Cardioprotection by ischemic preconditioning preserves mitochondrial function and functional coupling between adenine nucleotide translocase and creatine kinase.

M. N. Laclau, S. Boudina, J. B. Thambo, L. Tariosse, G. Gouverneur, S. Bonoron-Adèle, V. A. Saks, K. D. Garlid and P. Dos Santos. Cardioprotection by Ischemic Preconditioning Preserves Mitochondrial Function and Functional Coupling Between Adenine Nucleotide Translocase and Creatine Kinase. Journal of Molecular and Cellular Cardiology (2001) 33, 947-956. This study investigates the effect of ischemic preconditioning on mitochondrial function, including functional coupling between the adenine nucleotide translocase and mitochondrial creatine kinase, which is among the first reactions to be altered in ischemia. Three groups of Langendorff-perfused rat hearts were studied: a control group, a group subjected to 30 min ischemia followed by 15 min reperfusion, and a group subjected to ischemic preconditioning prior to 30 min ischemia and 15 min reperfusion. Ischemic preconditioning significantly delayed the onset and amplitude of contracture during ischemia, decreased enzymatic release, and improved the recovery of heart contractile function after reperfusion. Mitochondrial function was assessed in permeabilized skinned fibers. The protective effect of preconditioning was associated with preservation of mitochondrial function, as evidenced by maintenance of the high K(1/2)for ADP in regulation of mitochondrial respiration and V(max)of respiration, the near absence of respiratory stimulation by exogenous cytochrome c, and preservation of functional coupling between mitochondrial creatine kinase and adenine nucleotide translocase. These data suggest that ischemic preconditioning preserves the structure-function of the intermembrane space, perhaps by opening the mitochondrial ATP-sensitive K(+)channel. The consequence is preservation of energy transfer processes from mitochondria to ATP-utilizing sites in the cytosol. Both of these factors may contribute to cardioprotection and better functional recovery of preconditioned hearts.

Reduced basal NO-mediated dilation and decreased endothelial NO-synthase expression in coronary vessels of spontaneously hypertensive rats.

Basal vasomotor tone in coronary vessels is, in part, maintained by nitric oxide (NO) production by endothelial constitutive NO synthase (ecNOS). Alteration of coronary circulation observed in left ventricular hypertrophy secondary to hypertension could be associated with a decrease in NO production. The aim of this study was to measure: (1) coronary flow in the Langendorff-perfused heart model at baseline, after maximum vasodilation in response to adenosine (10(-5) M), after endothelium-dependent vasodilation in response to bradykinin (10(-8) M) and after ecNOS inhibition by nitro-L-arginine methyl ester (L-NAME) (10(-4) M); (2) medial thickening of coronary microvessels and perivascular collagen on histological heart sections; and (3) ecNOS expression by immunohistochemical staining in these vessels using 20-week-old spontaneously hypertensive (SHR) and Wistar-Kyoto control rats (WKY). These measurements were determined by computer-directed color analysis. When SHR were compared with WKY rats, we found: (1) a decrease in basal flow (10.1+/-0.6 v 15.3+/-1.2 ml/min/g, n=10, P<0.0001), in maximum flow (15.4+/-0.7 v 24.3+/-1.3 ml/min/g, n=10, P<0.001), in bradykinin-induced flow increment (1.5+/-0.3 v 2.6+/-0.3 ml/min/g, n=5, P<0.05) and in L-NAME-sensitive flow (3.3+/-0.6 v 6.3+/-0.9 ml/min/g, n=7, P<0.05); (2) an increase in medial thickness (9.4+/-0.6 v 5.4+/-0.3 microm, n=8, P<0.001) and in perivascular collagen area (1509+/-311 v 462+/-120 microm2, n=8, P<0.01) of coronary arterioles; and (3) a decrease in ecNOS expression in the endothelium (ecNOS-stained cross-sectional area in arterioles: 40.0+/-9.1 v 84.6+/-9.0 microm2, n=7, P

Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention.

