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Biomedical subjects

A J Pappano

Publications and source records attributed to A J Pappano.

At least 55 records · Page 3Linked to original sources
PubMed1986

Carbachol inhibits electrophysiological effects of cyclic AMP in ventricular myocytes.

Muscarinic agonists inhibit beta-adrenoceptor-mediated electrophysiological effects in mammalian cardiac ventricular tissues. However, the site or sites of interaction are not entirely clarified. To address this problem, the effect of carbachol on isoproterenol-, 3-isobutyl-1-methylxanthine-, and forskolin-induced action potential changes was examined in guinea pig ventricular myocytes. Following enzymatic dispersion, myocytes had a resting membrane potential of -81.3 +/- 3 mV in 5.4 mM K+ Tyrode solution, and stimulated action potentials were 348 +/- 17 ms in duration (n = 17). Elevated extracellular [K+] ([K+]o) depolarized the membrane 56.5 mV per 10-fold increase in [K+]o. The estimated intracellular K+ activity was 115.7 mM. Carbachol (10(-6) M) alone produced no electrophysiological changes but antagonized isoproterenol-, 3-isobutyl-1-methylxanthine-, and forskolin-induced action potential prolongation by 84 +/- 11, 88 +/- 17, and 83 +/- 14%, respectively. Transient depolarizations produced in isoproterenol (10(-8) M), 3-isobutyl-1-methylxanthine (10(-5) M), and forskolin (10(-7) M), but not those produced in ouabain (10(-6) M), were antagonized by carbachol (10(-6) M). These data show that enzymatically dispersed myocytes maintain pharmacological and electrophysiological properties similar to those of cells in tissues, carbachol antagonizes electrophysiological effects of isoproterenol, 3-isobutyl-1-methylxanthine, and forskolin, and carbachol inhibits cyclic AMP-mediated effects at a site or sites in the cyclic AMP cascade distal to the catalytic unit of adenylate cyclase.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Comparison of muscarinic receptor properties in hatched chick heart atrium and ventricle.

We have reported previously that chick myocardium responds to muscarinic agonists with a decrease in slow inward current in both atrial and ventricular muscle. A second ionic current, the background potassium current, is increased in the atrium but not in the ventricle. A possible explanation for the modulation of potassium current in atrium only is the existence of a unique muscarinic receptor population in atrium responsible for potassium conductance changes. We looked for differences in atrial and ventricular muscarinic receptors by pharmacological and biochemical techniques. The dissociation constants for binding of l-[3H]quinuclidinyl benzilate were 46 pM in both tissues. Estimates for binding of atropine in competitive binding experiments gave dissociation constants of 1.8 nM in atrium and 2.0 nM in ventricle. Pharmacologic evaluation of atropine occupancy of muscarinic receptor by Schild analysis showed no difference in the dissociation constants in atrium (1.7 nM) and ventricle (1.1 nM). Displacement of 0.1 nM [3H]quinuclidinyl benzilate with carbachol showed the atrium to have a higher apparent affinity for agonist than the ventricle (atrium IC50 = 8.2 X 10(-6) M, ventricle IC50 = 2.1 X 10(-5) M). Computerized curve fitting analysis detected three binding states (super high, high and low affinity) for carbachol in the atrium and ventricle in the absence and presence of 5'-guanylylimidodiphosphate (10(-4) M). We did not detect a qualitative difference between atrial and ventricular muscarinic receptors. Muscarinic-induced potassium conductance changes which occur in the atria do not appear to be due to a unique muscarinic receptor in atria.

Animals↗
PubMed1985

Cellular actions and pharmacology of calcium-channel blockers.

