Caldaret, an intracellular Ca2+ handling modulator, limits infarct size of reperfused canine heart

The cardioprotective effect of caldaret, a novel intracellular Ca(2+) handling modulator that acts through reverse-mode Na(+)/Ca(2+) exchanger inhibition and potential sarcoplasmic reticulum (SR) Ca(2+) uptake enhancement, against reperfusion injury was investigated. We employed a canine model of myocardial infarction induced by 90-min occlusion of left circumflex (LCX) coronary artery followed by 4 h of reperfusion. Intravenously infused caldaret (3 or 30 microg/kg per hour) for 30 min at LCX-reperfusion markedly reduced infarct size (by 51.3% or 71.9%, respectively). This cardioprotection was accompanied by an acceleration of left ventricular (LV) contraction and relaxation during reperfusion, but not by an increase in ischemic regional transmural myocardial blood flow (TMBF) or endocardial/epicardial blood flow ratio (Endo/Epi ratio) or a reduction in double-product throughout the protocol. Diltiazem (2000 microg/kg per hour) also reduced infarct size (by 36.1%), but unlike caldaret, was accompanied by the significant increase in Endo/Epi ratio in the ischemic region and decrease in double-product. There were significant inverse relationships between infarct size and ischemic regional TMBF in all groups. Caldaret, but not diltiazem shifted the regression line downward with a flatter slope. These results suggest that the amelioration of intracellular Ca(2+) handling dysfunction achieved by caldaret leads to cardioprotective effects against reperfusion injury following prolonged ischemia.     

Effect of diltiazem on coronary blood flow distribution in dog heart under ischemia

Effect of intracoronary infusion of diltiazem (1 microgram/min) on regional myocardial blood flow (RMBF) was studied using 15-microns radioactive microspheres in 11 excised cross-circulated canine left ventricles. With total coronary blood flow (CBF) and heart rate (HR) held constant, regional ischemia was induced by ligating the left anterior descending coronary artery (LAD). Diltiazem at the dose used had no effects on ventricular Emax before and after LAD ligation. RMBF expressed by the counts divided by the counts averaged in all segments in each layer significantly (p less than 0.05) increased under diltiazem only in the low-flow region that had less than 50% RMBF before diltiazem; from 21% (+/- 12%) to 35% (+/- 18%) in the epicardial, from 22% (+/- 12%) to 32% (+/- 18%) in the midwall, and from 24% (+/- 10%) to 31% (+/- 12%) in the endocardial layers. We conclude that the beneficial effect of diltiazem on the ischemic heart involves a direct action on the coronary vascular system and does not necessarily depend on the concomitant changes in hemodynamics.     

The effect of diltiazem on ST-segment elevation and myocardial blood flow distribution during pacing-induced ischemia

The purpose of this study was to determine if diltiazem can reduce the severity of pacing-induced ischemia independently of increases in overall and microregional ischemic blood flow. Sixteen anesthetized dogs were subjected to atrial pacing and had their left anterior descending coronary arteries (LAD) occluded until significant ST-elevation occurred. Cessation of pacing resulted in abolition of ST-segment elevation. ST-elevation as well as hemodynamics were measured during 5 min periods of pacing + LAD stenosis before, and 10, 40 and 70 min after treatment with intracoronary (i.c., just distal to the stenosis) diltiazem (1.8 micrograms/kg), i.v. diltiazem (180 micrograms/kg) or saline. Myocardial blood flow was measured using radioactive microspheres under baseline conditions, pacing, pacing + stenosis, and pacing + stenosis + drug (70 min post-drug). Both i.c. and i.v. diltiazem significantly and similarly reduced pacing-induced ST-elevation at 40 and 70 min post-drug with the highest measured reductions occurring for both at 70 min (50-60% reduction). Overall ischemic regional myocardial blood flow was unaffected by i.c. and i.v. diltiazem. Diltiazem given i.v. resulted in reduced flow in the lightly ischemic region and increased flows in the subepicardial half of the severely ischemic region. Diltiazem given i.c. resulted in a reduced subepicardial flow in the lightly ischemic region with no other changes occurring in the other regions. Thus, both i.c. and i.v. diltiazem can reduce the severity of pacing-induced ischemia and, in the doses given, in an equivalent fashion. Diltiazem also seems to be able to reduce severity of ischemia in a manner independent of increases in ischemic region flow and in fact can reduce flow in marginally ischemic tissue.     

