Protective role of chronic ubiquinone administration on acute cardiac oxidative stress.

Previous studies have shown that acute exogenous administration of coenzyme ubiquinone (CoQ10) can protect the heart against oxidant-mediated injury. The aim of this study was to investigate whether protection against cardiac oxidative stress could be obtained by increasing tissue levels of CoQ10, as achieved by chronic CoQ10 supplementation. Wistar rats were randomly divided into two groups: a control group given standard diet and a test group receiving diet supplemented with CoQ10 (5 mg/kg/day) for 4 weeks. Functional and metabolic changes induced by oxidative stress were investigated in isolated perfused hearts and in papillary muscles. Tissue concentrations of ubiquinones were significantly higher in the left ventricle of treated rats than in controls. H2O2 infusion (60 microM for 60 min) induced marked alterations of both developed pressure, which decreased to -58.8 +/- 16.8% of base line and end-diastolic pressure which increased almost 13-fold. These effects were reduced significantly (P < .05) in hearts from CoQ10-supplemented rats (-13.8 +/- 2.3 and +375.0 +/- 42.5%, respectively). In the same hearts, cumulative release of oxidized glutathione (a specific marker of oxidative stress) was 450.2 +/- 69.2 nmol/g of wet weight in the control group and only 89.6 +/- 22.3 nmol/g of wet weight in treated hearts (P < .01). In papillary muscles, after 60 min of perfusion with H2O2, active tension decreased, largely in controls whereas it was almost unchanged in the treated group (-34.4 +/- 7.5% of baseline vs. -0.1 +/- 0.05%, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effect of beta-blockade on dipyridamole-induced myocardial ischaemia. Role of heart rate.

This study was designed to investigate the effect of heart rate changes on dipyridamole echocardiographic tests in patients with coronary artery disease treated with propranolol. We prospectively studied 12 patients (8 men and 4 women; mean age 56.5 +/- 8.7 years) selected by: (a) angiographic evidence of significant coronary artery disease; (b) adequate echocardiographic window; (c) positive dipyridamole echocardiography test results in baseline conditions (step I); (d) test reproducibility in the absence of treatment; (e) negative dipyridamole echocardiography test results after 7 days of treatment with propranolol (120 mg.day-1) in twice divided doses daily (step II). In all patients treated with propranolol, dipyridamole echocardiographic testing was repeated 24 h after the last negative test. In these patients, transoesophageal atrial pacing was performed at peak dipyridamole infusion to increase heart rate to values similar to those observed at baseline (step III). At baseline, heart rate and rate-pressure product were significantly lower in patients treated with propranolol (-20.3% and -22.5% in group II, P < 0.001 vs step I; -24.3% and -26.4% in group III, P < 0.05 vs step I), but the different treatments did not produce significant differences in systolic and diastolic blood pressure. At peak dipyridamole infusion, heart rate and rate-pressure product increased with either placebo or propranolol treatments with respect to baseline, while remaining significantly lower with propranolol as compared to placebo (-29.6% and -29.5% in step II, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced aerobic metabolic efficiency in postischemic myocardium dysfunction in rats: role of aging.

It has been suggested that aging may enhance the deleterious effects of myocardial ischemia-reperfusion. This study evaluates the relationship between oxygen consumption and functional impairment during reperfusion following myocardial ischemia in adult and senescent rat hearts. Global ischemia induced a marked impairment of contractile function which was significantly higher in senescent than in adult hearts. During reperfusion postischemic dysfunction was more evident in senescent hearts: at the 10th minute, the developed pressure recovered less (p < 0.05) and end-diastolic pressure increased more (p < 0.05) in senescent than in adult hearts. However, oxygen consumption per unit of work was significantly higher throughout 60 min of reperfusion when compared to controls with no significant difference between adult and senescent hearts. This study demonstrates that following ischemia and reperfusion depression of function and inappropriately high oxygen consumption were observed in both adult and senescent hearts. However, aging was associated with greater contractile impairment, which occurred in the absence of further deterioration of metabolic efficiency of contraction.

Regression of left ventricular hypertrophy and improvement of renal hemodynamics in hypertensive patients treated with quinapril.

