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Biomedical subjects

A R Mattiazzi

Publications and source records attributed to A R Mattiazzi.

At least 19 recordsLinked to original sources
PubMed2001

Angiotensin II and cardiac excitation-contraction coupling: questions and controversies.

Angiotensin II (AngII) is a circulating peptide that produces a positive inotropic effect in the heart in several species, including humans. The subcellular mechanisms involved in producing this effect have been the focus of numerous studies; however, the results of these studies have generated considerable controversy. Although part of the controversy might arise from species and developmental differences, conflicting results have also been reported in the same species. To further complicate the understanding of the cardiac actions of AngII, the binding of the peptide to its transmembrane G-protein-coupled receptors has been shown to activate signalling cascades that involve numerous second messengers. Among these, inositol 1,4,5-triphosphate (IP3) and protein kinase C (PKC) have been shown to have the potential to modulate either one or both of the two basic mechanisms known to increase contractility: (i) an increase in the intracellular Ca2+ concentration ([Ca2+]i); or (ii) an increase in myofilament responsiveness to Ca2+. The aim of this review is to examine the effect of AngII on the fundamental components of cardiac excitation-contraction coupling: calcium currents, Na+/Ca2+ exchange, sarcoplasmic reticulum (SR)-CaZ+ release, calcium transients and contractile proteins. An answer to the following question is sought: Is the positive inotropic effect of AngII due to an increase in [Ca2+]i, to an increase in myofilament responsiveness to Ca2+, or to both?

Journal Article↗
PubMed1999

Chronic administration of nifedipine induces up-regulation of functional calcium channels in rat myocardium.

Previous studies from our laboratory demonstrated the up-regulation of cardiac dihydropyridine (DHP) receptors in rabbits chronically treated with nifedipine (NIFE). The goal of the present study was to further examine the functionality of this increased number of receptors by analysing different steps of excitation contraction coupling mechanism in adult rats chronically treated with NIFE (a single 10-mg oral dose/kg/day for 28 days). Ca2+ channel density was assessed by specific binding at the DHP receptors with [methyl-(3)H]PN 200-110 in rat ventricular membranes. Chronic NIFE treatment produced up-regulation of Ca2+ channels, being the maximal binding capacities 222+/-19 fmol/mg protein (n=14) and 310+/-21 fmol/mg protein (n=11) in untreated and treated animals, respectively (P<0.05). The functional consequences of this up-regulation of Ca2+ channels were determined in isolated ventricular myocytes by measuring L-type Ca2+ currents (I(Ca)) with the whole-cell configuration of patch-clamp technique and by intracellular Ca2+ (Ca2+(i)) transients estimated by the Indo-1/AM fluorescence ratio (410/482) simultaneously monitored with cell shortening. Peak I(Ca) density recorded at 0 mV was 32% greater in myocytes isolated from the treated group than in those obtained from the untreated group (-10.43+/-0.73 pA/pF (n=13) vs-7.10+/-0.59 pA/pF (n=12) P<0.05). Ca2+(i) transient amplitude and cell shortening, explored at 1 and 2 mM extracellular calcium ([Ca]0) were significantly higher in ventricular myocytes obtained fom NIFE-treated rats than in myocytes isolated from untreated animals. At 2 mM [Ca]0, the values of Ca2+(i) transient and shortening were 460+/-61 nM and 11+/-1 % of resting length (L(0)) in myocytes from treated rats (n=9) and 212+/-22 nM and 5.3+/-0.5% of L(0) in myocytes from control rats (n=6, P<0.05). The results demonstrate an up-regulation of functionally-active cardiac Ca2+ channels after NIFE treatment, and offer a possible explanation for a "withdrawal effect" at myocardial level after the suppression of the treatment with this drug.

Animals↗
PubMed1998

Evidence for an electrogenic Na+-HCO3- symport in rat cardiac myocytes.

