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S Visentin

Publications and source records attributed to S Visentin.

At least 37 records · Page 2Linked to original sources
PubMed1998

New 1,4-dihydropyridines conjugated to furoxanyl moieties, endowed with both nitric oxide-like and calcium channel antagonist vasodilator activities.

A series of 4-phenyl-1,4-dihydropyridines substituted at the ortho and meta positions of the phenyl ring with NO-donating furoxan moieties and their non-NO-releasing furazan analogues were synthesized and pharmacologically characterized. The vasodilator activities of these compounds were evaluated on rat aorta and expressed as EC50 values or as EC50iGC values when obtained in the presence of inhibitors of guanylate cyclase methylene blue (MB) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Affinities to 1, 4-DHP receptors on Ca2+ channels, expressed as IC50 values, were determined through displacement experiments of [3H]nitrendipine on rat cortex homogenates. A linear correlation between IC50 and EC50 values was found for compounds unable to release NO. EC50calcd values for derivatives containing NO-donor moieties, expression of the Ca2+-blocking component of their vasodilator activity, were interpolated on this linear regression. They showed a good correspondence with EC50iGC values determined in the presence of soluble guanylate cyclase inhibitors. Analysis of EC50iGC/EC50 ratios provided a useful tool to distinguish well-balanced hybrids from derivatives biased toward Ca2+-blocking or NO-dependent vasodilator activity. A detrimental effect on affinity to the 1, 4-DHP receptor, due to substitution at the ortho and meta positions of the 4-phenyl ring, was observed. SAR to explain this effect is proposed.

Animals↗
PubMed1998

Reproducibility of computerized ECG measurements and coding in a nonhospitalized elderly population.

The standard 12-lead electrocardiogram (ECG) is used in many epidemiologic studies to diagnose and predict cardiovascular disease. In view of this, knowledge about the reproducibility of ECG measurements and coding is essential. Minute-to-minute, day-to-day, and year-to-year variability of ECG measurements, composite scores, and Minnesota Code classification were assessed by use of a computer program, in 101 nonhospitalized elderly men and women. Interval ECG measurements were more reproducible than amplitude measurements. The best reproducibility was found for the overall QTc interval (coefficient of variation 3.1%, 4.0%, and 5.2% for the minute-to-minute, day-to-day, and year-to-year groups, respectively) and the poorest was found for the Cardiac Infarction Injury Score (coefficient of variation 67.1%, 78.5%, and 94.3%, respectively). Minnesota Code discrepancies occurred in 16%, 19%, and 22% of the ECGs in the minute-to-minute, day-to-day, and year-to-year groups, respectively. Reproducibility within specific code categories was much better. Overall, variability tended to increase with time. In the routine setting, electrode positioning had relatively little effect on total variability.

Aged↗
PubMed1998

Arachidonic acid-induced inhibition of microglial outward-rectifying K+ current.

In cultured microglial cells pro-inflammatory substances such as lipopolysaccharide and interferon-gamma induce outward-rectifying K+ channels (OR) exhibiting features of the Kv1.3 type. Here we studied the modulation of this channel by arachidonic acid (AA). Micromolar doses of AA (0.3-30 microM; ED50 1.55 microM) depressed OR currents at all the potentials tested. Such effect appeared in less than 30 s, reached the maximum in approximately 2 min, and partially reverted upon removal of AA. We then tested whether AA acted by mechanisms involving enzyme activation. The AA effect on OR remained unchanged in the presence of staurosporine (protein kinase C inhibitor), indomethacin (cyclooxygenase inhibitor), nordihydroguaiaretic acid (lipoxygenase inhibitor), and diphenylene iodonium (NADPH-oxidase inhibitor). The same effect was present in cell-free membrane patches in the outside-out configuration. In whole-cell recording AA induced the following changes in OR current: (a) decrease of OR current peak at all voltages tested; (b) increase of the activation rate and mild shift of the voltage-dependence of the activation; (c) acceleration of the inactivation rate with a concomitant appearance of a second and faster inactivation component; and (d) shift of the voltage-dependence of the inactivation curve. We also observed that upon AA application, the acceleration of activation and inactivation developed earlier than the second component of inactivation. We conclude that AA, by acting on both the channel protein and its lipid environment, causes a quick negative modulation of microglial OR current. We propose that a raised free AA may determine a loss of efficiency of OR in controlling the membrane potential and thus influence the functional reactivity of microglia to inflammatory stimuli.