1. In order to develop a predictive model for the preclinical evaluation of anthracycline cardiotoxicity and the means of preventing it, we have studied the functional parameters of perfused hearts isolated from rats receiving repeated doses of several anthracyclines. 2. The anthracyclines studied were doxorubicin, epirubicin, pirarubicin and daunorubicin, and we also studied a liposomal formulation of daunorubicin (DaunoXome) and the co-administration of dexrazoxane (ICRF-187) and doxorubicin. 3. Anthracyclines were administered i.p. at equimolar doses corresponding to 3 mg kg-1 per injection of doxorubicin, every other day for a total of six doses. Dexrazoxane was used at the dose of 30 mg kg-1 per injection and was administered either 30 min before or 30 min after doxorubicin. We evaluated any general toxicity towards the animals as well as alterations of left ventricular contractility and relaxation ex vivo. 4. Epirubicin and daunorubicin were significantly less cardiotoxic than doxorubicin, and neither pirarubicin nor DaunoXome caused significant alterations in cardiac function. There was a direct relationship between the decrease in cardiac contractility or relaxation and anthracycline accumulation in the heart, evaluated after the same treatment schedule. 5. Dexrazoxane induced a significant protection against doxorubicin-induced cardiac toxicity when administered 30 min before doxorubicin, whereas this protection was ineffective when administered 30 min after doxorubicin. Direct perfusion of DaunoXome in isolated hearts of untreated animals resulted in a 12-fold reduction of the accumulation of daunorubicin in heart tissue as compared to the perfusion of free daunorubicin, and did not cause alterations in cardiac function at a dosage for which free daunorubicin induced major alterations. 6. The isolated perfused rat heart appears to be a valuable model for screening of new anthracyclines and of strategies for circumventing anthracycline cardiotoxicity.

Evaluation of anthracycline cardiotoxicity with the model of isolated, perfused rat heart: comparison of new analogues versus doxorubicin.

We have compared the cardiotoxicity of 3 anthracyclines in a model of isolated perfused rat heart using the Langendorff technique. The contractile state and ventricular compliance were studied. Doxorubicin, epirubicin and pirarubicin were perfused at concentrations of 10(-6) and 10(-5) M during 70 min. The cardiac accumulation of the drugs was studied by HPLC. No significant alteration of cardiac functional parameters was observed at 10(-6) M. At 10(-5) M, epirubicin produced a significantly greater alteration of cardiac contractility than doxorubicin, whereas pirarubicin exerted first an inotropic effect followed by a recovery to initial values at the 60th min. Anthracycline accumulation in the heart was dose-dependent; epirubicin accumulated to a 30% greater extent than doxorubicin and pirarubicin heart concentrations were 4-5 times higher than those of doxorubicin at the end of the perfusion. These results suggest that doxorubicin and epirubicin have the same intrinsic cardiac toxicity, and that their distinct clinical cardiotoxicity must be explained by pharmacokinetic differences, whereas pirarubicin is much less cardiotoxic than the other anthracyclines because of different pharmacodynamic properties.

Effect of angiotensin II on calcium release phenomena in normal and hypertrophied single cardiac myocytes.

The effects of angiotensin II (Ang II) (10(-9) M to 10(-7) M) on calcium releases were established in ventricular myocytes from normal and renal hypertensive adult rats. From each peak systolic indo-1 ratio (405 nm/480 nm), amplitude variation, duration (rise time and fall time), and frequency of spontaneous calcium releases were investigated on freshly isolated cardiomyocytes at rest or under electrical stimulation. The following changes were observed: (1) in spontaneous contracting myocytes, an increase in frequency of calcium transients at 10(-7) M in normal cells (+157%, P < 0.05) and at whatever angiotensin II concentration in hypertrophied cells (10(-9) M: +79% P < 0.05; 10(-8) M +82%, P < 0.01; 10(-7) M: +285%, P < 0.01) with a greater sensitivity of hypertrophied cells to Ang II (P < 0.05 at 10(-9) M, P < 0.01 at 10(-8) M). (2) In stimulated myocytes, a prolongation of the duration of calcium transients at 10(-7) M in normal cells (+68%, P < 0.01) and at 10(-9) M, 10(-8) M, 10(-7) M in hypertrophied cells: (+36%, P < 0.05; +39%, P < 0.01; +77%, P < 0.01) with a greater sensitivity of hypertrophied myocytes (P < 0.05 at 10(-9) M and 10(-8) M). An increase in duration may be explained by the occurrence of calcium releases during the fall time of calcium transients. Thus, both in normal and hypertrophied myocytes, Ang II induced the occurrence of calcium releases with increased sensitivity of hypertrophied cells to Ang II. Such calcium releases are known to be a possible cause of arrhythmias termed "triggered activity".

[Effects of angiotensin II on spontaneous cytosolic calcium releases in ventricular myocytes of adult normal and hypertensive rats]. / Effets de l'angiotensine II sur les libérations spontanées calciques cytosoliques dans les myocytes ventriculaires isolés de rats adultes normaux et hypertendus.