Of 17 patients with mild to moderate essential hypertension, 8 showed echocardiographic evidence of left ventricular hypertrophy. Cardiac and renal function evaluated by glomerular filtration rate (GFR) were studied in all patients before and after 20 weeks of quinapril treatment. Systolic pressure decreased from 174.7 +/- 16.7 to 131.7 +/- 7.7 mmHg (p < .0001) and diastolic pressure decreased from 101.8 +/- 9.8 to 80 +/- 4.3 mmHg (p < .0001). Left ventricular mass index decreased in the eight patients with left ventricular hypertrophy (p < .01). Basal values of GFR were lower than normal in 41% of all patients; GFR increased significantly after 20 weeks of treatment (from 96.5 +/- 32.3 to 108.6 +/- 31.12 ml/min, p < .01); it decreased in only one patient. Patients reported few adverse effects to quinapril, and no important clinical laboratory abnormality was observed. Quinapril not only lowered arterial pressure, but it had a distinct effect on regression of left ventricular hypertrophy and favorable effects on renal function.

Role of aging on electrical, mechanical, and coronary modification induced by ouabain and epinine in isolated rat heart.

OBJECTIVE: The contractile response to digitalis and beta adrenoceptor agonists is lower in the senescent than in the adult myocardium, while the development of ventricular arrhythmias is increased. The aim of this study was to examine the effects of aging on cardiac response to digitalis and an adrenergic agonist used clinically. METHODS: The electrical and mechanical responses were tested in isolated and perfused hearts from 3-24 month old rats receiving 15 min infusion of digitalis drug (ouabain, 6 x 10(-5) M) alone, and after 5 min of beta adrenoceptor agonist drug (epinine, 1.5 x 10(-7) M). RESULTS: Ouabain action was associated with a rise in left ventricular end diastolic pressure (p < 0.01) which increased progressively with aging, and with an elevation of left ventricular developed pressure (p < 0.01) which decreased progressively with aging. Epinine induced a reduction of left ventricular end diastolic pressure (p < 0.01) and a rise in left ventricular developed pressure (p < 0.01) but both effects decreased progressively with aging. Ouabain reduced coronary flow and this decrease was more pronounced with aging (p < 0.01), while epinine caused an increase (p < 0.01) that diminished in older hearts. Ouabain given after epinine resulted in a greater increase in left ventricular end diastolic pressure than epinine (p < 0.01) but lower than that caused by ouabain alone (p < 0.01), a greater increase in left ventricular developed pressure than epinine and ouabain (p < 0.01), and a smaller reduction of coronary flow rate than ouabain alone (p < 0.01). All these effects, however, diminished progressively with aging. Arrhythmia scores were higher during ouabain than in control (p < 0.01) and in epinine treated hearts (p < 0.01); pretreatment with epinine did not modify arrhythmia score during ouabain administration. The number and severity of arrhythmias, however, increased with aging in all groups. CONCLUSIONS: Aging has a negative effect on both the positive inotropic and the arrhythmogenic effects of ouabain and epinine, although these phenomena are more pronounced during ouabain administration. However, when the two drugs are given simultaneously, epinine does not modify the arrhythmogenic effect of ouabain but reduces some of its deleterious haemodynamic effects.

Echocardiographic vs hemodynamic monitoring during isometric exercise in patients with coronary artery disease.

BACKGROUND: Isometric exercise is able to induce myocardial asynergies in patients with coronary artery disease as demonstrated by noninvasive monitoring performed during stimulation. AIMS OF THE STUDY: In the present study, a combined echocardiographic and hemodynamic monitoring of left ventricular contractility has been conducted in order to verify, with invasive and noninvasive techniques, the ability of isometric exercise in inducing transient myocardial ischemic phenomena. METHODS: The study population was composed of 20 patients with angiographic evidence of significant coronary stenosis (> or = 50%), and 10 subjects with normal coronary angiograms. All 30 subjects admitted to the study underwent an isometric exercise stress during echocardiographic and hemodynamic monitoring of left ventricular contractility. RESULTS: Nine out of 20 patients with coronary disease showed regional asynergy during the test (Group I). The remaining 11 patients showed normal myocardial contractility (Group II). None of the 10 control subjects showed mechanical signs of ischemia during the test. Left ventricular end diastolic pressure significantly increased in both Group I (10 +/- 2 to 24 +/- 4 mmHg) and Group II (12 +/- 3 to 26 +/- 3 mmHg) (p < 0.01) while it remained unchanged in the control group (9 +/- 2 to 13 +/- 2 mmHg; p = NS); dp/dt increase (% basal) was significantly higher in the control group (45 +/- 6%) than in either Group I (25 +/- 3%) or Group II (26 +/- 3%) (p < 0.01). CONCLUSIONS: Isometric exercise was able to induce left ventricular asynergies due to regional myocardial ischemia. Hemodynamic contractility monitoring easily distinguished the control subjects from the patients with coronary disease but was not able to discriminate patients with handgrip-induced regional asynergy. Thus, the echocardiographic technique offers more detailed information about regional myocardial function than do the common hemodynamic contractility indexes.

