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A Mugelli

Publications and source records attributed to A Mugelli.

At least 37 records · Page 2Linked to original sources
PubMed1996

Occurrence and properties of the hyperpolarization-activated current If in ventricular myocytes from normotensive and hypertensive rats during aging.

BACKGROUND: Cellular electrophysiological alterations may contribute to arrhythmogenesis in cardiac hypertrophy. An L-like current occurs in left ventricular myocytes (LVMs) isolated from the hypertrophied heart of old spontaneously hypertensive rats (SHR). Factors that influence L occurrence during development of cardiac hypertrophy were studied by determining its presence, amplitude, characteristics, and beta-adrenoceptor modulation. METHODS AND RESULTS: Patch-clamped LVMs from young (2 to 3 months old) or old (18 to 24 months old) normotensive Wistar-Kyoto rats (WKY) and SHR were used. A diastolic depolarization phase was present in old SHR. An If-like current occurred in > 90% of LVMs from old SHR and WKY and in approximately = 15% of LVMs from young rats (P < .05). Activation curves of If were similar in old rats, with the midpoint at -92.9 +/- 2.9 mV in WKY (n = 42) and -88.1 +/- 1.5 mV in SHR (n = 25); maximal specific conductance was 54.4 +/- 1.7 in SHR and 20.1 +/- 0.5 picosiemens/picofarad in WKY (P < .05). In WKY, If amplitude was linearly related to membrane capacitance, an index of cell size (r = .53, P < .001). This relation was absent in SHR, in which a significant positive correlation was found between the heart weight to body weight ratio and I(f) density. In both old WKY and old SHR, 0.1 mumol/L (-)-isoproterenol increased I(f) amplitude by shifting its activation curve toward more positive potentials. CONCLUSIONS: In LVMs from both WKY and SHR, the occurrence of I(f) increases with aging. Density appears linearly related to the severity of cardiac hypertrophy and increases with beta-adrenoceptor stimulation, which suggests that I(f) may contribute to an increased propensity of the hypertrophied heart for arrhythmias.

Aging↗
PubMed1996

The effect of oxygen free radicals on calcium current and dihydropyridine binding sites in guinea-pig ventricular myocytes.

1. We used electrophysiological and binding techniques to determine the effects of oxygen free radicals (OFRs) generated by dihydroxyfumaric acid (DHF, 5 mM) on calcium current and dihydropyridine binding sites in guinea-pig isolated ventricular myocytes. 2. Binding of [3H]-PN200-110 to isolated ventricular myocytes revealed one population of binding sites with a KD of 0.11 +/- 0.01 nM and Bmax of 139.1 +/- 6.9 fmol mg-1 protein (n = 24). After 15 min of exposure to DHF, the density, but not the affinity of [3H]-PN200-110 binding sites was significantly (P < 0.01) reduced to 35% of the control value (Bmax = 49.4 +/- 3.7 fmol mg-1 protein, KD = 0.11 +/- 0.01 nM, n = 15). In the presence of superoxide dismutase (SOD) and catalase (CAT) the reduction in [3H]-PN200-110 binding sites was almost completely prevented (Bmax = 120.5 +/- 7.4 in control, n = 4 and 98.8 +/- 7.4 fmol mg-1 protein in DHF plus SOD and CAT, n = 4). KD values were not modified (0.08 +/- 0.01 in control and 0.09 +/- 0.01 nM in DHF plus SOD and CAT). 3. The time-course of the reduction of [3H]-PN200-110 binding sites by OFRs was paralleled by the decrease in L-type calcium current (Ica,L) measured in patch-clamped guinea-pig ventricular myocytes either in the absence or in the presence of EGTA in the patch pipette. In the former conditions OFRs induced the appearance of calcium-dependent alterations, i.e. the transient inward current, within 10 min. After 30 min of incubation with DHF, [3H]-PN200-110 binding sites were reduced to 25% of the control value. 4. In myocytes incubated with the antilipoperoxidant agent, butylated hydroxytoluene (BHT, 50 microM), the decrease in [3H]-PN200-110 binding sites caused by DHF was partially prevented (Bmax values after 30 min exposure to DHF were 55.5 +/- 1.9 and 23.7 +/- 5.9 fmol mg-1 protein in the presence and in the absence of BHT respectively, P < 0.05). BHT did not affect the decrease in [3H]-PN200-110 binding sites during the first 15 min of exposure to DHF, but was able to prevent completely the further decrease occurring during the following 15 min of incubation with OFRs. 5. Our results demonstrate that the OFR-induced decrease in calcium current is associated with a reduction in DHP binding sites. The decrease in calcium current and in calcium channels may be implicated in the mechanical dysfunction associated with oxidative stress.