This study investigated the effects of angiotensin II (Ang II) (10(-9)M to 10(-7)M) on calcium releases in ventricular myocytes from normal and renal hypertensive adult rats (Goldblatt 2K-1C). Newly, isolated myocytes were loaded with fluorescent indo-1/AM and studied at rest or under electrical stimulation. The variation of the ratio of indo-1 emission (405 nm/480 nm) was taken as a measure of cytosolic calcium variations. Five parameters were investigated from each peak systolic indo-1 ratio before and after Ang II addition: amplitude variation, duration with analysis of a rise time and a fall time, and frequency of spontaneous calcium releases. Following changes were observed: in unstimulated myocytes exhibiting spontaneous contractile activity, increase in frequency of calcium transients, at 10(-7)M, in normal cells (+ 157 +/- 27%; p < 0.01) and whatever Ang II concentration in hypertrophied cells (+ 79 +/- 31%; p < 0.01; + 82 +/- 25%, p < 0.01; + 285 +/- 50%, p < 0.01 à 10(-9)M, 10(-8)M, 10(-7)M); in stimulated myocytes, prolongation of the duration of calcium transients explained by the occurrence of calcium releases during fall time. In addition, 50% of myocytes exhibited spontaneous releases of calcium in the interstimulus interval. Increase in calcium transients duration was statistically significant, whatever Ang II concentration in hypertrophied cells (+ 36 +/- 20%, p < 0.05; + 39 +/- 18%, p < 0.01; + 77 +/- 34%, p < 0.01 à 10(-9)M, 10(-8)M, 10(-7)M) and only at 10(-7)M in normal cells (+ 68 +/- 22% p < 0.01). Similar results were observed in fall time.(ABSTRACT TRUNCATED AT 250 WORDS)

[Metabolic aspects of hemodynamic behavior in left ventricular hypertrophy by 13C NMR]. / Aspects métaboliques par RMN du carbone 13 du comportement hémodynamique des hypertrophies ventriculares gauches.

During myocardial hypertrophy, histological modifications induce a partial ischemic state and hemodynamic perturbations are responsible for an increased myocardial oxygen demand. The purpose of this study is to better characterize the alterations of intermediary metabolism linked to hemodynamic perturbations by carbon 13 NMR using enriched substrates. Left ventricular hypertrophy was consecutive to a renal hypertension (Goldblatt 2K-1C, 9 weeks). Myocardial compliance and contractility (left ventricular end diastolic pressure (LVEDP), +dP/dt max, +dP/dt max normalized to developed pressure (+dP/dt max/DEVP)) were estimated on Langendorff isolated perfused hearts at a constant perfusion pressure (normo and hypertensive rats (RHR)). Using (2-13C) acetate enriched (10 nm) substrate, 13C NMR spectra were obtained from tissue perchloric extracts. Mathematical model proposed by Malloy was used to analyze these 13C NMR spectra terms of metabolic fluxes: Fc2 = The fraction of (2-13C) acetyl-CoA entering the tricarboxylic acid cycle; y = The ratio between the activity of anaplerotic reactions to that of citrate synthetase. The results showed after hypoxia: an increase of LVEDP more pronounced in RHR (RHR: 48 +/- 15 mmHg VS SHAM: 22 +/- 6 mmHg, p < 0.01); a significant impairment of coronary blood flow more important in RHR; a significant increase of the ratio y in hypertrophied hearts (RHR: 0.062 +/- 0.09 VS SHAM: 0.15 +/- 0.02, p < 0.05). In conclusion, this study allowed a new approach to correlate diastolic dysfunction with metabolic data consecutive to an increased sensitiveness hypertrophy to hypoxic damages.

Nicardipine and cardiac hypertrophy: effects on left ventricular mass. Haemodynamics and mechanical performance in renovascular hypertensive rats.