The calcium-channel blockers represent a diverse group of chemical structures that block calcium-selective channels in the plasma membrane of a variety of excitable cells. As the calcium fluxes carried by these channels allow ionic calcium (Ca2+) to gain access to the cell interior, where Ca2+ serves as an activator--messenger, calcium-channel blockers generally act to inhibit cell function. By reducing the depolarizing currents caused by the entry of positively charged Ca2+ into the negatively charged interior of resting cells, the calcium-channel blockers also inhibit excitatory processes that depend on calcium entry across the plasma membrane. These principles account for most of the effects of calcium-channel blockers on the cardiovascular system. In vivo, the calcium-channel blockers inhibit contractile function in the heart and vascular smooth muscle and, because the initial depolarizing currents in the sinoatrial and atrioventricular nodes are carried by calcium channels, slow the heart rate and prolong atrioventricular conduction. However, in vivo in human studies, there are differences among the calcium-channel blockers. The vasodilatory effects of the calcium channel blockers, which can reduce systemic blood pressure, offer a primary basis for their potential use in the treatment of hypertension. The tissue specificity exhibited by some of the calcium-channel blockers may enhance their therapeutic value in selected hypertensive patients. Of the three calcium-channel blockers now available for use in the United States (diltiazem, nifedipine, and verapamil), diltiazem and verapamil are approximately equipotent in inhibiting calcium-channel function in cardiac and vascular smooth muscle, whereas nifedipine is more potent in vascular smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1985

beta-Adrenoceptor agonist accelerates recovery from inactivation of calcium-dependent action potentials.

The voltage-activated Ca2+ channel in cardiac muscle plasma membranes is regulated by beta-adrenoceptor agonist, presumably by cyclic AMP-dependent phosphorylation of membrane proteins associated with this channel. In chick ventricle, we find that isoproterenol accelerates the recovery from inactivation of the maximum rate of rise (Vmax) of Ca2+-dependent action potentials without changing the steady-state inactivation of Vmax. These results confirm and extend those of others who found that beta-adrenoceptor agonists accelerated the repriming kinetics of bullfrog atrial Ca2+ current (iCa) channels. Patch clamp experiments showed that beta-adrenoceptor agonists change the kinetics of iCa channels so as to increase the probability that an iCa channel is available to open, primarily by reducing the intervals between bursts of channel openings. It is concluded that the altered kinetics of iCa channel repriming caused by beta-adrenoceptor agonist in multicellular preparations is consistent with the action of these drugs in increasing the probability of channel opening and the time spent in the open state.

Action Potentials↗
PubMed1985

Pertussis toxin treatment blocks hyperpolarization by muscarinic agonists in chick atrium.

Atrial and ventricular adenylate cyclase activity and atrial membrane potentials were measured in hearts from hatched chicks at 2-3 days after intravenous administration of pertussis toxin (0.5-1.0 micrograms, total) or saline. Both in atrium and ventricle, treatment with pertussis toxin antagonized inhibition by carbachol of basal and isoproterenol-stimulated adenylate cyclase activity without changing either basal or isoproterenol-stimulated adenylate cyclase. In atria from pertussis toxin-treated animals (5.4 mM potassium), carbachol hyperpolarized the resting membrane by 0.3 +/- 0.3 mV (n = 9) and did not increase resting potassium conductance. In contrast, carbachol hyperpolarized the resting membrane by 4.5 +/- 0.8 mV (n = 11) and increased resting potassium conductance more than 4-fold in saline-treated animals. Carbachol did not significantly affect the atrial action potential peak or duration at 50% repolarization of pertussis toxin-treated animals. This muscarinic agonist reduced action potential peak by 7.8 +/- 1.2 mV and the duration at 50% repolarization by 22.1 +/- 3.0 msec in atria from saline-treated animals. Pertussis toxin treatment also prevented the negative inotropic effect and the inhibition of calcium-dependent action potentials caused by carbachol in atrial muscle. Neither the affinity nor the maximal specific binding of [3H]quinuclidinyl benzilate in ventricular homogenates was changed by pertussis toxin treatment. The apparent affinity of carbachol for muscarinic receptor was slightly (approximately 2-fold) diminished in pertussis toxin-treated animals. The inhibition of carbachol-induced hyperpolarization by pertussis toxin treatment implicates a guanosine 5'-triphosphate-dependent protein (Ni or a similar protein) as an essential link that permits muscarinic receptor to regulate atrial potassium channels.

Action Potentials↗
PubMed1985

The parasympathetic neuroeffector junction of the heart.