Action Potentials↗
PubMed1995

Iloprost antagonizes the increase in internal calcium concentration induced by alpha-thrombin in human platelets: a study of desensitization.

We studied the interaction between the synthetic prostacyclin analog iloprost and the aggregating agent alpha-thrombin by measuring the internal calcium ion concentration ([Ca(2+)]i) of human fura-2-loaded platelets. Iloprost (0.003-100 micrograms/l) did not modify the resting calcium level; when added 2 minutes before exposure of the platelets to a submaximally active concentration of alpha-thrombin (10 U/l), iloprost dose-dependently antagonized the increase in [Ca(2+)]i. To evaluate if iloprost retained this antagonistic effect even after a prolonged contact, which is well known to cause a "desensitization" phenomenon, platelets were preincubated with iloprost (35 micrograms/l) for 3 hours. After washout, the effect of newly added iloprost (0.01-100 micrograms/l) on the alpha-thrombin-induced increase in [Ca(2+)]i was tested. Iloprost was still able to antagonize the increase in [Ca(2+)]i induced by alpha-thrombin in "desensitized" platelets; however, the dose-inhibitory response curve was significantly shifted to the right when compared with that obtained in control platelets (i.e., platelets preincubated for 3 hours with iloprost's solvent), and the resulting IC50 was significantly higher: 1.78 versus 0.2 micrograms/l (p < 0.001). Since the maximal inhibitory effect of iloprost could also be reached under these experimental conditions, we conclude that iloprost retains its ability to antagonize the increase in [Ca(2+)]i induced by alpha-thrombin in desensitized platelets.

Blood Platelets↗
PubMed1995

Beta-adrenoceptor subtypes in young and old rat ventricular myocytes: a combined patch-clamp and binding study.

