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Acute in-vivo desensitization of myocardial beta-adrenoceptors in dogs
J Mol 109
110
Cell
Cardiol
23 (Supplement
IV)
(1991)
ACIDOSIS IN MYGCARDIAL ISCHBMIA : A TENTATIVE ASSESSMENT AS A PROGNOSTICAL INDEX. N. Lavanchy, A. Rossi, J. Martin’. Laboratoire de Physiologie Cellulaire Cardiaque, URA CNRS 632. Universitt? Joseph Fourier; “Centre d’Etudes NuclCaires, GRENOBLE, France. It has been known for a long time that ischemia induces an intracellular acidosis which depresses the contractility of the heart muscle, modifies the metabolic reactions and the ionic exchanges. These observations support the view that any situation which induces a reduction in the ischemic acidosis should result in less metabolic changes and, thereby, should insure a better resumption of the contractile function upon reperfusion. 31P-NMR spectroscopy and simultaneous function monitoring were used to study the validity of such an assertion on the isolated rat heart submitted to globai severe partial ischemia. When a decrease in the heart work was imposed previously to ischemia, a decrease in the ischemic acidosis was observed, associated with a good contractile resumption upon reperfusion. The data were very contradictory when ischemia was induced (without any previous reduction in the heart work) in the presence of various drugs : (1) antagonists and agonists of B-adrenergic receptors, (2) a calcium antagonist and (3) drugs acting through metabolic pathways : for an identical ischemic pH value (6.1 fur ihample), the functioning could bc reestablished in the repcrfuvn heart IV either a higher level than or an identical level as in controls. Thus, the sole value of the intracellular acidosis does not per se constitute a reliable index of the severity of the damages and considering the increase in the free Pi content of the heart or, even better, the ratio free Pi 10 ATP contents of the ischemic myocardium provided a dependable prognosis for the residual contractile capabilities of the heart muscle.
ACUTE
IN-VIVO
DESENSITIZATION
OF
MYOCARDIAL
BETA-ADRENOCEPTORS
IN DOGS.
P. Le Franc, N. Bouananl, A. Corsm, M. Laplace and 8. Crozatler, INSERM U2, CHL H. Mondor, 94010 C&tell. Acute desensltlzatlon of beta-adrenoceptors (BAR) has been shown In-vitro and 1n-v1vo with massive lsoproterenol (I) mjectlons but the effect of doses In the therapeutic range has not been tested. Our goal was to examine the effect of lnfuslons of I on physlologlcal response to the agonist and BAR density (Bmax) In open-chest dogs anesthetized with fluothane and Instrumented with a left ventricular (LV) micromanometer. Reflexes were blocked with hexamethonlum. Group I (N = 8) and group 2 (N = 10) received I (0.1 and 0.5 pg/kg/mln IV respectively during 30 rnln). In Group 1, changes In heart rate (H.R.) were n,): different during test Injections of I before (test 1) and after Infusion of I (test 2) but H.R. response was SI nlflcantly smaller in group 2 during test 2 (35 _f 5 beats/mln) compared f with test I (68 - 7 beats/mln, pi.001). In both groups$ dP/dt changes were not different 1n tests I and 2. Bmax measured using I-CYP was 66.0 - 8.1 fmol/mg in a control group (C) and 52.2 r 4.5 (NS) and 42.9 + 4.9 (p<.OOl) In groups I and 2 respectively. Low afflnlty bInclIng sites were not slgnlflcantly modified but the decrease of total BAR density was due to a loss of high affinity sites (C: 57.7 t 6.9 fmol/mg, group I: 38.1 2 2.0 (NS), group 2: 29.3 t 3.6 (pc.01 with C). Thus, dose-dependent loss of high afflnlty blndlng Sites for I was observed after 30 rnln lnfuslon of I. It was associated with a decreased H.R. response with the largest dose.
