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G T Wetzel

Publications and source records attributed to G T Wetzel.

36 records · Page 2Linked to original sources
PubMed1994

Sodium-calcium exchange in neonatal myocardium: reversible inhibition by halothane.

Neonatal myocardium is distinctly more sensitive to extracellular calcium levels than is mature myocardium. This has been ascribed to the poorly developed sarcoplasmic reticulum of neonatal myocardium. Recent evidence has suggested that there is an increased dependence of neonatal myocardium on the sodium-calcium exchange current, and that sodium-calcium exchange may be a major source of calcium influx in neonatal myocardial cells. We determined the effect of halothane on the sodium-calcium exchange current on single neonatal (2- to 5-day-old) rabbit ventricular myocytes by means of the whole cell voltage clamp. Lower (1.5%) halothane decreased sodium-calcium exchange current by 49%, from 29 +/- 3 to 15 +/- 6 pA. Higher (3%) halothane decreased this current by 66%, from 50 +/- 9 to 17 +/- 9 pA. Thus halothane has a reversible inhibition of sodium-calcium exchange current in neonatal myocardium. Inhibition of sodium-calcium exchange current would be expected to have a magnified effect on contractility in neonatal as opposed to adult myocardium, and could theoretically ameliorate reperfusion injury due to influx of calcium via the sodium-calcium exchanger.

Animals↗
PubMed1993

Ca2+ channel kinetics in acutely isolated fetal, neonatal, and adult rabbit cardiac myocytes.

Measurement of transsarcolemmal voltage-gated Ca2+ current (ICa) in myocytes isolated from immature rabbit heart has demonstrated an unexpectedly low level of Ca2+ channel activity. We have characterized the kinetic properties of ICa in acutely isolated 21-day fetal, 1-5-day-old neonatal, and adult cardiac myocytes by the whole-cell voltage-clamp technique. The membrane potential for half-maximal steady-state inactivation became less negative with maturation (-24 +/- 3 [mean +/- SEM] mV, n = 5; -19 +/- 2 mV, n = 5; and -11 +/- 2 mV, n = 6 for fetal, neonatal, and adult myocytes, respectively; p < 0.005). In contrast, the membrane potential for half-maximal steady-state activation was not statistically different among the age groups studied. These parameters accurately predicted the voltage dependence of the sustained ICa present at the end of a 400-msec depolarization. This "window" current was significantly smaller in immature cells than in adult cells and occurred at a more negative membrane potential in the younger age groups. The time course of inactivation of ICa was not significantly different between age groups. However, ICa was inhibited by increasing the frequency of stimulation. This effect was most prominent in immature cells, particularly at more positive holding potentials. This developmental alteration in the frequency dependence of ICa was due in part to a prolonged time constant of recovery from inactivation in the younger age groups. In summary, the kinetic properties of ICa in immature cardiac cells place them at a relative disadvantage in terms of the total Ca2+ influx during a depolarization. Thus, the role of ICa in the control of cell contraction may change with development.

Aging↗
PubMed1992

Acute effects of amiodarone on sodium currents in isolated neonatal ventricular myocytes: comparison with procainamide.

Recent studies suggest that amiodarone's acute clinical effects in infants and children are related predominantly to its class I antiarrhythmic activity. However, the effects of amiodarone on Na+ currents have not been investigated directly in immature cardiac cells. Accordingly, the tight seal whole cell voltage clamp technique was used to measure time- and voltage-dependent Na+ currents in acutely isolated neonatal ventricular myocytes from 2- to 5-day-old rabbits, before and after addition of amiodarone (0.1-10 microM). To evaluate the class I antiarrhythmic activity of amiodarone in this age group, the effects of amiodarone on Na+ currents were compared with those of procainamide. Similar to procainamide, amiodarone significantly decreased peak inward Na+ current in neonatal ventricular myocytes. Moreover, both amiodarone and procainamide shifted the steady-state inactivation curve to more negative membrane potentials and delayed recovery of the Na+ current from inactivation. Thus, the effects of amiodarone on the Na+ current in immature myocardium are qualitatively similar to those of procainamide, suggesting that amiodarone may act acutely as a class I antiarrhythmic agent in the newborn heart.