1. We used electrophysiological and binding techniques to assess the presence of beta 1- and beta 2-adrenoceptors (beta 1AR and beta 2AR) in rat cardiac myocytes and to determine their ratio during aging. Experiments were performed in left ventricular myocytes enzymatically dissociated from the heart of 3-(young) or 22-month-old (old) Wistar Kyoto rats. 2. In patch-clamp experiments, myocytes from old rats showed a prolonged action potential duration (at -20 mV: 41.7 +/- 3.6 vs 26.2 +/- 3.1 ms; at -60 mV: 154.4 +/- 17.7 vs 87.1 +/- 6.9 ms, P < 0.05) and an augmented membrane capacitance (an index of cell size) (271.7 +/- 20.2 vs 164.3 +/- 14.6 pF, P < 0.05) compared to young rats. beta 2AR stimulation, achieved by superfusing myocytes with the selective beta 2AR agonist, zinterol (10 microM) or with (-)-isoprenaline (1 microM) in the presence of the selective beta 1AR antagonist, CGP 20712A (0.1 microM), significantly increased L-type calcium current (ICa,L) in rat ventricular myocytes. The percentage increase was similar in both young and old rats, either with zinterol (26.9 +/- 3.6% and 24.2 +/- 2.8%, respectively) or isoprenaline plus CGP 20712A (30.4 +/- 3.7% and 22.4 +/- 4.1%, respectively). Isoprenaline alone (beta 1AR and beta 2AR stimulation) caused a much smaller increase in ICa,L in old rats (58.4 +/- 12.1%) than in younger ones (95.3 +/- 8.1%) (P = 0.067). 3 The number of ,BAR mg-' protein, measured with saturation binding assays of the non selective ,betaAR antagonist [3H]-CGP 12177 was 1989.4+/-189.5 for 3- and of 1580.7 +/-161.5 for 22-month-old rats.Competition for [3H]-CGP 12177 binding by CGP 20712A gave biphasic curves which demonstrated two classes of binding sites. Densities (as percentages of total PAR density), and affinities for the two binding sites were: 80.4 +/- 2.2% (Ki = 6.6 +/- 1.3 nM) betaAR and 19.6 +/- 2.2% (Ki = 6.9 +/- 2.2 microM) beta2AR in young rats and 66.1 +/- 1.2% (Ki=8.3+/- 1.1 nM) beta1 AR and 33.9+/- 1.2% (Ki=5.2+/-0.6 PM) P2AR in old rats. Thebeta1AR/beta2AR ratio was significantly (P<0.01) reduced in old rats with respect to the younger ones.4 By combining electrophysiological and binding measurements, we calculated beta1AR and beta2ARdensities as number of receptors per microM2 of cell surface. In old rats, beta1 density was significantly decreased compared to young rats (8.4+/-2.0 vs 15.4+/-3.7 receptors microM-2, P<0.05), while beta2AR density remained unchanged at both 3 and 22 months (3.8 +/- 0.7 and 4.2+/-1.1 receptors microM-2, respectively).5 Our results demonstrate that both beta1AR and beta2AR are functionally present in rat ventricular myocytes of young and old rats. The decreased responsiveness to betaAR stimulation during aging appears to be associated with a selective reduction in the density of beta1AR.

Action Potentials↗
PubMed1995

Age and laxative use in hospitalized patients. A report of the "Gruppo Italiano di Farmacovigilanza nell'Anziano--GIFA".

Laxatives are frequently taken especially by older persons, who have multiple diseases and are disabled. Major differences exist among countries in the type of laxatives taken, and knowledge of the intake patterns is important because of the potential adverse effects associated with particular ingredients. Laxatives and factors related to their use are described in a sample of 3257 patients admitted to 58 hospitals of the Gruppo Italiano di Farmacovigilanza nell'Anziano (GIFA) in 1991. The mean age was 68.2 years, median 73 years, more than 30% were age > or = 80 years, and 48.7% were men. The overall prevalence rates of laxative use during hospital stay and prior to admission were 11.5% and 11.3%, respectively. Increasing age was independently associated with laxative use after adjusting for gender, activities of daily living, cognitive function, number of active medical problems, medications taken, Italian region and length of stay. After excluding the prescriptions for hyperammoniemia, lactulose was the most frequently taken laxative (prevalence: 6.7% during hospital stay and 4.3% prior to hospital admission), followed by anthranoid laxatives such as senna, cascara, rhein and aloe (1.9% in-hospital and 3.3% pre-hospital). Other less frequently taken laxatives were picosulfate, phenolphthalein, lactitol, glycerol, bisacodyl and docusate. These patterns differ substantially from those reported by surveys conducted in other countries. Further studies are needed to assess the risks and benefits related to the intake of specific laxative ingredients.

Age Distribution↗
PubMed1995

Synthesis of N1-substituted benzamidines. Effects on blood coagulation, platelet aggregation and antiarrhythmic activity.

A series of N1-substituted-4-alkoxybenzamidines was synthesized and tested in vitro for their inhibitory effects on blood coagulation and agonist induced platelet aggregation. The antiarrhythmic activity against chloroform-induced arrhythmias in mice was also evaluated. The biological activity of the title compounds is reported in comparison with that of procainamide; among the new products described, IVi and IVe were found to have the most potent anti-platelet and antiarrhythmic activity, respectively. The structure-activity relationships are discussed.