Beneficial effect of nipradilol (K-351) on acute myocardial ischemia. Study of the relationship between regional myocardial blood flow and energy metabolism

To examine the effects of nipradilol on ischemic myocardium, experiments were performed on regional myocardial blood flow (MBF) and energy metabolism in anesthetized, open-chest dogs. Nipradilol at a dose of 0.3 mg/kg was i.v.-administered 10 min after coronary ligation. MBFs at various sites, including ischemic and non-ischemic areas, were determined by the hydrogen gas clearance method. The levels of ATP and creatine phosphate (CP) at the site of MBF determination were measured 60 min after ligation, and mitochondrial function (RCI, QO2) in the ischemic and non-ischemic areas was determined. Following nipradilol administration, aortic pressure and heart rate were significantly lowered. In ischemic areas with MBF below 40 ml/min/100 g, nipradilol had no influence on MBF. However, the tissue level of ATP in nipradilol treated hearts was significantly higher as compared with untreated hearts. In the area of mild ischemia with MBF of 40-60 ml/min/100 g, nipradilol preserved the tissue ATP and CP levels in spite of a decrease in MBF. Moreover, an inhibition of the decrease in mitochondrial respiratory function was observed in ischemic areas with MBF below 20 ml/min/100 g. Thus, nipradilol administered following ischemia preserved ATP content and mitochondrial function in the ischemic myocardium with reduction of heart rate and aortic pressure. This suggests that nipradilol exerts a cardioprotective effect in acute ischemia. It seems that the cardioprotective effect is due to a decrease in myocardial oxygen demand and preservation of mitochondrial function.     

Treatment with l-cis diltiazem before reperfusion reduces infarct size in the ischemic rabbit heart in vivo.

l-cis Diltiazem, an optical isomer of diltiazem, protects against myocardial dysfunction in vitro, whereas its Ca2+ channel blocking activity is about 100 times less potent than that of diltiazem. However, there is no evidence that l-cis diltiazem actually protects against ischemia/reperfusion injury in vivo. To assess this, we employed an anesthetized rabbit model, where the left circumflex artery was occluded for 15 min and reperfused for 360 min. Treatment with diltiazem before and during ischemia (bolus 200 microg/kg and 15 microg/kg per minute for 25 min, i.v.; 575 microg/kg total) showed slightly depressed hemodynamic parameters, while l-cis diltiazem (1150 microg/kg) had no effect. Treatment with l-cis diltiazem produced a high recovery of the thickening fraction and limited the infarct size in a dose-dependent manner. Furthermore, the treatment with l-cis diltiazem (1150 microg/kg) or diltiazem (575 microg/kg) 5 min before reperfusion also limited the infarct size, but not after reperfusion. These results suggest that l-cis diltiazem affects some events in the onset of reperfusion, independently of Ca2+-channel-blocking action. Our observations are the first to show that l-cis diltiazem demonstrated its cardioprotective action in the ischemic rabbit heart in vivo.     

Measurement of oxygen tension in the ischemic myocardium using encased polargraphic oxygen electrodes