Animals↗
PubMed1997

Protein kinase C involvement in the resting and interferon-gamma-induced K+ channel profile of microglial cells.

The whole-cell configuration of the patch-clamp technique was used to study the involvement of protein kinase C (PKC) in the modulation of K+ channels in cultured microglia from newborn rats. We previously showed that 24-hr treatments with interferon-gamma (IFN-gamma) induce an increase of inward-rectifying (IR) and outward-rectifying (OR) current density and that the effect on OR was shared by bacterial lipopolysaccharide (LPS) (Visentin et al.: J Neurosci Res 42:439-451, 1995). In the present study, IFN-gamma (1-500 U/ml, 24 hr) enhanced IR current density up to threefold. The IFN-gamma effect was not detectable after shorter treatments (1-5 hr) and was abrogated by a protein synthesis inhibitor. The PKC activator phorbol myristate acetate (PMA) also increased IR current density, whereas the inactive alpha-4 isoform was ineffective. When IFN-gamma and PMA were co-applied, the effect was more than additive. Among the PKC inhibitors tested, staurosporine (STA)-but not calphostin C (CALP)-abolished the effect of IFN-gamma and of PMA and antagonized only partially that of co-applied IFN-gamma and PMA. OR currents were affected by treatment (24 hr) with PKC modulating agents in an opposite fashion. PMA depressed OR currents in control and in IFN-gamma (or LPS) treated cultures, even when added after pretreatment (with LPS) that was long enough to enhance OR channel expression. Both STA and CALP enhanced OR density in resting and IFN-gamma-stimulated cells but did not counteract the depressing effect of PMA. In conclusion, our data on IR suggest a relationship between the IFN-gamma effect on current density and PKC activation. However, we cannot conclude with certainty that IFN-gamma acts through PKC activation. Our data on OR support an inverse relationship between PKC activation and OR current density. Nevertheless, the lack of effect of PKC inhibitors on PMA-induced OR depression suggests that PMA may, in this case, act on a target different from PKC.

Animals↗
PubMed1995

Ion channels in rat microglia and their different sensitivity to lipopolysaccharide and interferon-gamma.

In order to study the voltage-dependent ion channels in microglia, and their possible modulation by pro-inflammatory substances like lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) we employed the patch-clamp technique on purified rat microglial cell subcultures grown for 1 - 5 days in control condition or after a 24 hour treatment with those agents. Regardless of the culture condition, almost 100% of the cells presented inward-rectifying (IR) K+ currents identified by the following features: (a) extracellular K(+)-dependence of Vrev and whole-cell conductance; (b) inward-rectifying property; (c) channel blocking mechanism by Cs+; and (d) single channel conductance of 27 pS. A 'n' type outward-rectifying (OR) K+ current was present in 30% of the cells during the first 2 days of subcultivation. Its occurrence was strongly dependent on the preparation, varying from 0% to almost 80%, and it decreased to 13% of the cells after three days in culture. It showed the following features: (i) threshold of activation close to -30 mV; (ii) sigmoid current onset; (iii) voltage-dependent kinetics; and (iv) sensitivity to 4-aminopyridine (4-AP) and tetraethylammonium (TEA). Furthermore, we detected two ion currents not previously described in microglia: (i) a slowly activating outward current which appeared at potentials more positive than +20 mV and with a reversal potential close to 0 mV, tentatively identified as a proton current; and (ii) a Cl- conductance identified in ion substitution experiments as the current sensitive to the Cl- channel blocker SITS. The two agents, LPS (20 - 2,000 ng/ml) and IFN-gamma (10 - 100 u/ml), shared the following effects: (a) enhancement of membrane capacitance, and (b) increase of OR current amplitude and frequency of occurrence. Moreover, IFN-gamma was also able to increase IR current density, especially in cells with ameboid morphology, while LPS was ineffective. We conclude that the voltage-dependent ion channel pattern of microglia is more complex than previously thought and that activating agents such as LPS and IFN-gamma share some electrophysiological effects, but differ in others.