Age-related effects of platelet activating factor (PAF) in the isolated perfused rat heart.

Platelet Activating Factor (PAF) is a phospholipid that has been implicated as an important mediator of anaphylactic cardiac dysfunction and involved in the toxic effects of the ischaemia-reperfusion process. In the elderly, these phenomena are thought to be exaggerated by the age-related changes in response to several chemical factors and myocardial ischaemia. We evaluated the effects of PAF (acetyl-o-alkyl-l-phosphatidylcholine) on left ventricular systolic (LVSP) and diastolic (LVDP) pressure, coronary flow rate (CFR) and heart rate (HR) in adult (6 months, AH) and senescent (24 months, SH) rat hearts. The perfusion of PAF (10(-8), 10(-7) and 10(-6) M) induced a concentration-related reduction of LVSP, CFR and HR and a linear increase in LVDP. Contractile modifications were more pronounced in senescent hearts: LVSP decreased (P < 0.01) and LVDP increased with respect to younger animals (P < 0.01 vs. AH). This negative inotropic effect was also present in electrically paced hearts. PAF produced conduction arrhythmias ranging from second-degree atrio-ventricular conduction block to cardiac standstill both in adult and senescent hearts; at a higher dose (10(-6) M), cardiac standstill appeared after 96.5 +/- 15.3 s in adult hearts and after 45.5 +/- 17.6 s in senescent hearts (P < 0.01). Lyso-PAF did not modify while specific PAF antagonist compounds CV-3988 inhibited all electromechanical responses both in adult and senescent hearts. These data suggest that age influences the effect of PAF on contractile parameters, coronary flow and conduction arrhythmias by acting on receptors, whose function is unaffected by age.

Age-related effects of ischemia, lidocaine and verapamil on overdrive-induced suppression of ventricular pacemakers in isolated rat heart.

The effect of age on ventricular automaticity in the isolated perfused rat heart was determined under different conditions. When the ventricle is electrically stimulated at a faster rate, drive cessation is followed by a temporary suppression of ventricular automaticity (overdrive suppression). The effects of ischemia, lidocaine and verapamil on overdrive suppression were studied in isolated perfused adult and senescent rat hearts with complete atrio-ventricular block, by monitoring ventricular escape rate and escape rhythm recovery time after 1 minute of overdrive at a constant multiple (x3) of the spontaneous rate. The results demonstrated that: 1) lidocaine decreases ventricular automaticity especially in senescent hearts; 2) verapamil does not modify ventricular automaticity in basal conditions in either adult or senescent hearts; 3) myocardial ischemia causes a reduction in ventricular automaticity and more markedly in senescent hearts; and 4) lidocaine exaggerates the effect of ischemia, while verapamil seems to antagonize its depressant effect more in adult than in senescent hearts.

Dipyridamole echocardiography as a useful and safe test in the assessment of coronary artery disease in the elderly.

We prospectively studied the sensitivity, specificity, feasibility, and safety of high-dose dipyridamole echocardiography, compared to exercise electrocardiography in 130 subjects (67 younger and 63 elderly patients) referred for angiographic evaluation of suspected or proven coronary artery disease. Sensitivity, specificity, and feasibility of dipyridamole echocardiography were respectively 75.5%, 100%, and 88.0% in younger patients and 82.9%, 100%, and 79.4% in elderly patients (P = NS). The sensitivity of exercise electrocardiography was 72.7% in young and 66.6% in elderly patients (P = NS); specificity 66.0% vs 60.0% (P = NS); feasibility 83.6 vs 63.5 (P = 0.05). Forty-nine younger and 38 elderly patients performed both tests. Sensitivity of dipyridamole echocardiography compared to exercise electrocardiography was 76.2% vs 73.8% in young patients and 83.3% vs 70% in the older group (P = NS). The feasibility of the two tests was significantly different in the elderly group only (dipyridamole echocardiography 79.4% vs exercise electrocardiography 63.5%; P less than 0.01). The incidence of side effects during dipyridamole echocardiography was similar in the two groups, except for dyspnea which was observed in 20% of older and 5% of younger patients (P less than 0.05). Our data demonstrate that the dipyridamole test combined with echocardiographic monitoring of regional myocardial contractility may be considered a valid non-invasive method for evaluating coronary artery disease in the elderly and that this test is a satisfactory alternative to the exercise stress test.