The ability to continuously monitor the delicate balance between blood flow and oxygen consumption would be a great asset in the study of myocardial ischemia. The present study was performed, in anesthetized dogs, to validate the use of encased polargraphic oxygen electrodes in the study of myocardial ischemia. Polargraphic oxygen electrodes were placed in the area to be rendered ischemic at fixed tissue depths of 3 mm (epicardium) and 9 mm (endocardium). Endocardial and epicardial oxygen tensions as well as the ratio of endocardial to epicardial oxygen tension and left circumflex coronary flow were monitored. Ischemia was induced by decreasing left circumflex coronary flow by 50%. Upon completion of a 20-min poststenotic period, endocardial pO₂, endocardial/epicardial ratio, and coronary flow were significantly decreased (59 ± 7, 52 ± 7, and 55 ± 4%, respectively) whereas epicardial pO₂ was slightly decreased. Nitroglycerin (10 μg/kg, i.v.) markedly increased endocardial pO₂ and endocardial/epicardial ratio above poststenotic control (13 ± 5 mmHg and 64 ± 10%, respectively) whereas epicardial pO₂ was not significantly decreased. The increases in endocardial pO₂ occurred at a point where coronary flow and mean arterial pressure were not significantly changed. Conversely, dipyridamole (125 μg/kg, i.v.) significantly increased coronary flow (26 ± 2 ml/min/100 g) although it did not appreciably alter endocardial or epicardial pO₂. It is concluded that encased polargraphic oxygen electrodes provide a quantitative method for determination of oxygen tension in the ischemic myocardium.     

Effect of intracoronary diltiazem on ST-segment elevation and myocardial blood flow during pacing-induced ischemia

This study was performed to determine if diltiazem can reduce the severity of pacing-induced ischemia independently of its peripheral hemodynamic effects and of increases in ischemic region blood flow. Twelve anesthetized dogs were subjected to atrial pacing and had their left anterior descending coronary arteries (LAD) occluded gradually until ischemia ensued (greater than 10 mV epicardial ST-segment elevation). Cessation of pacing resulted in abolition of ST-segment elevation. ST-segment elevation, as well as peripheral and coronary hemodynamics, was measured during 5-min periods of pacing + LAD stenosis before and 0, 30, and 60 min after treatment with intracoronary (just distal to the stenosis) saline or 1.8 micrograms/kg diltiazem. Myocardial blood flow was measured using radioactive microspheres during pacing, pacing + stenosis, and pacing + stenosis + drug treatment at 60 min. Diltiazem significantly reduced ST-segment elevation approximately 50% at 0, 30, and 60 min compared with elevations seen in animals treated with saline as well as predrug values. No changes in blood pressure, heart rate, or LAD flow occurred with diltiazem. Overall ischemic tissue flow and its transmural distribution were not different with diltiazem compared with saline treatment. Thus, diltiazem can decrease the severity of pacing-induced ischemia independently of its peripheral effects and of increased ischemic region blood flow.     

Effects of diltiazem and propranolol on irreversibility of ischemic cardiac function and metabolism in the isolated perfused rat heart

Ischemia was induced by lowering the afterload pressure of the perfused working rat heart, and continued until the heart was reperfused by raising the after load. After ischemia, the following changes were observed: decreases in the pressure-rate product (peak aortic pressure X heart rate) and coronary flow; depletion of adenosine triphosphate and creating phosphate; and accumulation of lactate. When the heart was exposed to ischemia for more than 20 min, reperfusion of the ischemic heart could not restore the pressure-rate product and the tissue adenosine triphosphate completely, suggesting that irreversible ischemic damage occurred. Diltiazem (2.41 X 10(-6), 1.21 X 10(-5), and 2.41 X 10(-5) M) or propranolol (1.69 X 10(-5) and 3.38 X 10(-5) M) was provided for the heart 5 min before the onset of ischemia. In the presence of diltiazem or propranolol, the levels of adenosine triphosphate and creatine phosphate were preserved even after 20 min of ischemia. Reperfusion with the normal perfusate after 20 min of ischemia. Reperfusion with the normal perfusate after 20 min of ischemia with the buffer containing diltiazem or propranolol recovered the pressure-rate product that had been decreased by ischemia, depending on the concentration of diltiazem or propranolol provided. These results indicate that diltiazem, as well as propranolol, delays the onset of irreversible ischemic damage of the heart, suggesting their protective effects on the ischemic myocardium.     

Diltiazem ameliorates contractile dysfunction without shortening of action potential duration in ischemic heart of anesthetized dogs.

The purpose of the following experiment was to determine whether amelioration of myocardial contractile dysfunction by diltiazem is mediated by shortening of monophasic action potential duration (MAPD) during myocardial ischemia in anesthetized dogs. Diltiazem improved regional contraction during reperfusion after 10-min occlusion. The shortening of MAPD and increase in [K+]e were blunted by treatment with diltiazem. These results suggest that shortening of action potential duration during myocardial ischemia is unlikely to be a reason for the amelioration of contractile dysfunction.     