Animals↗
PubMed1994

Effects of cocaine on the serotonin-induced inward current in rat nodose ganglion neurons.

Application of 5-hydroxytryptamine (5-HT) to freshly isolated rat nodose ganglion neurons produced a fast inward current when measured using the whole-cell patch-clamp technique. This current was blocked by the 5-HT3 receptor antagonist MDL72222. The selective 5-HT3 receptor agonist 2-methyl-5-HT induced a similar current. Cocaine (0.1-300 microM) applied simultaneously with 5-HT (0.25-50 microM) inhibited the 5-HT-induced current. The inhibition did not appear to be voltage dependent. If cocaine was preapplied for about 30 sec, the effect of cocaine on 5-HT current was increased. Both the peak and the steady-state 5-HT current was depressed by cocaine. However, the peak current was more sensitive to cocaine than the steady-state current. The concentration-response curves of cocaine in different agonist concentrations revealed that cocaine competitively inhibited the 5-HT3 receptor-mediated current with a pA2 value of 5.8 and an apparent KD of 1.6 microM. These results suggest that in addition to the other well known mechanisms, the 5-HT3 receptor-ion channel complex is another site for cocaine action.

Animals↗
PubMed1990

Sodium current block caused by group IIb cations in calf Purkinje fibres and in guinea-pig ventricular myocytes.

The action of group IIb cations [Cadmium (Cd2+), Zinc (Zn2+), Mercury (Hg2+)] on the cardiac fast sodium current (INa) was investigated in calf Purkinje fibres and in ventricular cells isolated from guinea-pig hearts. In calf Purkinje fibres, INa was depressed by submillimolar concentrations of Zn2+ and Hg2+. With both cations, the current reduction occurred at all voltages in the range of current activation and the voltage dependence of peak current was unchanged. The degree of peak current inhibition depended on the cation concentration but not on voltage. The position of the inactivation curve on the voltage axis was unaltered at cation concentrations giving substantial current inhibition, and moved to the right only with concentration exceeding 1-1.5 mM. These effects can be interpreted as due to INa channel blockade. The action of Zn2+ and Hg2+ was similar to that described earlier of Cd2+ on Purkinje fibres (DiFrancesco et al. 1985b). INa was also inhibited by group IIb cations in isolated guinea-pig ventricular cells. Depression of INa by Cd2+, Zn2+ and Hg2+ was essentially voltage-independent, in agreement with its being caused by channel block. The dependence of INa block by Cd2+ upon external Na concentration [Na+0] was investigated in ventricular myocytes. The fraction of INa block by 0.1 mM CdCl2 was 0.50 at 140 mM, 0.81 at 70 mM and 0.83 at 35 mM [Na+]0. A similar increase of block efficiency at low [Na+0] was observed with 0.05 mM CdCl2. In both the Purkinje fibre and the ventricular cell, the order of potency of INa block by group IIb cations was Hg2+ greater than Zn2+ greater than Cd2+. Manganese (Mn2+, 2-5 mM), an ion of group VIIa, also depressed the INa in Purkinje fibres and ventricular myocytes. This effect was however due mainly to a positive shift on the voltage dependence of current kinetics rather than to a reduction of the conductance of the channel (GNa), and can be accounted for by an ion-screening action of Mn2+ on the external membrane surface. The block by group IIb cations is a typical property of cardiac Na+ channels and characterizes the cardiac as opposed to other types of Na+ channel.