111 ATRIAL NATRIURETIC FACTOR DECREASES BOTH CALCIUM AND TRANSIENT OUTWARD CURRENTS IN ISOLATED HUMAN ATRIAL CELLS. B. Le Grand, E. Deroubaix, J.P. Couetil, E. Coraboeuf. Laboratoire de Physiologie Compatie (URA CNRS 1121), Universitb Paris XI, Orsay, France. The atrial natriuretic factor (ANF) is a peptide released from atrial cells in response to pressure-induced atrial distension. The existence of a relationship between right atrial pressure and circulating ANF level has been clearly demonstrated whereas the affect of ANF on ionic currents of human atrial cells is less well documented. Here we focused our interest on the effects of ANF on the high-threshold L-type calcium current, in (no low-threshold T-type calcium currents has been observed in our rsolatad human atrial c&) and on the calcium-Independent transient outward current, ilo, because these two antagonistic currents largely modulate the human atrial action potential plateau. We found that 10 nM ANF decreased both &t&Y;;;;and ilo (by = 35%). This effect was ndent on the intracellular GTP conce ing that a G protein is involved in the antagonized by the non-hydrolysabla G ANF action. By decreasing the decrease of i- might reduce ANF secretion (negative feed-back mechanism) whereas the concomitant decrease in ilo might reduce the action potential shortening resulting from iCa depression (protective effect against re-entry). s.37
110
Cell
Cardiol
23 (Supplement
IV)
(1991)
ACIDOSIS IN MYGCARDIAL ISCHBMIA : A TENTATIVE ASSESSMENT AS A PROGNOSTICAL INDEX. N. Lavanchy, A. Rossi, J. Martin’. Laboratoire de Physiologie Cellulaire Cardiaque, URA CNRS 632. Universitt? Joseph Fourier; “Centre d’Etudes NuclCaires, GRENOBLE, France. It has been known for a long time that ischemia induces an intracellular acidosis which depresses the contractility of the heart muscle, modifies the metabolic reactions and the ionic exchanges. These observations support the view that any situation which induces a reduction in the ischemic acidosis should result in less metabolic changes and, thereby, should insure a better resumption of the contractile function upon reperfusion. 31P-NMR spectroscopy and simultaneous function monitoring were used to study the validity of such an assertion on the isolated rat heart submitted to globai severe partial ischemia. When a decrease in the heart work was imposed previously to ischemia, a decrease in the ischemic acidosis was observed, associated with a good contractile resumption upon reperfusion. The data were very contradictory when ischemia was induced (without any previous reduction in the heart work) in the presence of various drugs : (1) antagonists and agonists of B-adrenergic receptors, (2) a calcium antagonist and (3) drugs acting through metabolic pathways : for an identical ischemic pH value (6.1 fur ihample), the functioning could bc reestablished in the repcrfuvn heart IV either a higher level than or an identical level as in controls. Thus, the sole value of the intracellular acidosis does not per se constitute a reliable index of the severity of the damages and considering the increase in the free Pi content of the heart or, even better, the ratio free Pi 10 ATP contents of the ischemic myocardium provided a dependable prognosis for the residual contractile capabilities of the heart muscle.
ACUTE
IN-VIVO
DESENSITIZATION
OF
MYOCARDIAL
BETA-ADRENOCEPTORS
IN DOGS.
P. Le Franc, N. Bouananl, A. Corsm, M. Laplace and 8. Crozatler, INSERM U2, CHL H. Mondor, 94010 C&tell. Acute desensltlzatlon of beta-adrenoceptors (BAR) has been shown In-vitro and 1n-v1vo with massive lsoproterenol (I) mjectlons but the effect of doses In the therapeutic range has not been tested. Our goal was to examine the effect of lnfuslons of I on physlologlcal response to the agonist and BAR density (Bmax) In open-chest dogs anesthetized with fluothane and Instrumented with a left ventricular (LV) micromanometer. Reflexes were blocked with hexamethonlum. Group I (N = 8) and group 2 (N = 10) received I (0.1 and 0.5 pg/kg/mln IV respectively during 30 rnln). In Group 1, changes In heart rate (H.R.) were n,): different during test Injections of I before (test 1) and after Infusion of I (test 2) but H.R. response was SI nlflcantly smaller in group 2 during test 2 (35 _f 5 beats/mln) compared f with test I (68 - 7 beats/mln, pi.001). In both groups$ dP/dt changes were not different 1n tests I and 2. Bmax measured using I-CYP was 66.0 - 8.1 fmol/mg in a control group (C) and 52.2 r 4.5 (NS) and 42.9 + 4.9 (p<.OOl) In groups I and 2 respectively. Low afflnlty bInclIng sites were not slgnlflcantly modified but the decrease of total BAR density was due to a loss of high affinity sites (C: 57.7 t 6.9 fmol/mg, group I: 38.1 2 2.0 (NS), group 2: 29.3 t 3.6 (pc.01 with C). Thus, dose-dependent loss of high afflnlty blndlng Sites for I was observed after 30 rnln lnfuslon of I. It was associated with a decreased H.R. response with the largest dose.
111 ATRIAL NATRIURETIC FACTOR DECREASES BOTH CALCIUM AND TRANSIENT OUTWARD CURRENTS IN ISOLATED HUMAN ATRIAL CELLS. B. Le Grand, E. Deroubaix, J.P. Couetil, E. Coraboeuf. Laboratoire de Physiologie Compatie (URA CNRS 1121), Universitb Paris XI, Orsay, France. The atrial natriuretic factor (ANF) is a peptide released from atrial cells in response to pressure-induced atrial distension. The existence of a relationship between right atrial pressure and circulating ANF level has been clearly demonstrated whereas the affect of ANF on ionic currents of human atrial cells is less well documented. Here we focused our interest on the effects of ANF on the high-threshold L-type calcium current, in (no low-threshold T-type calcium currents has been observed in our rsolatad human atrial c&) and on the calcium-Independent transient outward current, ilo, because these two antagonistic currents largely modulate the human atrial action potential plateau. We found that 10 nM ANF decreased both &t&Y;;;;and ilo (by = 35%). This effect was ndent on the intracellular GTP conce ing that a G protein is involved in the antagonized by the non-hydrolysabla G ANF action. By decreasing the decrease of i- might reduce ANF secretion (negative feed-back mechanism) whereas the concomitant decrease in ilo might reduce the action potential shortening resulting from iCa depression (protective effect against re-entry). s.37