Action Potentials↗
PubMed1994

Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes isolated from hypertensive rats.

1. Left ventricular myocytes isolated from the heart of young (2-month-old) and old (18- to 20-month-old) spontaneously hypertensive rats (SHRs) were studied in the whole-cell configuration. Since multicellular preparations from old SHRs show a diastolic depolarization phase, we performed experiments to test whether it was associated with the presence of a hyperpolarization-activated If-like current. 2. In control Tyrode solution, a time-dependent increasing inward current activated by hyperpolarization was recorded in myocytes from old SHRs showing a diastolic depolarization phase. A barium-insensitive, caesium-sensitive, time-dependent inward current was recorded in a minority (4 of 33) of cells from young SHRs (membrane capacitance, 160 +/- 7 pF) but in 93% (25 of 27, P < 0.01) of myocytes from old SHRs (membrane capacitance, 355 +/- 19 pF, P < 0.01). 3. The current was fully activated at -120 mV and voltage of half-maximal activation was -88.1 +/- 1.5 mV; it was blocked by extracellular CsCl (4 mM) in a voltage-dependent manner. Reducing [K+]o from 25 to 5.4 mM caused a shift of the reversal potential from -17.3 +/- 3.8 to -25.7 +/- 2.7 mV and a 60% decrease of current conductance. 4. These findings suggest that an If-like current is present in rat ventricular myocytes from old SHRs, where it might favour the occurrence of spontaneous action potentials.

Action Potentials↗
PubMed1994

Electrophysiological basis for the enhanced cardiac arrhythmogenic effect of isoprenaline in aged spontaneously hypertensive rats.

We used normotensive (WKY) and spontaneously hypertensive rats (SHR) of 2, 6 and 18 months of age to get insight into the mechanisms responsible for the increased incidence of ventricular arrhythmias in hypertensive heart disease. We studied: (1) isoprenaline-induced spontaneous activity in isolated papillary muscle; (2) action potential characteristics; (3) beta-adrenoceptor and A1-adenosine receptor number and affinity; and (4) intracellular cyclic AMP (cAMP) levels. The saturation binding assay was performed in enzymatically isolated ventricular myocytes using the hydrophilic antagonist 3H-CGP 12177 for beta-adrenoceptors and 3H-DPCPX for A1-adenosine receptors. cAMP was measured by a competitive binding assay in myocytes before and after exposure to isoprenaline. Intracellular action potential was recorded from papillary muscles by means of 3 M KCl-filled glass microelectrodes. The presence of isoprenaline-induced automaticity was assessed by interrupting the electrical stimulation periodically. In isolated papillary muscles, isoprenaline (10 nM) induced spontaneous activity more frequently in 18-month-old SHR (90.0%) than in 6-(25.0%, P < 0.05) and 2-month-old SHR (0%, P < 0.001). No age-related statistically significant differences in isoprenaline-induced automaticity were observed in WKY. The incidence of isoprenaline-induced automaticity was higher in 18-month-old SHR than in age-matched WKY (22.2%, P < 0.05). KD and Bmax for beta-adrenoceptors and A1-receptors were not significantly modified in different groups. cAMP levels before and after isoprenaline stimulation were significantly lower in 18-month-old SHR than in age-matched WKY. Action potential duration (APD) was markedly prolonged in both normotensive and hypertensive rats during aging. APD was significantly prolonged in 18-month-old SHR compared to the WKY. A "diastolic depolarization", caused by the presence of delayed after-depolarizations, became apparent in the oldest animals. The slope of the delayed after-depolarization was increased by isoprenaline (1-10 nM) in 18-month-old SHR and this effect was significantly greater than that observed in 18-month-old WKY (P < 0.05). In conclusion, beta-adrenergic responsiveness is enhanced in hypertensive rats during aging, resulting in a greater incidence of abnormal automaticity. This effect does not appear to be related to changes in beta-adrenoceptor or A1-receptor density or affinity; it is likely that the electrophysiological alterations may play a role in this phenomenon.