SUBJECT OBJECTIVE: The aim was to determine the effects of nicardipine treatment (10-15 mg.kg-1.d-1 intraperitoneal) on left ventricular hypertrophy, coronary haemodynamics, and mechanical performance in renovascular hypertensive rats. DESIGN: Systemic and coronary haemodynamic variables were evaluated by using microspheres in conscious rats, while mechanical performance and elasticity were measured on isolated papillary muscles from the same animals. EXPERIMENTAL ANIMALS: Male Sprague-Dawley rats, weight 150-180 g, were used. Nine treated rats were compared with control groups, consisting of 9 sham operated, 12 untreated hypertensive, and 9 nephrectomised rats. MEASUREMENTS AND MAIN RESULTS: Eight weeks after clipping, removal of the ischaemic kidney allowed the normalisation of ventricular mass and the reversal of changes induced by hypertrophy except prolongation of timing parameters. Nicardipine administration led to an efficient but incomplete control of blood pressure, which fell from 208(SEM 5) mm Hg in untreated hypertensive rats to 155(4) mm Hg in treated rats, p less than 0.01. After eight weeks of treatment, the reduction in left ventricular mass, from 3.10(0.10) mg.g-1 in untreated rats to 2.72(0.018) mg.g-1 in treated rats was significant (p less than 0.01) but was less than the pressure decrease. In treated hypertensive rats, coronary blood flow was increased and redistributed at rest in favour of the subepicardial layers but was significantly reduced after maximum vasodilatation, to 1.618(0.077) litre.min-1.100 g, in nicardipine treated rats. A reversal of impaired myocardial mechanical indices towards control values was observed except for time to peak force and time to half relaxation. CONCLUSIONS: Nicardipine treatment allowed blood pressure control, reduction of left ventricular mass, and improvement in mechanical performance, but was unable to restore minimal coronary vascular resistance. The results suggest that, although blood pressure decrease is obviously important, it may not be the sole factor in the reversal of cardiac hypertrophy.

Effects of perindopril on left ventricular hypertrophy, coronary blood flow, and mechanical properties of cardiac muscle in renovascular hypertensive rats.

We studied the effects of perindopril on left ventricular hypertrophy, systemic and coronary hemodynamics, and mechanical cardiac performance in renovascular hypertensive rats (Goldblatt, two-kidneys, one-clip). Systemic and coronary hemodynamics, before and after carbochrome infusion, were assessed by radioactive microspheres injection via an atrial catheter in conscious rats. Mechanical performance was measured on isolated papillary muscle from the same animal. Twelve treated hypertensive rats were compared with 10 nontreated hypertensive rats and nine sham-operated normotensive rats of the same age. Perindopril treatment induced a complete control of blood pressure (mean blood pressure from 156 +/- 22 mm Hg in the untreated group to 100 +/- 24 mm Hg in the treated group (P less than .01), compared to 106 +/- 18 mm Hg in the sham group). This was associated with a nearly complete regression of left ventricular hypertrophy (left ventricular mass/body weight 2.26 +/- 0.38 mg/g in the treated group v 3.1 +/- 0.6 in the untreated group [P less than .01], compared to 2 +/- 0.25 mg/g in the sham group [p = NS]). Minimal left ventricular coronary resistances after carbochrome were slightly higher in the hypertensive group compared both to sham and treated group. A reversal of impaired myocardial mechanical parameters towards control values was observed, except for some parameters of relaxation. We conclude that perindopril allows in this model a complete control of blood pressure, and a regression of left ventricular hypertrophy with normalization of coronary hemodynamics and contractile function.

[Effects of ventricular hypertrophy following experimental renovascular hypertension on the elasticity of the papillary muscle]. / Incidence d'une hypertrophie ventriculaire consécutive à une hypertension rénovasculaire expérimentale sur l'élasticité du muscle papillaire.

A precise method was developed for detecting muscular stiffness changes in the left ventricular hypertrophy by chronic pressure overload in rats (2 kidney-1 clip renal hypertensive rats). The technique of Quick-Release allowed the measurement of the "stress-strain" relation (delta-epsilon), the elastic stiffness (d delta/d epsilon) and the stiffness constant (K) in isolated papillary muscle from normal and hypertrophied hearts at rest and at the maximal time course of activation during isometric contraction. (Table: see text). The results of this study reported that the cardiac hypertrophy induced by experimental pressure overload was not associated with significant alteration of myocardial stiffness. So, it would seem that a muscular stiffness modification was unresponsible for the ventricular compliance change of clinical and experimental results.

[Effects of nicardipine on left ventricular hypertrophy of the rat with renovascular arterial hypertension]. / Effets de la nicardipine sur l'hypertrophie ventriculaire gauche du rat porteur d'une hypertension artérielle rénovasculaire.