Intracoronary diltiazem limits infarct size during prolonged angioplasty balloon inflation

An animal model of failed coronary angioplasty was used to evaluate the effect of intracoronary diltiazem on regional ischemia and the degree of myocardial necrosis. Ischemia was produced in closed-chest, pentobarbital-anesthetized male mongrel dogs by inflation of 2.5–3.0 mm diameter balloons introduced under fluoroscopy into the left anterior descending or left circumflex coronary arteries. Animals were randomly assigned to control or diltiazem administered at the time of balloon inflation. Diltiazem, 900 μg/kg, was administered in divided doses through the lumen of the angioplasty balloon catheter. Diltiazem reduced the mean arterial pressure by 27 ± 6 mm Hg and blunted tachycardia following occlusion, which was also seen in controls. After 50 min of ischemia, a left thoracotomy was performed, and the left atrium was cannulated for injection of radiolabeled microspheres at 70 min. The animal was then reperfused by deflating the balloon. Regional segment function showed similar dyskinesis in the ischemic area of both groups. At 4 h the animal was sacrificed and the heart was removed for measurement of the area at risk and infarct size using a dual staining technique. Infarct size, when determined as the percent of the area at risk, was significantly reduced in diltiazem treated animals, 9 ± 2%, as compared to control animals, 22 ± 5%. Regional myocardial blood flow did not differ between groups. Therefore, intracoronary diltiazem produced a significant reduction in myocardial injury. This intervention may be useful to delay cell death in the setting of failed coronary angioplasty. © Wiley-Liss, Inc.     

Effects of diltiazem on lactate, ATP, and cytosolic free calcium levels in ischemic hearts.

Changes in tissue lactate, ATP, and cytosolic free calcium (Cai) were examined in isolated, perfused rat hearts receiving 20 min of zero-flow global ischemia (37 degrees C). Addition of diltiazem before ischemia caused a concentration-dependent decrease in lactate accumulation. This effect was not mediated by modulation of norepinephrine release since depletion of catecholamines by reserpine did not alter lactate accumulation, and diltiazem treatment reduced lactate accumulation in catecholamine-depleted hearts. Diltiazem-treated hearts showed a concentration-dependent decrease in tissue ATP utilization that was associated with the decrease in tissue lactate during ischemia. Basal time averaged Cai, determined by fluorine NMR using 5FBAPTA, was 620 nM. Diltiazem (0.9 microM) decreased this value to 489 nM and reduced heart rate and maximum pressure developed (81.3 and 53.9% of control, respectively) before ischemia. Cai increased fourfold between 9 and 15 min of ischemia in hearts receiving no drug, while there was no increase in Cai in diltiazem-treated hearts. These results show that diltiazem reduces the use of ATP and therefore production of lactate during ischemia, and indicate a relationship between preservation of ATP and maintenance of Cai that may be important in the beneficial effects of diltiazem during myocardial ischemia.     

Electrophysiologic and blood-flow responses in the endocardium and epicardium to disopyramide and MS-551 during myocardial ischemia in the dog.