1. The perforated whole-cell configuration of patch clamp and the pH fluorescent indicator SNARF were used to determine the electrogenicity of the Na+-HCO3- cotransport in isolated rat ventricular myocytes. 2. Switching from Hepes buffer to HCO3- buffer at constant extracellular pH (pHo) hyperpolarized the resting membrane potential (RMP) by 2.9 +/- 0.4 mV (n = 9, P < 0.05). In the presence of HCO3-, the anion blocker SITS depolarized RMP by 2.6 +/- 0.5 mV (n = 5, P < 0.05). No HCO3--induced hyperpolarization was observed in the absence of extracellular Na+. The duration of the action potential measured at 50 % of repolarization time (APD50) was 29.2 +/- 6.1 % shorter in the presence of HCO3- than in its absence (n = 6, P < 0.05). 3. Quasi-steady-state currents were evoked by voltage-clamped ramps ranging from -130 to +30 mV, during 8 s. The development of a novel component of Na+-dependent and Cl--independent steady-state outward current was observed in the presence of HCO3-. The reversal potential (Erev) of the Na+-HCO3- cotransport current (INa,Bic) was measured at four different levels of extracellular Na+. A HCO3-:Na+ ratio compatible with a stoichiometry of 2:1 was detected. INa,Bic was also studied in isolation in standard whole-cell experiments. Under these conditions, INa,Bic reversed at -96.4 +/- 1.9 mV (n = 5), being consistent with the influx of 2 HCO3- ions per Na+ ion through the Na+-HCO3- cotransporter. 4. In the presence of external HCO3-, after 10 min of depolarizing the membrane potential (Em) with 45 mM extracellular K+, a significant intracellular alkalinization was detected (0.09 +/- 0. 03 pH units; n = 5, P < 0.05). No changes in pHi were observed when the myocytes were pre-treated with the anion blocker DIDS (0.001 +/- 0.024 pH units; n = 5, n.s.), or when exposed to Na+-free solutions (0.003 +/- 0.037 pH units; n = 6, n.s.). 5. The above results allow us to conclude that the cardiac Na+-HCO3- cotransport is electrogenic and has an influence on RMP and APD of rat ventricular cells.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1983

Negative inotropic effect of verapamil, nifedipine and prenylamine and its reversal by calcium or isoproterenol.

The type of antagonism between verapamil, nifedipine or prenylamine and calcium or isoproterenol on myocardial contractility, was investigated in cat papillary muscles. Dose response curves to calcium or to isoproterenol were performed in the absence and presence of a single dose of either verapamil, nifedipine or prenylamine. Non significantly different maximum values of tension (T) and maximal rate of rise of tension (+dT/dtmax) were obtained at the "plateau" of the dose responses curves to calcium in the absence and presence of the slow channel inhibitors. The (Ca2+)50, i.e. the calcium concentration necessary to obtain 50% of the maximal effect (T or +dT/dtmax), was significantly greater in the presence of the calcium channel blockers (Lineweaver-Burk method). The decrease in time to peak tension (TTP) associated with the negative inotropic effect of calcium channel blockers was also completely off-set by the addition of extra calcium. A Shild plot with a slope close to the unity confirmed simple competitive antagonism between calcium and nifedipine or prenylamine but not between calcium and verapamil. Isoproterenol was unable to completely overcome the negative inotropic effect of verapamil 10(-5) M and nifedipine 5 X 10(-7) M on T and +dT/dtmax. In addition, it enhanced the decrease in TTP produced by these two calcium entry blockers. The results do not support the view of a competitive antagonism between isoproterenol and verapamil or nifedipine on myocardial contractility. They also indicate that in restoring the decrease in myocardial contractility produced by calcium channel blockers, it is not the same to add extra calcium than isoproterenol.

