy. pVO2 (expressed ils Ihc nercentaze OC thcrorethical V02 max) and AT wcrc significantly rclatcd to PHT (r = 0.46 and 0.46 ; p < 0.01) Lo E/A ( r = i)$. and-- 0.35 ; p < 0.01) but not td IRT ncithcr LOKF. Pts will, pVO2 > 50 u/o( 69 ? 17 %) had a-significantlyklwcr E/A (1.36 + 0.69) than pts with pVO2 < 50% (34 k 7 % E/A = 2.35 ? 1.30 ; p < 0.02) despite a similar EF ( 27 f 4 % vs 28 17 % ; NS). 23 pts with secondary mitral rcgurgiiat~o~~ grade II and Ill jlcft atriai Uopplcr) had IowerpVOZ as compared to thi: remaining 8 pts with no regurgitation ( 12.5 + 3.1 vs 19.9 + 7.4 ml/min/kg ; p < 0.01). Step by step multivariate correlation analysis showed that the severity of mitral regurgitation was indcpcndcntly rclatcd to pVO2 (p < 0.01). In conclusion, WC suggest that alteration of LV filling paramctcrs and mitral regurgitation may contribute more than EF to exercise limitation in pts with CHF. S.52