The hypothetical role of potassium conductance on the genesis of R-wave amplitude increase during ischemia in the isolated rat heart.

The effect of increased potassium conductance on the genesis of R-wave amplitude increase during acute myocardial ischemia has been studied in the isolated perfused rat heart by simultaneously recording the R-wave amplitude of epicardial electrograms (VEE), heart rate (HR), coronary flow rate (CFR), left ventricular diastolic pressure (LVDP), and left ventricular systolic pressure (LVSP). The experiments were performed during basal and partial or total ischemic conditions at spontaneous or fixed HR. In some experiments, potassium conductance was increased by means of high-calcium (8 mM) or acetylcholine chloride (10(-6) M) perfusion. In the control experiments, partial ischemic perfusion produced an increase in VEE and LVDP and a decrease in HR, CFR, and LVSP; total ischemic perfusion exaggerated these variations. High-calcium perfusion provoked an increase in VEE and LVDP and a decrease in HR, CFR, and LVSP during basal conditions (p less than 0.01 vs. control experiment); these modifications increased progressively during partial ischemic perfusion (p less than 0.01 vs. control experiment) and during total ischemic perfusion (p less than 0.01 vs. control experiment). Perfusion with acetylcholine chloride produced variations similar to those observed in high-calcium solution except that LVDP under basal conditions remained unchanged from control. When the HR was maintained at a constant value by means of atrial pacing the results were similar to those observed in the unpaced hearts. In conclusion, in the isolated perfused rat heart, increasing potassium conductance may influence the genesis of R-wave amplitude increasing during acute myocardial ischemia.

Effect of flecainide acetate on reperfusion- and barium-induced ventricular tachyarrhythmias in the isolated perfused rat heart.

Flecainide acetate is a new antiarrhythmic drug which suppresses different kinds of experimental arrhythmias. We studied the efficacy of flecainide acetate on reperfusion- and barium-induced ventricular tachyarrhythmias in the isolated perfused rat heart by monitoring heart rate, coronary flow rate, left ventricular systolic pressure, dp/dtmax, and the voltage of the epicardial electrogram. Seventy-five male rats were randomized into 5 groups. In group I, after a 15 min period of stabilization, hearts were perfused by ischemic perfusion and then reperfused. In group II, flecainide acetate (10(-6) M) was given after stabilization and before ischaemic perfusion. In group III, barium chloride (10(-3) M) was given after stabilization. In group IV, flecainide acetate was given after stabilization and before barium chloride administration. In group V, acetylcholine chloride (10(-6) M) was given after stabilization and before barium chloride administration. In group I, we noted during ischemia a reduction in heart rate, coronary flow rate, left ventricular systolic pressure and dp/dtmax and an increase in the voltage of the epicardial electrogram. In group II, after administration of flecainide acetate, we observed a reduction in heart rate, left ventricular systolic pressure and dp/dtmax; during the ischaemic period there was no difference in these parameters with respect to group I. Reperfusion induced ventricular arrhythmias in 12 out of 15 hearts in group I and in only 3 out of 15 in group II (p less than 0.005). Barium induced ventricular arrhythmias in the 15 hearts studied in group III as well as in group IV. On the contrary, acetylcholine chloride in group V prevented the occurrence of barium-induced ventricular arrhythmias (p less than 0.005 vs group III and IV). Thus, flecainide acetate is able to reduce reperfusion-induced ventricular arrhythmias, but is unable to reduce barium-induced ventricular arrhythmias, presumably because of a different mechanism of these two types of arrhythmias.

Arrhythmogenic age-related effects of lysophosphatidylcholine in the rat heart.