Animals↗
PubMed1981

Effects of fatigue and altered pH on isometric force and velocity of shortening at zero load in frog muscle fibres.

temporaria (0.9-2.5degrees C) were stimulated to produce a 1 s isometric tetanus at regular intervals until constant mechanical responses were attained. Various degrees of force depression ("fatigue") were produced by decreasing the contraction interval from 30 or 15 min (control to 120, 60, 30 and 15s, respectively. In this was the steady-state tetanic force could be reversibly reduced to approximately 70% of the control value. The velocity of shortening at zero load, V0, was determined at each level of fatigue using an approach for direct measurement of V0. V0 was not significantly affected as long as the decrease in force was less than 10%. With further reduction of the isometric tension there was a progressive decline of V0 according to the following empirical relationship between percentage depression of force (delta P0) and maximum speed (delta V0) of shortening: delta V0 = 0.006 delta P02.48- 1.0 (correlation coefficient, 0.86). Cine photographic recording of nylon markers on the fibre surface provided evidence that fatigue developed uniformly along the fibre with no sign of failure of excitation in any segment. The change in mechanical performance during fatigue could be reproduced inthe non-fatigued fibre by reducing the pH of the external medium within the range 8.0-6.6 using a bicarbonate-CO2 buffer. A decrease in pH thus reduced both the rate of rise and the total amplitude of isometric force and prolonged the relaxation phase. Furthermore, there was a drop in V0 that was related to the force decline in approximately the same way as observed during fatigue. The results support the idea the fatigue involves both a reduced state of activation of the contractile system and a specific (activation independent) inhibition of crossbridge turnover. Increased intracellular H+ concentration is likely to contribute to the development of both these effects during fatigue.

Animals↗
PubMed1981

Shortening fraction: its dependence on the Starling mechanism.

The influence of increasing muscle length (ML) from L0 to 15 to 20% of L0 and calcium concentration (Ca2+) from 1.34 to 10 mmol . litre-1 on shortening fraction has been analysed in cat papillary muscles. Shortening fraction was calculated by dividing the amount of shortening by the muscle length at which that shortening occurred. When the muscle shortened at contrast total load, increasing muscle length from approximately or equal to L0 to approximately or equal to 15% above L0, increased the shortening fraction from 0.2 +/- 0.1% to 7.1 +/- 0.7% (P less than 0.01) and from 1.0 +/- 0.5% to 12.2 +/- 0.5% (P less than 0.01) at low and high (Ca2+) respectively. The highest shortening fraction values obtained (7 and 12%) correspond to calculated ejection fraction values of 20 and 32% respectively. At a given muscle length, increasing (Ca2+) significantly increased the shortening fraction (P less than 0.01). At constant afterload the shortening fraction increased from 3.5 +/- 1% to 9.1 +/- 1.9% when the muscle length changed from approximately or equal to 5% to approximately or equal to 20% above L0 and from 3,3 +/- 1.6% to 14.3 +/- 0.7% when the muscle was stretched from L0 to approximately or equal to 20% above L0 at low and high calcium respectively. Shortening fraction values of 9 and 14% correspond to calculated ejection fraction values of 25 and 37% respectively. The results indicate that the shortening fraction is altered not only by changes in cardiac contractility but also by the Starling mechanism.

Animals↗
PubMed1981

Positive inotropic and relaxant effects of papaverine on cat papillary muscle.

The effects of papaverine and isoproterenol on the isometric twitch and high KCl-induced contractures were compared in papillary muscles from reserpinized cats. Papaverine (10(-5) M) significantly increased developed tension (T), maximal rate of rise of tension (+dT/dt max) and maximal velocity of relaxation (--dT/dt max) in 52.3 +/- 6.1, 74.1 +/- 6.7 and 82.1 +/- 12.1% respectively with respect to control values. Time to peak tension (TTP) and contracture tension decreased in 9.1 +/- 2.0% and 50.9 +/- 5.6% respectively with respect to controls (P less than 0.05). Isoproterenol in a dose (8 X 10(-10) M), that produced an increase in +dT/dt max non significantly different to the one elicited by papaverine (65.6 +/- 9.0%), increased (in % with respect to control values), T in 55.3 +/- 7.3, --dT/mx in 73.8 +/- 13.1 and decreased TTP in 6.6 +/- 1.1 and contracture tension in 40.7 +/- 6.3 (P less than 0.05). The effects of isoproterenol on all the parameters studied were not statistically different from the ones of papaverine. It is concluded that in cat papillary muscles, papaverine has a positive inotropic action and an isoproterenol-like relaxant effect.