This review has directed attention to the anatomical, biochemical, physiological, and pharmacological features of cardiac parasympathetic neuroeffector transmission. The relationships among these properties have permitted a synthesis of the operation of the parasympathetic nervous system at the subcellular, cellular, tissue, and organ level in the heart. However, the attempt to obtain a comprehensive model of parasympathetic neuroeffector transmission in the heart has not only unmasked many features of junctional activity that are poorly understood, but also indicated significant gaps between in vitro and in vivo experimental situations.

Acetylcholine↗
PubMed1985

A role for adenylate cyclase in the subsensitivity to isoproterenol during ontogenesis of the embryonic chick ventricle.

Isoproterenol (ISO) increases contractility and cyclic AMP content in ventricles of embryonic and hatched (H) chicks. A transient decrease in beta agonist sensitivity for both effects (10-fold shift in ISO EC50) is seen in 18-day embryos (18 E) (Pappano and Biegon, 1982). Beta adrenoceptor-coupled adenylate cyclase (AC) and receptor binding were characterized in 14,000 X g ventricular particulates from 10 to 11E, 17 to 19E and 1-week-old chicks (5-6H). The concentration for half-maximal enzyme activation (Kact) for ISO [+100 microM 5'-guanylylimidodiphosphate (Gpp(NH)p)]-stimulated AC is greatest in the 17 to 19E (1.6 microM vs. 0.1-0.2 microM in the 5-6H and 10-11E). Maximal enzyme activity in the presence of ISO + Gpp(NH)p (picomoles of cyclic AMP/20 min X mg of protein), however, is greatest in the 10 to 11E (2018 +/- 80 vs. 1020 +/- 80 and 1120 +/- 60 in the 17 to 18E and 5 to 6H, respectively). The Kact values for NaF and Gpp(NH)p are the same for all three ages (2.4 mM and 8 microM, respectively), whereas maximal activity with these effectors of the regulatory and catalytic protein-dependent AC decreases with increasing age. Neither the Kact nor maximal activity of catalytic AC, assessed with MnCl2 and forskolin, changes with age. The respective Kact values for MnCl2 and forskolin are 0.3 mM and 4 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1984

Cellular actions and pharmacology of the calcium channel blocking drugs.

The calcium channel blockers represent a group of diverse chemical structures that block calcium-selective channels in the plasma membranes of a variety of excitable cells. As the calcium fluxes carried by these channels allow the calcium ion (Ca2+) to gain access to the cell interior, where calcium serves as an activator messenger, calcium channel blockers generally act to inhibit cell function. By reducing the depolarizing currents caused by the entry of positively charged Ca2+ into the negatively charged interior of resting cells, the calcium channel blockers also inhibit excitatory processes that depend on calcium entry across the plasma membrane. These principles account for most of the effects of calcium channel blockers on the cardiovascular system. The calcium channel blockers inhibit contractile function in the heart and vascular smooth muscle and, because the initial depolarizing currents in the sinoatrial and atrioventricular nodes are carried by calcium channels, slow the heart rate and prolong atrioventricular conduction. The negative inotropic and vasodilatory effects of the calcium channel blockers, both of which can reduce systemic blood pressure, offer a theoretic basis for their potential use in the treatment of hypertension. The tissue specificity exhibited by some of the calcium channel blockers may enhance their therapeutic value in selected hypertensive patients. Of the three calcium channel blockers now available for use in the United States (diltiazem, nifedipine, and verapamil), diltiazem and verapamil are approximately equipotent in inhibiting calcium channel function in the heart and vascular smooth muscle, whereas nifedipine is more potent in smooth muscle. This tissue specificity can be used to advantage in the management of hypertension. These pharmacologic principles underlie the growing appreciation of the potential value of the calcium channel blockers in the treatment of hypertension.

Action Potentials↗
PubMed1984

Block of avian cardiac fast sodium channels by tetrodotoxin is enhanced by repetitive depolarization but not by steady depolarization.