Action Potentials↗
PubMed1994

Temperature modulates calcium homeostasis and ventricular arrhythmias in myocardial preparations.

OBJECTIVE: The aim was to evaluate the effect of temperature on reoxygenation induced ventricular arrhythmias in isolated hearts, on delayed afterdepolarisations and Iti current in Purkinje fibres, and on sarcoplasmic reticular function and Ca2+ handling of single cardiac myocytes. METHODS: Isolated guinea pig hearts were retrogradely perfused at 37 degrees C with a hypoxic medium for 15 min and reoxygenated for 10 min either at 33 degrees C or at 37 degrees C. Intracellular microelectrodes were used to assess the presence of delayed afterdepolarisations and triggered activity in sheep Purkinje fibres exposed to strophanthidin at different temperatures. Iti current was evaluated in voltage clamp experiments. In rat cardiomyocytes, loaded with the fluorescent Ca2+ dye, indo-1, the sarcoplasmic reticular Ca2+ content was assessed at 30 degrees C and at 37 degrees C, either by a caffeine spritz puffed onto a cell from a patch pipette or by a post-rest contraction. RESULTS: Hypothermic reoxygenation reduced the incidence of ventricular arrhythmias in isolated hearts (30%, n = 10, at 33 degrees C and 75%, n = 30, at 37 degrees C, p < 0.05). In Purkinje fibres, hypothermia decreased the amplitude of delayed afterdepolarisations. Moreover, at 32 degrees C, the amplitude of Iti current was decreased to 59.2(SEM 2.6)% of the normothermic value [27.5(6.7) nA, n = 4, p < 0.005] and time to peak increased to 159.7(10.2)% [value at 37 degrees C = 470(41) ms, n = 4, p < 0.01]. In cardiac cells, sarcoplasmic reticular Ca2+ release induced by caffeine spritz or by post-rest contraction was increased at 30 degrees C. However, following a pacing period at 1 Hz, hypothermia prolonged the time to onset of the first spontaneous Ca2+ oscillation [59(14) s at 30 degrees C and 27(9) s at 37 degrees C, n = 5, p < 0.05] and reduced the oscillation frequency [1.1(0.4) min-1 at 30 degrees C and 3.1(0.9) min-1 at 37 degrees C, n = 5, p < 0.05]. CONCLUSIONS: Mild hypothermia increases sarcoplasmic reticular Ca2+ content but decreases the likelihood of spontaneous Ca2+ release. This may explain the reduction of delayed afterdepolarisations and Iti current amplitude in Purkinje fibres and it could represent a mechanism for the protection provided by hypothermia against ventricular arrhythmias.

Action Potentials↗
PubMed1994

Ionic basis of action potential prolongation of hypertrophied cardiac myocytes isolated from hypertensive rats of different ages.

OBJECTIVE: The aim was to determine the ionic basis of action potential lengthening associated with cardiac hypertrophy. METHODS: Action potentials and ionic currents of left ventricular myocytes isolated from normal and hypertrophied hearts were recorded with patch pipettes. Since cardiac hypertrophy is a time dependent process, myocytes isolated from hearts of spontaneously hypertensive rats (SHR) of different ages (3 and 18 months old) were compared with those of age matched normotensive controls (Wistar Kyoto rats, WKY). RESULTS: Membrane capacitance, an index of cell size, was significantly higher in SHR than WKY. The degree of action potential prolongation was independently correlated with hypertension and its duration, resulting in a statistically significant lengthening of action potential in 18 month old SHR compared to age matched WKY and to 3 month old SHR. ICa,L density was not significantly modified in hypertrophied myocytes compared to normal controls. Depolarising steps positive to -40 mV activated an outward current, which was composed of both transient (ItO) and maintained components (Ilate) and played a major role in controlling repolarisation in rat ventricular myocytes. Ito density was significantly reduced in SHR myocytes compared to age matched WKY and was also smaller in 18 month old compared to 3 month old SHR. Ilate was not statistically different in 3 and 18 month old SHR and WKY. Current-voltage relationships for IK1 were completely superimposable in all groups. CONCLUSIONS: Prolongation of action potential in the hypertrophied heart of SHR is due to specific alterations in the repolarising potassium current Ito. The phenomenon is directly related to the duration of hypertension.