The aim of this study was to determine whether a quantitative relation exists between changes in regional myocardial blood flow (RMBF) and those in electrophysiologic determinants recorded via left ventricular endocardial and epicardial bipolar electrograms after administration of disopyramide (DP) and a class III antiarrhythmic drug, MS-551 (MS), during myocardial ischemia in the dog. Dogs were given DP (1 mg/kg, i.v., n = 14), MS (1 mg/kg, i.v., and 0.1 mg/kg/min, d.i.v., n = 13), or saline (n = 12). The effective refractory period (ERP) was determined by an S1-S2 extrastimulus method, and RMBF by a nonradioactive microsphere technique. The duration of regional electrograms (DRE) was measured as an indicator of conduction time in the myocardium. DP blunted ischemia-induced shortening of ERPs and lengthened DREs at the endocardial and epicardial sites, with a greater effect seen epicardially (p < 0.01 each). DP reduced RMBF, especially at the endocardial surfaces of the ischemic zone (p < 0.05). MS prolonged ERPs at the endocardial and epicardial sites in the ischemic and normal zones (p < 0.05-0.01), but there were no significant differences between the two sites. MS prolonged DREs (p < 0.05), but the magnitude of the prolongation of the DREs was similar to the values in the control group. MS had no effects on RMBF. DP treatment prolonged DREs at both sites in the ischemic zone more markedly than MS or saline treatment (p < 0.01 each). DP reduced RMBF at the endocardial site of the ischemic zone more markedly than MS or saline (p < 0.05 in each). Accordingly, MS prolonged ERPs, but did not increase disparities between endocardial and epicardial sites in the ischemic myocardium, whereas DP had a greater ERP-prolonging effect at the epicardial site than at the endocardial site. DP reduced endocardial RMBF more markedly than epicardial RMBF. These observations suggest that differences in ERPs between endocardial and epicardial ischemic myocardium caused by DP treatment are not due to the difference in RMBF reduction between the two tissue layers, and that DP and MS do not affect the same population of ion channel(s) when ERPs are prolonged.     

Effects of intracoronary nifedipine on blood flow and segment shortening in normal and ischemic myocardium: potentiation by ischemia of the negative inotropic effect

The effects of intracoronary nifedipine on myocardial blood flow (flow probe or microspheres) and regional function (ultrasonic crystals in subendocardium) were examined both in the normal myocardium and in myocardium made ischemic by a partial coronary occlusion in the open-chest anesthetized dog. In a first group of experiments (n = 7), without ischemia, nifedipine infused into the left anterior descending coronary artery (LAD) during a 1-min period (doses 0.75-8 nmol/kg body weight) decreased coronary vascular resistance with a maximal effect at 4 nmol/kg. Systolic segment shortening was decreased from 10.7 to 7.4% (p less than 0.05) by 6 nmol/kg, whereas lower doses had no effect. In a second experimental group (n = 7), a partial LAD occlusion was applied to decrease subendocardial segment shortening by about 50%. Nifedipine (2 nmol/kg) injected into the partially occluded LAD induced a marked segmental bulging during early systole and systolic segment shortening was eliminated (from 4.2 to -3.1%, p less than 0.02) in the LAD-dependent myocardium. Concomitant with the decreased regional function, nifedipine caused a transmural redistribution of myocardial blood flow in the ischemic area, the endocardial/epicardial blood flow ratio increasing from 0.49 to 0.61 (p less than 0.02). It is concluded that ischemia potentiates the direct depressant effect of nifedipine on myocardial regional function.     

Effects of acute global low-flow ischemia on triggered arrhythmias in d-sotalol-induced long Q-T intervals in perfused rabbit hearts

Little information is available on how acute ischemia modifies the electrophysiologic substrate associated with long Q-T interval conditions. We studied the effects of low-flow ischemia (10 min at 5.0 ml/min followed by 10 min of 2.5 ml/min) in Langendorff perfused rabbit hearts during control and in hearts 20 min after the addition to the perfusate of 92 microM d-sotalol, which reliably produced triggered activity. Epicardial electrograms, a left ventricular endocardial monophasic action potential (MAP), and simulated X and Y lead electrocardiograms were used to characterize myocardial activation and recovery during ventricular pacing. In the control hearts, conduction velocity as indicated by the mean epicardial activation time accelerated for most of the period of ischemia (maximum decrease of -9.4 +/- 7.9%). The mean activation-recovery interval, MAP duration, and Q-T interval were moderately decreased (-4.9 +/- 8.6%, -7.5 +/- 4.4%, and -4.6 +/- 2.3%, respectively). The mean standard deviation of the activation-recovery interval (epicardial heterogeneity of recovery) was increased by 34.6 +/- 23.4%. d-Sotalol had no effect on conduction but prolonged myocardial recovery time, increased heterogeneity, and produced triggered arrhythmias in all hearts. Within 2 min of ischemia triggered activity was eliminated. With d-sotalol, ischemia slowed conduction and produced relatively larger decreases in the activation-recovery interval, MAP duration, and Q-T interval (-11.8 +/- 10.3%, -13.9 +/- 12.0%, and -15.8 +/- 11.2%). The increased epicardial heterogeneity seen with d-sotalol was attenuated by ischemia. Thus ischemia superimposed on long Q-T conditions had antiarrhythmic as well as arrhythmogenic effects.     