The blockade of Na+ channels by tetrodotoxin (TTX) was studied in the avian heart with the maximum rate of rise (Vmax) of phase 0 of the action potential used as an indicator of Na+ conductance (gNa). Inhibition by TTX of Vmax occurred at lower concentrations (IC50 congruent to 20 nM) than those reported in mammalian hearts (IC50, 1 to 10 microM). The IC50 was not affected by K+-induced membrane depolarization. Inhibition of closed Na+ channels by TTX was demonstrated and the degree of inhibition was increased by repetitive excitation. The time constant for recovery (tau Rec) from inactivation of Vmax was increased by TTX, a result consistent with the ability of the toxin to trap Na+ channels in the inactivated state. Reduction of the external Na+ concentration [( Na+]0 by 50% reduced the IC50 5.3-fold. This shift can largely be accounted for by the non-linear relationship between Vmax and gNa, that is, there need not be an important effect of [Na+]0 on toxin binding to its receptor. The interaction between TTX and its receptor in the avian heart is about as sensitive as that observed in peripheral nerve. However, like its less-sensitive mammalian heart counterpart, the TTX-Na+ channel interaction is frequency-dependent and apparently little influenced by membrane voltage or [Na+]0.

Animals↗
PubMed1984

Development of different electrophysiological mechanisms for muscarinic inhibition of atria and ventricles.

The negative inotropic effect of acetylcholine (ACh) in atrial muscle can be accounted for by a decrease of a voltage- and time-dependent slow inward current (Isi) carried by Ca2+/Na+ and an increase of outward time-dependent current carried by K+ (IK1) through inwardly rectifying channels. The negative inotropic effect of ACh in ventricular muscle is associated with a reduction of Isi; there is no important effect of ACh on IK1 in ventricular muscle. Because atrial and ventricular muscles display IK1 that is sensitive to Ba2+ and have similar numbers of muscarinic receptor sites, it is concluded that ventricular muscle lacks a metabolic link between the muscarinic receptor and inwardly rectifying K+ channels. Although there is much evidence for cyclic nucleotides as the mediator between muscarinic receptors and Isi channels, cyclic nucleotides do not seem to connect these receptors with inwardly rectifying K+ channels. According to this hypothesis, identification of a metabolic link between muscarinic receptors and IK1 channels should be demonstrable in atrial but not ventricular muscle.

Acetylcholine↗
PubMed1983

L-palmitylcarnitine and calcium ions act similarly on excitatory ionic currents in avian ventricular muscle.

Palmitylcarnitine, an amphiphile that accumulates in and leaks from ischemic heart tissue, affected the fast sodium ion channel and the slow calcium channel in avian ventricular muscle. In the presence of 5.4 mM external potassium ion, palmitylcarnitine reduced the maximum rate of rise of the action potential and increased action potential duration at the plateau level without changing the resting potential. Steady state inactivation of the maximum rate of rise, an index of fast sodium ion current, was shifted by 3-6 mV to more positive potentials by palmitylcarnitine. Elevation of external calcium ion to 5.4 mM (normal = 1.8 mM), like palmitylcarnitine, reduced the maximum rate of rise and shifted the voltage at which the action potential was half maximum by 3 mV to more positive potentials without changing the resting potential. Elevated external calcium ion, unlike palmitylcarnitine, reduced the duration of action potentials initiated from a resting potential of -80 mV. Palmitylcarnitine and elevated external calcium ion increased the amplitude, the maximum rate of rise, and duration of calcium ion dependent action potentials recorded in the presence of 25 mM [K+]0 that completely inactivated the fast sodium ion channel. Steady state inactivation of the maximum rate of rise of calcium-dependent action potentials was consistently shifted to more positive potentials by palmitylcarnitine (3 mV) and by elevated external calcium ion (6 mV) when the initial external calcium ion was 0.9 mM. Palmitylcarnitine, like elevated calcium, evoked a positive inotropic effect in the presence of propranolol. The similarity of the effects of palmitylcarnitine (3 X 10(-5) to 3 X 10(-4)M) with those of elevated external calcium is consistent with the hypothesis that palmitylcarnitine, like elevated external calcium, influences sodium and calcium channel operation by an effect on membrane surface charge.

Action Potentials↗
PubMed1983

A comparative study of the blockade of calcium-dependent action potentials by verapamil, nifedipine and nimodipine in ventricular muscle.