Action Potentials↗
PubMed1992

Prolonged propionyl-L-carnitine pre-treatment of rabbit: biochemical, hemodynamic and electrophysiological effects on myocardium.

Recently it has been reported that prolonged treatment with propionyl-L-carnitine, a carnitine derivative, results in a positive inotropic effect. To gain further insight into its mode of action, we pre-treated 253 rabbits for up to 10 days with daily doses of 1 mmol/kg propionyl-L-carnitine or L-carnitine intraperitoneally, using saline-treated animals as control. Twenty-four hours after the last injection, we isolated papillary muscles for electrophysiological investigations. Whole hearts were used in perfusion experiments for biochemical and hemodynamic measurements. In addition, mitochondria were harvested from these hearts for the analysis of their function. Plasma and cardiac levels of free carnitine, along with plasma short-chain acylcarnitines, increased at least two-fold after treatment with carnitine or its propionyl-ester, with concomitant rises in tissue long-chain acylcarnitine and long-chain acyl-CoA. At the time of animal sacrifice, treatment did not increase plasma or tissue propionyl-L-carnitine content. The studies carried out with perfused hearts and isolated mitochondria failed to show an effect of propionyl-L-carnitine pre-treatment on high-energy phosphate metabolism or respiration. Papillary muscles from animals, treated for 10 days, showed a lengthening of the action potential duration from 63 +/- 4 to 102 +/- 6 ms (P less than 0.001) at -10 mV. Perfused hearts from these rabbits displayed positive inotropy, as indicated by an improved pressure development at higher ventricular filling volumes, e.g., from 39 +/- 4 to 60 +/- 3 mmHg (P less than 0.05) at 3.6 ml. Pre-treatment with L-carnitine or saline failed to affect the electrophysiological and hemodynamic variables. Thus, prolonged treatment of rabbits with propionyl-L-carnitine, but not with L-carnitine, improved contractility and lengthened action potential duration in isolated muscle preparations.

Action Potentials↗
PubMed1992

Beta 1- and beta 2-adrenoceptors in sheep cardiac ventricular muscle.

The presence of beta 2-adrenoceptors in the sheep ventricular myocardium was assessed by the radioligand binding technique and functional studies. In membrane preparations, the competition curve between [3H]-dihydroalprenolol and the selective beta 1-antagonist CGP 20712A (0.1 nM-1 mM) was clearly biphasic, and revealed the presence of two different binding sites showing an affinity (pKD) for CGP 20712A of 9.5 +/- 0.9 and 4.5 +/- 0.4, respectively. The relative proportion of beta 1:beta 2 adrenoceptors was about 70:30 in both the right and left ventricle. In ventricular trabeculae driven at 1Hz, isoprenaline (1-300 nM) caused a dose-dependent increase in the force of contraction, the maximum effect being 298 +/- 26 mg, associated with reduction of time to peak tension (t1, clinotropic effect) and relaxation time (t2, 298 +/- 26 mg, associated with reduction of time to peak tension (t1, clinotropic effect) and relaxation time (t2, lusitropic effect). The inotropic dose-response curve for isoprenaline was significantly shifted to the right by pretreatment of the preparations with 0.1 microM CGP 20712A or with the selective beta 2-antagonist ICI 118551 (50 nM). In the presence of CGP 20712A (0.1 microM), isoprenaline, up to a concentration of 10 microM, did not affect either t1 or t2; on the other hand, pretreatment of the preparations with ICI 118551 (50 nM) fully antagonized the clinotropic but not the lusitropic effect of isoprenaline. In the presence of CGP 20712A procaterol (0.01-10 microM), a beta 2-adrenoceptor agonist, induced a positive intropic effect which was not associated with any significant modifications in t1 or t2. This effect was completely abolished by ICI 118551 (50 nM). The positive inotropic action of isoprenaline (1 microM) was associated with a significant decrease in action potential duration measured at -60 mV (220 +/- 8 and 193 +/- 10 ms in the absence and presence of isoprenaline, respectively; P less than 0.05). In the presence of CGP 20712A (0.1 microM) alone, isoprenaline (1 microM) still induced a significant increase in contractility but the action potential profile was only slightly affected. The effects of isoprenaline were fully antagonized by the simultaneous presence of CGP 20712A and ICI 118551 (10 nM). It is concluded that both beta 1- and beta 2-adrenoceptors appear to coexist in sheep ventricular myocardium where their stimulation mediates a positive inotropic effect. However, their functional role on the relaxation phase of the twitch may be different.