Ventricular arrhythmias are the most common cause of death among patients with coronary artery disease; this is more evident in the elderly, who tend to have more severe coronary artery disease and age-dependent modifications of cardiac electrophysiology. Lysophosphoglycerides, which accumulate in the ischemic myocardium, are responsible for oscillatory after-potentials and may contribute to the development of ventricular arrhythmias. The aim of this study was to examine the effects of lysophosphatidylcholine (5 x 10(-5) M) in the absence or presence of epinephrine (10(-6) M) in isolated, perfused hearts from adult (6-12 months old) and senescent (24 months old) rats. Rat hearts (30/group) were randomly divided into four groups each of which included hearts of 6, 12 and 24-month old rats. The groups comprised a control group, a group treated with epinephrine, a group treated with lysophosphatidylcholine and a group treated with both epinephrine and lysophosphatidylcholine. Analysis of arrhythmias indicated a linear correlation between epinephrine- and lysophosphatidylcholine-induced ventricular arrhythmias and age. The incidence of arrhythmias was higher in the hearts treated with epinephrine and lysophosphatidylcholine together than in those treated with either substance separately (p less than 0.01). The results indicate that age influences the arrhythmogenic action of lysophosphatidylcholine, and that epinephrine contributes to this effect.

[Action of magnesium salts on the toxic effects of calcium overload in the isolated and perfused rat heart]. / Azione dei sali di magnesio sugli effetti tossici del sovraccarico di calcio nel cuore di ratto isolato e perfuso.

The toxic effect of calcium overload and the action of magnesium sulfate (4 mM) and magnesium chloride (4 mM) on heart rate, coronary flow rate, left ventricular systolic pressure, dp/dt max and voltage epicardial electrogram were studied in the isolated and perfused rat heart. Increasing calcium load by increasing [Ca]o from 1 to 6 mM we observed a progressive increase in heart rate coronary flow rate, left ventricular systolic pressure, dp/dt max and a decrease in voltage epicardial electrogram. During the exposure to [Ca]o 8 mM the toxic manifestations of calcium overload developed and we observed a reduction in heart rate, coronary flow rate, left ventricular systolic pressure, dp/dt max and an increase in voltage epicardial electrogram. Magnesium sulfate and magnesium chloride had similar effect: in fact, in both procedures we observed a decrease in heart rate, left ventricular systolic pressure, dp/dt max, voltage epicardial electrogram and an increase in coronary flow rate at [Ca]o 2 mM. When magnesium salts were administered at the same time as the heart was exposed to [Ca]o 8 mM, we observed a reduction in the toxic effect of calcium overload. When magnesium salts were administered after the appearance of the calcium overload, they did not revert the toxic effect of calcium overload but prevented the insurgence of cardiac standstill. Thus, in the isolated perfused rat heart, the toxic manifestations of calcium overload develop at [Ca]o 8 mM and magnesium salts are able to reduce the toxic effects of calcium overload and the appearance of cardiac standstill according to their calcium-antagonism mechanism.

Electrical and mechanical actions of magnesium sulfate during ischemia and reperfusion on isolated perfused rat heart.

Experimental and clinical studies have shown the action of magnesium salts on myocardial tissue and its antiarrhythmic action on digitalis-induced ventricular arrhythmias. We have evaluated the effects of magnesium sulfate (2.5 mM) on heart rate (HR), coronary flow rate (CFR), left ventricular systolic pressure (LVSP), dP/dt max and voltage epicardial electrogram (VEE) during ischemia and reperfusion in isolated perfused rat heart. Forty-five male rats were randomized into 3 groups. In the control group, after a 15 min period of stabilization, hearts were perfused by ischemic perfusion for 30 min and then reperfused. In group I, magnesium sulfate was given after stabilization and before the ischemic period. In group II, calcium concentration was increased by 0.5 mM and magnesium sulfate was given after stabilization and before the ischemic period. In the control group, we observed during ischemia a reduction in HR, CFR, LVSP, dP/dt max and an increase in VEE. In group I, after the administration of magnesium sulfate, we noted a decrease in HR, LVSP, dP/dt max, VEE and during the ischemic period there was no difference in these parameters with respect to the control group. In group II, the increase of extracellular calcium concentration caused an increase in LVSP, dP/dt max and the administration of magnesium sulfate abolished these effect, bringing the values back to basal values. Reperfusion provoked ventricular arrhythmias in 11/15 and 12/15 hearts in the control group and group II respectively, and only 3/15 in group I (p less than 0.005 group I vs control and group II). Thus, our results demonstrated that magnesium sulfate has varied effects on electrical and mechanical parameters and prevents reperfusion arrhythmias according to the hypothesis of a calcium-antagonist mechanism of magnesium.