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Biomedical subjects

A Mugelli

Publications and source records attributed to A Mugelli.

15 recordsLinked to original sources
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.

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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.

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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

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.

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PubMed1990

Cardiac electrophysiologic effects of a new calcium antagonist, lacidipine.

Lacidipine is a new 1,4-dihydropyridine derivative with potent and long-lasting antihypertensive activity. We used intracellular microelectrodes to characterize the electrophysiologic properties of lacidipine on different cardiac preparations. Lacidipine (10(-8) -10(-6) M) dose-dependently decreased contractility of driven sheep Purkinje fibers. For concentrations less than or equal to 10(-7) M, this effect was associated with a selective decrease of the plateau height. Higher concentrations (3 X 10(-7) and 10(-6) M), however, affected action potential amplitude, overshoot, and maximum rate of depolarization. In the same range of concentrations, lacidipine did not affect normal automaticity of guinea-pig sinus node and sheep Purkinje fibers. Lacidipine (10(-6) M) consistently blocked barium-induced abnormal automaticity in Purkinje fibers and reduced the amplitude and Vmax of the slow action potentials induced by histamine (10(-5) M) in guinea pig papillary muscle depolarized by potassium (22 mM). The effect of lacidipine on the slow inward current (Isi) was studied in shortened Purkinje fibers under voltage-clamp conditions. Lacidipine (10(-7)-10(-6) M) reduced the Isi without affecting the I-V relationship. None of the effects of lacidipine was reversed by 2-h washout. The results indicate that lacidipine has calcium-antagonistic properties in cardiac tissues. Its cardiac effects occur at concentrations 100 times higher than those active in the vascular smooth muscle. The lack of recovery of the lacidipine effects suggests that its interaction with the calcium channel may occur at an inner site of the cell membrane.

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PubMed1977

Studies on the positive inotropic effect of dopamine in the guinea-pig heart.

The positive inotropic effect of dopamine has been studied in isolated ventricular strips of guinea-pig heart. The concentration-inotropic response curve for dopamine was significantly shifted to the right by pretreatment with reserpine. In preparations obtained from animals pretreated with reserpine (2.5 mg/kg, 24 h prior to the experiment) the dose-response curve was not significantly affected by haloperidol, a dopamine vascular receptor antagonist (10(-6)-3X10(-6) M). The inotropic effect of dopamine was antagonized by practolol (3X10(-7)-10(-6) M), but not by phentolamine (3X10(-6)-10(-5) M); moreover the alpha-adrenoceptor blocking drug (10(-5) M) did not affect the curve for dopamine in the presence of practolol (3X10(-7) M). In preparations in which fast sodium channels were blocked by K+ -rich medium, slow electrical responses (calcium-mediated action potentials) as well as contractions were induced by high concentrations of dopamine (10(-4)-3X10(-4) M); again these responses were unaffected by phentolamine or haloperidol, but were blocked by practolol. It was concluded that in the guinea-pig ventricular muscle dopamine induced a positive inotropic effect through both indirect and direct action, and that the latter is due to the activation of beta-adrenoceptors.

Animals↗
PubMed1977

A histamine-induced decrease of action potential duration in cardiac muscle mediated by the H2 receptors.

The effects of histamine (10(-7)--10(-5) M) on the cardiac action potential have been studied in ventricular strips of guinea pig heart, electrically driven at a constant rate. A decrease of action potential was constantly observed at histamine concentrations above 10(-6) M. No significant variations of the other electrophysiological parameters were induced by the amine. The decrease in the duration of the action potential was blocked by burimamide at a concentration (10(-4) M) which induced only a slight changes in action potential outline. It is suggested that the shortening of the repolarization phase induced by histamine is due to the H2 receptor-mediated activation of the calcium inward current, which can increase the intracellular calcium concentration influencing the potassium permeability.

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PubMed1976

Frequency dependence of the alpha-adrenoceptor-mediated positive inotropic effect in guinea pig heart.

Evidence for the role of alpha-adrenoceptors in the production of a positive inotropic effect has been obtained chiefly in heart preparations stimulated at a low rate (1 or 1.4 Hz). However, our previous results suggested that the alpha-receptor-mediated positive inotropic effect could be frequency dependent. In the present study cumulative concentration-inotropic effect curves were obtained in guinea pig ventricle strips treated with adrenaline and stimulated at 1 and at 2.5 Hz. Phentolamine (3 X 10(-6) M) and practolol (10(-6) M) were employed as antagonists. Phentolamine antagonized the effect of low concentrations of adrenaline (10(-9)-10(-8) M) in preparations driven at 1 Hz, but did not modify the curve of the agonist at the higher stimulation rate. In preparations driven at 1 Hz, practolol antagonized the effect of adrenaline at concentration above 3 X 10(-8) M without affecting the curve at lower concentrations, the beta-blocker competitively anatagonized the effect of the agonist at 2.5 Hz. It was concluded that a shortening of the interval between beats abolishes the alpha-mediated positive inotropic effect.

Animals↗
PubMed1975

Studies on the positive inotropic effect of phenylephrine: a comparison with isoprenaline.

1. The effects of phenylephrine and isoprenaline on the isometric contraction of guinea-pig ventricle were compared over the whole range of their respective dose-response curves. 2. In preparations driven at 2.5 Hz the increase in contractile force induced by either isoprenaline of phenylephrine was linearly correlated to an increase in maximum velocity of force development. The relaxation time was shortened by isoprenaline but not by phenylephrine. 3. The negative inotropic effect induced by delta [N-(3,4-dimethoxyphenethyl)-N-methyl-amino]-alpha-(3,4,5-trimethoxyphenyl)alpha-isopropylvaleronitrile hydrochloride (D(600)) was reversed by isoprenaline, but little influenced by phenylephrine. 4. The study of the interval-force relationship shows that the increase in contractile force induced by phenylephrine (3 X 10(-5) M) was relatively greater at low frequencies of stimulation, and that the maximum effect was reached at the frequency of 1 Hz. 5. The positive inotropic effect of phenylephrine (10-4 M) was significantly higher at a frequency of 1 Hz than at 2.5 Hz; the effect of isoprenaline (3 x 10-8 M) was not significantly different at the two driving frequencies. 6. In preparations driven at 1 Hz the inotropic effect of the lower concentrations of phenylephrine was due to an increase in the time to peak tension without any change of the maximum velocity of force development; however an increase of this parameter became evident only after higher concentrations of the amine (10-5 M or more), associated with a progressive shortening of the time to peak. 7. A correlation between mechanical and electrophysiological effects of phenylephrine is attempted; the suggestion is advanced that the prolongation of the action potential and of the active state duration may be an important factor in the inotropic effect of phenylephrine.

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