The role of beta-adrenoceptors in coronary blood flow distribution in normal and ischemic canine myocardium.

beta-Adrenoceptor agonists increase myocardial ischemic injury, mainly by elevating myocardial oxygen consumption. Moreover, it has been shown that isoprenaline may "steal" regional myocardial blood flow (RMBF) from ischemic to non ischemic areas and from epicardium to endocardium. The mechanisms of these two isoprenaline-induced redistributions of RMBF have been investigated by the use of radioactive microspheres in an experimental model of canine myocardial ischemia with simultaneous measurement of ST-segment elevation. Isoprenaline increased RMBF in both epi- and endocardial non ischemic areas and in epicardial ischemic areas, leading to a significant decrease in the endo/epi ratio. After atenolol, isoprenaline still increased RMBF but to a lesser extent and the endo/epi ratio was still decreased. Salbutamol, in doses inducing no significant changes in cardiac parameters or myocardial oxygen consumption, produced effects similar to those of isoprenaline. These results indicate a non-homogeneous beta2-stimulation-induced vasodilation in endo- and epicardium, which might be due either to the higher epicardial coronary vasocilatory reserve or to a heterogeneous distribution of transmural beta2-adrenoceptors. Isoprenaline also decreased the ischemic/non ischemic total blood flow ratio (I/NI) and caused further increases in ST-segment elevation. These effects were abolished by atenolol pretreatment, indicating the deleterious effects of isoprenaline-induced tachycardia in this I/NI decrease and in the ischemic injury.     

Energy preserving effect of l-cis diltiazem in isolated ischemic and reperfused guinea pig hearts: a 31P-NMR study

We determined the effect of 1-cis diltiazem, the enantiomer of diltiazem (d-cis isoform), on the energy metabolism of isolated guinea pig hearts during ischemia-reperfusion. We used 31P-NMR to measure the high-energy phosphate content and intracellular pH (pHi) during global ischemia for 30 min followed by reperfusion for 30 min. Before ischemia, the left ventricular developed pressure (LVDP) was reduced less by 10 microM l-cis diltiazem than by 3 microM diltiazem or 500 nM nifedipine. However, 10 microM l-cis diltiazem preserved the intracellular ATP content during ischemia and reperfusion, reduced the end-diastolic pressure increase during ischemia and reperfusion, and restored LVDP after reperfusion. Nifedipine at 50 nM, which reduced the LVDP more than 10 microM l-cis diltiazem, showed no cardioprotective effect. Ten micromolar l-cis diltiazem and 3 microM diltiazem, but neither 50 nor 500 nM nifedipine, reduced the pHi decrease that occurred 25 or 30 min after the onset of ischemia. Therefore, l-cis diltiazem has a cardioprotective effect on ischemic and reperfused myocardium and is less cardiodepressive than diltiazem and nifedipine. The effect of l-cis diltiazem during ischemia and reperfusion involves energy preservation, which is probably independent of its Ca2+-channel blocking action.     

The effect of diltiazem on myocardial recovery after regional ischemia in dogs

The effect of diltiazem on post-ischemic metabolic and functional recovery was investigated in regionally ischemic dog hearts. The duration of ischemia was 60 min, followed by 60 min of reperfusion. Diltiazem (bolus injection of 0.1 mg X kg-1 body weight prior to ischemia, followed by a continuous infusion of 0.1 mg X kg-1 X h-1) had no effect on residual coronary flow in the centre of the ischemic area, but blunted the reactive hyperemia response after restoration of flow. The drug partially prevented the depletion of ATP and glycogen in the severely underperfused subendocardial layers, i.e. when residual flow was below 0.1 ml X min-1 X g-1. Reduction of the content of these substances in the subepicardial layers was moderate and not influenced by diltiazem. Segment shortening in the subepicardial layers disappeared whereas segment lengthening was observed in the subendocardial layers during the ischemic period. Diltiazem did not prevent the loss of contractile function. Despite an initial restoration of contractile function within 10 min after reperfusion, no significant beneficial effect of diltiazem treatment on mechanical function of the reperfused area was present thereafter.     