Animals↗
PubMed1977

Lack of effect of hypercapnic acidosis on elasticity of cat papillary muscles.

Chages in external pH from 7.40 to 6.95 obtained by changing the pCO2 of the medium at constant bicarbonate concentration produced in cat papillary muscles a significant decrease in isometric tension with no changes in time to peak tension. Active and resting stiffness, as determined by two different methods, did not change under conditions of hypercapnic acidosis.

Animals↗
PubMed1977

Effect of hypercapnic acidosis on induction of arrhythmias by catecholamines in cat papillary muscles.

The effect of changes in PCO2 upon induction of arrhythmias in cat papillary muscles was studied. The average norepinephrine (NE) dose necessary to produce spontaneous contractions in muscles stimulated at rates of 10/min was higher at high PCO2. Whereas 2 100 +/- 295 X 10(-8) mol/litre of NE was necessary during acidosis, only 824 +/- 295 X 10(-8) mol/litre was necessary to produce spontaneous contractions in alkalosis. In quiescent muscles, the necessary doses in acidosis and alkalosis were 2 209 +/- 531 X 10(-8) and 518 +/- 159 X 10(-8) mol/litre respectively. With isoproterenol 458 +/- 84 X 10(-8) mol/litre was necessary to reach the end point at high PCO2, whereas only 131 +/- 52 X 10(-8) mol/litre was required at low PCO2. The lower sensitivity to catecholamine-induced arrhythmias with hypercapnic acidosis does not appear to be related to the re-uptake of the neurotransmitter by the nerve ending since it is also present with isoproterenol.

Acid-Base Equilibrium↗
PubMed1976

The influence of temperature on the time course of the mechanical activity in rabbit papillary muscle.

The influence of temperature on the time course of the mechanical activity was investigated in isolated papillary muscles of the rabbit. By using the "damped release" technique activity curves were determined in terms of velocity of shortening of the contractile unit at a constant length. At any of the temperatures studied, the time course of the mechanical activity exhibited a slow onset and did not form a distinct plateau. At low contraction frequencies and normal (2 mM) calcium concentration lowering the temperature from 32.5 to 26.5 degrees C did not markedly affect the rate of development of the activity but increased the peak amplitude and the total duration of the activity as well as the time from the stimulus to 90% of the maximum. It also resulted in a slower decay phase. At higher contraction frequencies and/or increased calcium concentration the rate of development of the activity was reduced by decreasing the temperature from 32.5 degrees C to 26.5 degrees C, whereas the maximal activity reached similar levels at the two temperatures. It is concluded that an alteration in temperature affects several different steps in myocardial excitation-contraction coupling, the net change in maximum amplitude of the mechanical activity being influenced by both extracellular calcium concentration and contraction frequency.

Animals↗
PubMed1975

Depression of human myocardial contractility with "respiratory" and "metabolic" acidosis.

The effect of a similar degree of "respiratory" and "metabolic" acidosis was studied in seven isolated in vitro human pectinate muscles and eight ventricular muscle bundles. Either "respiratory" or "metabolic" acidosis (from 7.36 plus or minus 0.03 to 7.01 plus or minus 0.02 and 6.98 plus or minus 0.03, respectively) depressed in vitro contractility in human atrial or ventricular muscle to a similar extent. Previous contradictory responses of myocardial tissue to alterations in pH appear to be the result of species differences.

Acidosis↗