This study investigate the effects of Nicardipine treatment on regression of left ventricular hypertrophy (LVH), coronary hemodynamic and myocardial mechanical performance. 30 Sprague-Dawley male rats were divided into 3 groups: sham operated rats control group (SHC), untreated hypertensive rats group (RHR-U), treated hypertensive rats group (RHR-N). Systemic and coronary hemodynamics were determined by using left atrial injection of radioactive microspheres, 16 weeks after clipping. Mechanical performance was measured on isolated papillary muscle from the same animal. Results (mean +/- SEM) (Table: see text). Nicardipine treatment (10 to 15 mg intraperitoneal dosage during 8 weeks), led to: an efficient but incomplete control of hypertension. a reduction of left ventricular mass in proportion lesser than pressure decrease. a raise of coronary blood flow at rest with inversion of flow distribution between endocardium an epicardium. a decrease of "maximal" coronary blood flow. a reversal of impaired myocardial mechanical parameters towards control values except for contraction timing parameters. Decrease of "maximal" coronary blood flow could have deleterious effects on cardiac function.

Diltiazem and left ventricular hypertrophy in renovascular hypertensive rats.

The effects of diltiazem treatment (40-50 mg/kg/day orally for 8 weeks) of left ventricular hypertrophy on systemic and coronary hemodynamics and mechanical cardiac performance were investigated in renovascular hypertensive rats (Goldblatt, two-kidney, one clip). Systemic and coronary hemodynamics were determined by using radioactive microspheres in conscious, unrestrained rats. Mechanical performance was measured on isolated papillary muscle from the same animal. Nine treated hypertensive rats were compared with control groups: 12 untreated hypertensive and nine sham-operated rats. Diltiazem treatment led to an effective but incomplete control of blood pressure (from 208 +/- 5 mm Hg in the untreated hypertensive group to 155 +/- 3 mm Hg in the treated hypertensive group; p less than 0.01) associated with a significant but incomplete decrease of the left ventricular mass (from 3.10 +/- 0.19 mg/g in untreated hypertensive rats to 2.35 +/- 0.04 mg/g in treated hypertensive rats; p less than 0.01). A close correlation was found between left ventricular mass and systolic blood pressure in untreated, treated, and pooled groups (r = 0.84, p less than 0.001, n = 30). The left ventricular weight to systolic blood pressure ratio was equivalent in all three groups, so that the reduction of left ventricular mass in diltiazem-treated rats was commensurate with the reduction of blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effects of perindopril on left ventricular hypertrophy, coronary reserve and mechanical properties of the papillary muscle of the rat with renovascular arterial hypertension]. / Effets du périndopril sur l'hypertrophic ventriculaire gauche, la réserve coronaire et les propriétés mécaniques du muscle papillaire du rat avec hypertension artérielle rénovasculaire.

We investigate the effect of a new angiotensin-converting enzyme inhibitor: Perindopril (IRIS) on regression of left ventricular hypertrophy (LVH), coronary blood flow and mechanical performance of isolated papillary muscle in renovascular hypertensive (Goldblatt 2 kidneys-1 clip) Sprague-Dawley male rats. Sham operated rats (G1) and half of hypertensive rats (G2) were studied after 8 weeks. The other half of 8 weeks long hypertensive rats (G3) were treated during 8 weeks with Perindopril in drinking water at a dosage adjusted to maintain blood pressure (BP) measured with tail cuff method under 140 mmHg. The study of each rat included 1) coronary blood flow and resistance measurements under resting conditions and after coronary dilation by carbochrome infusion (9 mg/kg) using left atrial injection of radioactive microspheres (method of Wicker and Tarazi) 2) the study of mechanical performance of the isolated papillary muscle 3) weight of left ventricle after separation of septum and free wall whose subendocardial and subepicardial layers were counted separately. Results (mean +/- SD): (table; see text) MAP: mean pressure. LV/BW: left ventricular mass (mg) per gram of body weight; CR (C): minimal coronary resistance after carbochrome (mmHg/ml/min/100 mg); DL/Dt: peak velocity of shortening at L max preload; Vrelax: peak velocity of relaxation; THR: time of half relaxation; p less than 0.05; p less than 0.01 compared to SHAM. In this model, hypertension induced a 50 p. 100 LVH whose regression was nearly complete after 8 weeks of treatment with Perindopril. Minimal coronary resistance after carbochrome were higher in hypertensive rats compared to sham and return to normal after regression of LVH.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulmazole effects on mechanical performance of hypoxic and reoxygenated isolated mammalian myocardium.