Action Potentials↗
PubMed1992

[Myocardial protection in hypothermia depends on the modulation of intracellular Ca2+ homeostasis].

The effect of a mild hypothermia (30 degrees C) on sarcoplasmic reticulum (SR) Ca2+ content and release has been evaluated in single cardiac cells loaded with the fluorescent indicator, indo-1. SR Ca2+ content, assessed by rapid caffeine application, is more pronounced at 30 than at 37 degrees C. However, hypothermia reduces the occurrence of spontaneous SR Ca2+ oscillations. In fact, following electrical stimulation, the time to onset of first SR Ca2+ oscillation was increased and their frequency reduced. Since spontaneous SR Ca2+ releases are implicated on the genesis of certain forms of ventricular arrhythmias, the protection provided by a mild hypothermia may be dependent on the modulation of intracellular Ca2+ homeostasis.

Animals↗
PubMed1991

Cardiac electrophysiological effects of a new dihydropyridine calcium antagonist (BBR 2160).

BBR 2160 is a new dihydropyridine derivative belonging to the group of the so-called tiampidines. We used intracellular microelectrodes to characterize the electrophysiological properties of BBR 2160 on sheep Purkinje fibres and guinea-pig papillary muscle. BBR 2160 (10(-7) and 10(-6) M) dose dependently decreased the contractility of driven Purkinje fibre and papillary muscle. This effect was associated with a lowering of the plateau phase and a shortening of action potential duration in papillary muscle. The effect of the drug developed quite slowly over time. The amplitude and Vmax of normal action potential were not affected by BBR 2160. Instead BBR 2160 reduced the amplitude and Vmax of the slow action potentials (which are a relatively good index of the slow inward current) induced by histamine (10(-5) M) in K(+)-depolarized (22 mM) papillary muscle. The results suggest that BBR 2160 has calcium-antagonistic properties in cardiac tissue.

Action Potentials↗
PubMed1991

Lack of correlation between the antiarrhythmic effect of L-propionylcarnitine on reoxygenation-induced arrhythmias and its electrophysiological properties.

1. The antiarrhythmic effect of L-propionylcarnitine (L-PC) was evaluated in the guinea-pig isolated heart; arrhythmias were induced with hypoxia followed by reoxygenation and by digitalis intoxication. 2. L-PC 1 microM, was found to be the minimal but effective antiarrhythmic concentration against reoxygenation-induced ventricular fibrillation. No antiarrhythmic effect was observed against digitalis-induced arrhythmias. D-Propionylcarnitine, L-carnitine and propionic acid did not exert antiarrhythmic effects. 3. During hypoxia and reoxygenation L-PC consistently prevented the rise of the diastolic left ventricular pressure, and significantly reduced the release of the cardiac enzymes creatine kinase (CK) and lactic dehydrogenase (LDH). 4. The electrophysiological effects of L-PC were then studied on either normal sheep cardiac Purkinje fibres or those manifesting oscillatory after potentials induced by barium or strophanthidin. 5. L-PC (1 and 10 microM) did not significantly modify action potential characteristics and contractility of normal Purkinje fibres, or the amplitude of OAP induced by strophanthidin or barium. 6. It is concluded that the antiarrhythmic action of L-PC on reoxygenation-induced arrhythmias is not correlated with its direct electrophysiological effects studied on normoxic preparations.