Animals↗
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.

Action Potentials↗
PubMed1990

Adenosine-induced changes in atrial action potential: contribution of Ca and K currents.

In this study, we examined the relative contribution of the increase in acetylcholine-regulated potassium current (IK ACh) and decrease in calcium current (ICa) to the adenosine (Ado)-induced shortening of action potential duration (APD). In isolated guinea pig atrial myocytes, membrane potentials and currents were measured by the whole cell patch-clamp technique. ICa and IK ACh were individualized by blocking the K currents with Cs+ and ICa with Cd2+. The effects of Ado on membrane potential and currents were concentration dependent. Ado (10 microM) shortened APD at 0 mV and at 90% of repolarization (APD0,90) to 7 +/- 1 and 26 +/- 6 ms from control values of 23 +/- 3 and 89 +/- 6 ms, respectively. Concomitant with the changes in APD, Ado decreased ICa from -9.2 +/- 1.3 to -6.8 +/- 10 microA/microF (26% decrease) but increased IK ACh from +3.5 +/- 0.5 to +7.8 +/- 0.8 microA/microF (123% increase). When rundown of ICa was taken into account, the maximum decrease in ICa caused by Ado was 12%. The effect of Ado on ICa and IK ACh was not altered by treatment of the cells with either Cs+ or Cd2+. The shortening of ADP0,90 strongly correlated with the increase in IK ACh but minimally with the decrease in ICa. A 22% reduction in ICa caused by lowering extracellular Ca2+ concentration ([Ca2+]o) from 3.6 to 1.8 mM was associated with an 11 and 14% shortening of APD0 and APD90, respectively. In the same myocytes an 18% decrease in ICa by 10 microM Ado reduced APD0 and APD90 by 58 and 61%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1989

Enhanced sensitivity of heart cells to adenosine and up-regulation of receptor number after treatment of guinea pigs with theophylline.

Experiments were carried out in hearts from guinea pigs that were fed either the adenosine receptor antagonist theophylline (0.6 mg/ml) or no drug. The A1 adenosine receptor radioligand [125I]aminobenzyladenosine bound to a single affinity class of receptors in heart cell membranes from control animals with Bmax and KD of 18.3 +/- 1.0 fmol/mg protein and 3.7 +/- 0.6 nM, respectively (n = 8). Heart cell membranes from animals fed theophylline for 2, 7, and 14 days bound the radioligand with about the same affinity, but the number of binding sites was significantly increased (p less than 0.01) to 30.6 +/- 1.7 (n = 3), 30.0 +/- 0.8 (n = 3), and 27.3 +/- 2.9 (n = 4), respectively. Nearly identical results were obtained with membranes prepared from enzymatically dispersed ventricular myocytes. Fourteen days of theophylline treatment also produced a small increase (12%, p less than 0.01) in the number of binding sites in membranes derived from cerebral cortexes. Isolated ventricular myocytes prepared from animals fed no drug or theophylline for 7 days were used to determine the effect of adenosine on 20 nM isoproterenol-stimulated calcium current (ICa) measured by the whole-cell patch-clamp technique. Adenosine reduced isoproterenol-stimulated ICa without affecting the activation or inactivation kinetics of the current; ICa density was reduced less by 5 microM adenosine in cells from control (25 +/- 3 to 21 +/- 3 microA/microF) than in cells from theophylline-fed animals (26 +/- 5 to 17 +/- 2 microA/microF). Although a high concentration (0.5 mM) of adenosine abolished isoproterenol-stimulated ICa in cells from control or theophylline-fed animals, the IC50 for adenosine was sixfold less in cells derived from theophylline-fed animals than in cells from control animals (4.6 +/- 0.6 microM and 28.3 +/- 1.4 microM, respectively, p less than 0.01). In contrast, the increase in ICa in response to isoproterenol alone and the potency of acetylcholine to antagonize this effect of isoproterenol were the same in both groups of cells. A maximally effective concentration of R-phenylisopropyladenosine (0.1 mM) inhibited isoproterenol-stimulated cyclic AMP accumulation less in cardiomyocytes from control than from theophylline-fed animals (28.7 +/- 1.8% vs. 42.0 +/- 4.2%, p less than 0.05). In summary, exposure of the myocardium to theophylline increases the number of adenosine receptors and the effects of receptor occupancy by agonists. These findings imply that the endogenous concentration of adenosine is high enough in the normoxic guinea pig heart to chronically maintain adenosine receptors in a partially down-regulated state.