The present study intended to investigate the effects of 2-[2-methoxy-4-(methylsulfinyl)phenyl]-3H-imidazo[4,5-b]pyridine (sulmazole, AR-L 115 BS) on mechanical performance of rat myocardial fibers under hypoxia, and subsequent reoxygenation. Because of a possible caffeine-like mechanism of action of sulmazole similar experiments were performed with theophylline and the results compared. 1. Under normoxic conditions, sulmazole and theophylline displayed a positive inotropic action with acceleration of relaxation at small concentrations (sulmazole: 6.4 mumol l-1; theophylline 7.35 mumol l-1). Increasing doses led to a negative inotropic effect with slackened relaxation and loss of its load sensitivity (up to 390 mumol l-1 for sulmazole; up to 350 mumol-1 for theophylline). In agreement with other reports, the dose-effect curve was shifted towards low concentrations. 2. During ischemic crisis, therapeutic doses of sulmazole (6 mumol l-1) and theophylline (7 mumol l-1) induced no additional depression of contractility and protected relaxation. During subsequent reoxygenation, better recovery of contractility was observed without any very significant improvement of relaxation. 3. During reoxygenation beyond 120 mumol l-1, increasing doses of sulmazole depressed contractility. An additional depressive effect on mechanical performance was observed during hypoxia only for the highest dose (390 mumol-1).

Effects of contrast media used in angiocardiography on the mechanical performance and the relaxation of normal and ischaemic myocardium.

The aim of this study was to investigate the mechanisms of the cardiodepressive action of ionic and non-ionic contrast media currently used in coronary arteriography. Experiments carried out on isolated preparations of cat papillary muscle, treated with increasing concentrations of Telebrix 39, Radioselectan, Hexabrix and Iopamidol 370 and 300, on the one hand and, on the other hand, a pre-determined dose of Telebrix and Iopamidol 300 during hypoxia and subsequent reoxygenation, showed that, at constant Ca2+ concentrations: (1) The cardiodepressive effects of contrast media are correlated with the hyperosmolality that they induce. When osmolality was higher than 400 mOsm, all the products caused a reduction of the peak force (PF: 40.49 +/- 5.15%), the maximum velocity of contraction (Vmax: 39.85 +/- 3.66%) and of the peak velocity of relaxation (Vrelax: 23.30 +/- 2.20%) (P less than 0.01). The time to peak force (TPF), on the other hand, remained constant, whereas the half-relaxation time (THR) was increased. No significant differences were observed between these effects and those induced by control iso-osmolar solutions when the same osmolality was induced. In practice, however, the critical hyperosmolality value of 400 mOsm is never reached when using non-ionic contrast media such as Hexabrix and Iopamidol 300. This could explain the excellent tolerance to these substances. (2) During hypoxia and reoxygenation, the effect of hyperosmolality is more marked. Thus, the non-ionic contrast medium, Iopamidol 300 (340 mOsm), reduces the hypoxic contractility depression (PF: 53.10 +/- 2.60% compared to the control values of 47.60 +/- 5.00%, P less than 0.01), whereas, at the same dose, the ionic medium Telebrix is hyperosmolar (440 mOsm) and induces a more pronounced hypoxic depression of contractility (P less than 0.01). The critical hyperosmolality is never reached during ventriculography (320 mOsm), whatever the medium used, but it can be observed during coronary arteriography. It is, therefore, important to use non-ionic contrast media in the investigation of unstable angina and of acute myocardium infarction.

[Effect of nitrate derivatives on the contractility and relaxation of papillary muscle in hypoxia and reoxygenation]. / Effets des dérivés nitrés sur la contractilité et la relaxation du muscle papillaire en hypoxie et en réoxygénation.

The direct action of nitrate derivatives on myocardial contractility is not fully understood. The effects of Glyceryl Trinitrate (1 mM/L.) and Sodium Nitro prussiate (3 X 10(-5) M/L.) on papillary muscle were studied during 30 minutes hypoxia followed by 60 minutes reoxygenation: Both conditions were analysed every 5 minutes: 1. Contractility was assessed by maximal shortening velocity with no load (Vmax), maximal isometric force (PF), number of active cross-bridges and peak time (TPF), a characteristic of the period of activity. 2. Relaxation was assessed by the relaxation velocity (V relax) and the 1/2 relaxation time (THR). The two nitrate derivatives had the same effects: during anoxia, a notable reduction of the maximal force was observed; myocardial depression continued during the first 15 minutes of reoxygenation. After the 30th minute of investigation all parameters increased significantly (107-110 p. 100, p less than 0,01); TPF and THR returned to normal. A positive inotropic effect and improvement of the relaxation phase were observed at the end of reoxygenation. This effect is not attributed to improved segmental performance especially as it occurred at dosages close to those used in therapeutics.