Animals↗
PubMed1991

Implantable pharmacological defibrillator (AIPhD): preliminary investigations in animals.

The treatment of ventricular fibrillation (VF) by means of automatic implantable cardioverter defibrillators (AICD) poses many severe problems and limitations at the present time. In order to overcome these problems, we propose a totally new way to terminate VF or ventricular sustained tachycardia (VST). Our proposal consists of replacing the electric shock, which is dangerous, delayed, and sometimes ineffective, with a "chemical" shock: i.e., a chemical bolus retroperfused in the coronary sinus (CS) immediately after VF arises. The possible device is hypothesized and preliminary investigations in animals, performed to verify the theoretical assumption, are presented. In rabbits, and in larger animals (sheep and swine). Drugs were perfused in the coronary bed: lidocaine was used in 86% and bretylium tosylate in 14% of the animals. The results were: lidocaine immediately terminated VF in 100% and sinus rhythm was restored in rabbits; lidocaine terminated VF in VST in sheep; and in swine, bretylium immediately produced sinus rhythm in one case; in another one, only delayed sinus rhythm was achieved but lasted a short time; in the last case ventricular tachycardia at 128 beats/min appeared. Because new drugs, which are really "defibrillating" drugs, are available (bretylium tosylate, bethanidine, clofilium, tricyclic antidepressants, phenotiazine derivatives), we plan to investigate these defibrillating drugs in isolated hearts, found in suitable animals like dogs (sheep and swine are difficult to defibrillate) and in humans during routine electropharmacological studies.

Animals↗
PubMed1991

Cellular electrophysiological basis for oxygen radical-induced arrhythmias. A patch-clamp study in guinea pig ventricular myocytes.

BACKGROUND: Oxygen radicals have been implicated in the pathogenesis of reperfusion arrhythmias. However, the basic electrophysiological alterations accompanying the effects of oxygen radicals on action potential (AP) are poorly understood. METHODS AND RESULTS: We investigated the effects of oxygen radicals generated by dihydroxyfumarate (DHF, 5 mM) on AP parameters and on ionic currents in patch-clamped guinea pig ventricular myocytes. DHF consistently caused a marked prolongation of AP duration, which was already significant after 60 seconds of exposure and continued to increase over time. Within 5 minutes, the majority of cells developed early afterdepolarizations (EADs) or became unexcitable. Both AP prolongation and occurrence of EADs were completely prevented in the presence of the oxygen radical scavengers superoxide dismutase (SOD) and catalase (CAT). Prolongation of AP duration was accompanied by a marked decreased in time-dependent potassium current (IK) and calcium current (ICa). The inward rectifier K current (IK1) was unaffected, suggesting no widespread changes in membrane properties. IK and ICa alterations were also significantly reduced by SOD and CAT. In additional experiments, intracellular calcium levels were kept constantly low by addition of 200 microM ethyleneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetra-acetic acid (EGTA) to the pipette solution. Under these conditions, the effects of DHF on AP duration and the occurrence of EADs were largely prevented. However, EGTA did not prevent cells from becoming unexcitable, nor did it affect the decrease in both IK and ICa upon exposure to DHF. CONCLUSIONS: Exposure to an exogenous source of oxygen radicals may induce major electrophysiological alterations in isolated myocytes, which might be related to changes in specific ionic currents and in level of intracellular calcium. These alterations occur with a time course consistent with the rapid onset of ventricular arrhythmias in reperfused hearts.

Action Potentials↗