Acetylcholine↗
PubMed1987

Electrophysiological effects mediated by the stimulation of cardiac beta 2-adrenoceptors with tulobuterol.

We studied the electrophysiological effects of the specific beta 2-agonist tulobuterol in the guinea-pig sinus node and in sheep cardiac Purkinje fibers. Stimulation of beta 2-adrenoceptors by tulobuterol resulted in a slight increase in the rate of firing of the sinus node. In Purkinje fibers, however, automaticity was not affected up to concentrations of 10(-6) M. Consistently, tulobuterol (10(-8)-10(-6) M) did not affect the pacemaker current studied under voltage-clamp conditions. In the same range of concentrations (10(-8)-10(-6)M) tulobuterol dose-dependently increased the contractile force of driven Purkinje fibers. Tulobuterol, at a very high concentration (10(-5) M), had membrane depressant effects as demonstrated by the block of automaticity induced in the spontaneously beating Purkinje fibers and by the reduction of the maximum rate of depolarization in driven preparations. Our results suggest that stimulation of beta 2-adrenoceptors with tulobuterol in sheep Purkinje fibers is associated with an inotropic rather than a chronotropic effect. On the whole, the data confirm the lack of cardiac side effects of tulobuterol.

Adrenergic beta-Agonists↗
PubMed1986

The role of temperature on the development of oscillatory afterpotentials and triggered activity.

Increasing evidence suggests that calcium dependent oscillatory afterpotentials (OAP) may play a pivotal role in the genesis of reperfusion-induced arrhythmias. Many factors may influence the vulnerability of the heart to reperfusion arrhythmias, some of which may possibly affect the development of OAP. Since intramyocardial temperature changes during ischemia and reperfusion, it may be speculated that the rapid rewarming of the ischemic area during reperfusion favors the development of associated arrhythmias. We thought it important to examine the effects of sudden changes in temperature on OAP and subsequent triggered activity. Evidence is presented that raising the bath temperature from 34 degrees C to 37 degrees C causes a transient increase above the control level of the OAP amplitude, and that if the OAP is large enough to reach the threshold a triggered rhythm ensues. These results suggest that sudden rewarming of calcium overloaded cell (as it happens during reperfusion of the ischemic myocardium) may favor the development of abnormal automaticity due to OAP.

Animals↗
PubMed1985

Cadmium-induced blockade of the cardiac fast Na channels in calf Purkinje fibres.

The fast transient inward current elicited by depolarizations above about -60 mV in calf Purkinje fibres was found to be depressed by Cd in concentrations less than 1 mM. The Cd-sensitive current, which strongly depended on external Na, was recorded in the presence of 2 mM MnCl2 and was blocked by TTX, indicating that a contamination from slow Ca-dependent currents could be discounted. The current reduction caused by Cd was also observed in nominally Ca-free solutions. The Cd-induced depression of the fast Na current was not accompanied by changes in the current kinetic parameters, as revealed by comparing inactivation curves and peak current voltage relations at different Cd concentrations, and could be attributed to a voltage-independent channel blocking action. Half-blockade occurred at 0.182 +/- 0.06 mM (n = 4). Plots of peak current amplitude as a function of the Cd concentration showed that the cooperation of two Cd ions was required to block a single channel.

Animals↗