Cardioprotection by the calcium antagonist PN 200-110 in the absence and presence of cardiodepression.

The globally-ischaemic Langendorff rabbit heart model has been used to study the cardioprotective effects of the dihydropyridine PN 200-110 (PN) at two doses, one having no negative inotropic effect and a higher dose causing a 62 +/- 5% reduction in contractility. Following 45 min no-flow global ischaemia, recovery was monitored for a period of 90 min reperfusion. Hearts were paced at a constant rate throughout experiments. Contractile force and coronary flow were recorded continuously. Tracer microspheres were injected at regular intervals to assess regional flow distributions, drill biopsies were taken to determine tissue high energy phosphate content, and enzyme leakage in the coronary effluent measured during the first 15 min of reperfusion. Untreated hearts recovered 21 +/- 2% of their initial contractile force and flow to all heart regions was reduced. In particular, endocardial flow fell to 20% of its pre-ischaemic level, with the ratio of flow to the endocardium (endo)/epicardium (epi) decreasing from ca. 1.0 to 0.4. Hearts treated with 2 X 10(-8)M PN (included in the perfusate from 30 min before ischaemia until 30 min after ischaemia) recovered 49 +/- 2% of their initial, pretreatment contractile force, and following the ischaemia the endo/epi ratio was not significantly changed from the pre-ischaemic value. The lower PN dose (3 X 10(-10)M) afforded a lesser degree of protection, contractility recovering to 29 +/- 4% of the initial level, with an endo/epi ratio of 0.7 after 90 min reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of molsidomine and nitroglycerin on the regional blood flow in the normal and acutely ischemic myocardium (author's transl)]

In anaesthetized dogs regional myocardial blood flow (radioactive particle distribution technique) and several haemodynamic parameters were measured before and after acute ligation of left descending coronary artery. By injection of N-carboxy-3-morpholino-sydnonimine ethylester (molsidomine, Corvaton) or infusion of nitroglycerin it was tried to influence blood flow of the infarcted areas of the myocardium. 1. Ligation of the coronary artery induces myocardial infarction of anterior wall, predominantly restricted to the endocardial portions of the heart muscle. 2. Molsidomine and also nitroglycerin do not change overall blood flow of the heart in the sense of vasodilation. 3. In the infarcted area the ratio: blood flow of endocardial layers to blood flow of epicardial layers, is improved by molsidomine. 4. The positive effect of molsidomine becomes clearer in the border zone of infarction. Nitroglycerin remains without effect. 5. The effects of the compound molsidomine are explained by stronger action on extravascular factors of colonary vascular resistance (decrease in enddiastolic pressure).     

Diltiazem. A reappraisal of its pharmacological properties and therapeutic use

Diltiazem is a calcium antagonist effective in the treatment of stable, variant and unstable angina pectoris and mild to moderate systemic hypertension, with a generally favourable adverse effect profile. It is also effective in terminating supraventricular tachycardia and in controlling the ventricular response to atrial fibrillation/flutter. Atrioventricular block, the risk of which may be exacerbated by concomitant beta-adrenoceptor antagonist therapy, occurs rarely as an adverse effect of diltiazem treatment. Diltiazem appears to exert complex cardioprotective effects which have been of benefit after intracoronary administration to patients undergoing coronary angiography and bypass procedures. In addition, long term diltiazem treatment has produced a significant reduction in subsequent cardiac events in patients with non-Q wave myocardial infarction. Thus, diltiazem is an effective and well-tolerated first-line or alternative treatment of patients with ischaemic heart disease, systemic hypertension, and supraventricular arrhythmias, with possible potential in limiting ischaemia-induced myocardial damage.