The electrophysiological and chemical properties of the Ca++-channel blocking drugs verapamil, nifedipine and nimodipine were compared. In avian ventricular muscle depolarized by 25 mM K+-saline, the primary Na+ conductance was inactivated and the peak of action potential varied by 30 mV/10-fold change in extracellular Ca++. A double reciprocal plot of the maximum rate of rise vs. [Ca++]0(-1) yielded a straight line, a result consistent with the surface density hypothesis for the electrogenic permeation of cell membranes by Ca++. Verapamil, nifedipine and nimodipine caused the peak of action potential to deviate significantly from its Ca++-electrode property. Verapamil, but not nifedipine or nimodipine, blocked the Ca++-dependent action potential in a frequency-dependent manner. However, the dihydrophyridines (nifedipine and nimodipine) and verapamil were similar insofar as they inhibited the maximum rate of rise of the Ca++-dependent action potential competitively at concentrations less than or equal to 10(-6) M. These results are consistent with the hypothesis that low concentrations of these drugs inhibit the Ca++-dependent action potential by reducing the secondary inward current which is carried largely by Ca++. At higher concentrations, blockade of the maximum rate of rise by all of the Ca++-channel blocking drugs could not be described as competitive, noncompetitive or uncompetitive. The inability to describe the equilibrium actions of high concentrations of verapamil, nifedipine and nimodipine in such terms may arise from drug effects on membrane currents in addition to secondary inward current.

Action Potentials↗
PubMed1982

Acetylcholine inhibits positive inotropic effect of cholera toxin in ventricular muscle.

Acetylcholine (ACh, 10(-6) M) had no effect on basal adenylate cyclase activity (3.4 +/- 0.56 pmol cyclic AMP . min-1 . mg wet wt-1), adenosine 3',5'-cyclic monophosphate (cyclic AMP) content (0.88 +/- 0.09 pmol/mg wet wt), or the force of contraction in paced (2.5 Hz) chick embryo right ventricles superfused with Tyrode solution. After 60-180 min of superfusion in the presence of cholera toxin (5 x 10(-6) g/ml), adenylate cyclase activity (1.7 times), cyclic AMP content (2.4 times), and contractility (2.4 times) had increased significantly above basal levels. ACh reversed the positive inotropic effect of cholera toxin but did not change the increased activity of adenylate cyclase and content of cyclic AMP obtained in cholera toxin. Stimulation of adenylate cyclase by isoproterenol (ISO) was inhibited by ACh in the absence and presence of cholera toxin. ACh did not change guanosine 3',5'-cyclic monophosphate (cyclic GMP) content in the absence or presence of cholera toxin. Cholera toxin has actions on chick embryo ventricle similar to those of the beta-adrenergic agonist, ISO, and the phosphodiesterase inhibitor, isobutylmethylxanthine. The ability of ACh to reverse the positive inotropic effect of cholera toxin without preventing the accumulation of cyclic AMP may involve the prevention or reversal of cyclic AMP-dependent phosphorylation. In this regard, reduction of Ca2+ influx through voltage-sensitive membrane channels may be an essential component of muscarinic inhibition.

Acetylcholine↗
PubMed1981

Developmental changes in the sensitivity of the chick embryo ventricle to beta-adrenergic agonist during adrenergic innervation.

As early as the 4th embryonic day, the ventricle of the chick embryo responded to isoproterenol (Iso) with an increase in the force of contraction; at all ages studied, this positive inotropic effect was accompanied by an increased rate of tension development. There was a transient, 10-fold decrease in the sensitivity (increase in ED50) of the right ventricle to Iso between the 16th and 21st embryonic day. This change in the sensitivity to Iso was not due either to an increased inactivation of Iso by non-neuronal cells or to a change in the thickness of the ventricle. It was found that adrenergic nerves were first capable of altering ventricular contractility on the 16th embryonic day. Whereas they interfered with the function of adrenergic nerves, injections of reserpine or 6-hydroxydopamine had no effect on the subsensitivity to Iso. Furthermore, these agents did not affect the normal developmental changes in heart weight. We conclude that the local release of transmitter from adrenergic nerves does not cause the transient subsensitivity of the ventricle of the chick embryo to beta-adrenergic agonists.

Adrenergic beta-Agonists↗