Amiodarone↗
PubMed1992

Developmental changes in membrane Ca2+ and K+ currents in fetal, neonatal, and adult rabbit ventricular myocytes.

Whole-cell calcium current (ICa) and inwardly rectifying potassium current (IK1) were studied in 21-day fetal, 28-day fetal (total gestation, 31 days), 2-5-day neonatal, and adult rabbit ventricular myocytes isolated by enzymatic dissociation. Whole-cell peak ICa and IK1 at -100 mV increased significantly after birth. Cell size approximated from cell membrane capacitance also increased with age, with the most significant increase occurring after birth. When normalized to cell surface area, peak ICa density increased from day 21 of gestation to the neonate and then increased again from neonate to adult. In all age groups, peak ICa occurred at a test potential of +10 mV, and the shape of the Ca2+ current-voltage relation did not change with age. These findings suggest that there are no significant developmental changes in the voltage dependence of ICa. Therefore, the measured age-related increase in Ca2+ current density may result from increased channel expression. IK1 also exhibited a pattern of increasing current density with age. For IK1, the increase in current density was most rapid between day 21 and the perinatal period and much slower after birth. These results demonstrate that ICa and IK1 undergo significant changes during late fetal and postnatal development.

Action Potentials↗
PubMed1992

ATP-sensitive potassium channels in neonatal and adult rabbit ventricular myocytes.

The properties of the ATP-sensitive potassium (KATP) current were studied in freshly isolated rabbit ventricular myocytes using the patch clamp technique. Removing ATP from the bath (intracellular) solution activated a large K+ conductance in patches from neonatal cells with properties similar to those of KATP channels in other preparations. In membrane patches from neonatal ventricular myocytes, the density of KATP channels was higher than the density of inwardly rectifying K+ channels and the mean patch KATP current was approximately 10 times that of the inwardly rectifying K+ current, at a patch membrane potential of -60 mV. Glibenclamide (10 microM) in the bath solution decreased the number of functional KATP channels, the open-state probability, and the mean patch membrane current. The single-channel conductance of the KATP channel was dependent on the external K+ concentration, and the relationship between channel conductance and external K+ concentration was fit by an exponential equation. In addition, the voltage dependence, channel density, and open-state probability of this channel were compared between neonatal and adult isolated ventricular myocytes. The single-channel conductance and channel density of the KATP channel in neonatal myocytes were significantly smaller than in adult cells. These results suggest that age-related changes occur in the properties of KATP channels.

Action Potentials↗
PubMed1991

Single-channel recording of inwardly rectifying potassium currents in developing myocardium.

Properties of the inwardly rectifying K+ channel, which contributes to the maintenance of the resting membrane potential, were studied in neonatal rabbit ventricular myocytes using the patch-clamp technique. Inward rectification was evident in single-channel current-voltage (I-V) relations at potentials positive to the potassium equilibrium potential (Ek = 0 mV with [K+]o = [K+]i = 150 mM, [Mg2+]i = 2 mM). The single-channel conductance was 3.2 +/- 0.1 pS in physiological (5.4 mM) [K+]o. The zero-current potential shifted 48.4 +/- 2.4 mV for a ten-fold change in [K+]o in neonatal cells. External Ba2+ blocked the current in a dose-dependent manner. The voltage dependence, open-state probability and channel density of this channel were compared between neonatal and adult ventricular myocytes isolated by similar techniques. The open-state probability of the channel was approximately the same in neonatal (0.39 +/- 0.06, n = 13) as in adult cells (0.4 +/- 0.05, n = 11). However, in symmetrical transmembrane K+ concentration [( K+]o = [K+]i = 150 mM), the single channel conductance was significantly smaller in neonatal (25 +/- 0.3 pS, n = 25) as compared with adult cells (31 +/- 0.4 pS, n = 12). In addition, the relationship between resting membrane potential and [K+]o was measured in neonatal and adult myocytes. The resting membrane potential in the neonate was less dependent on [K+]o than in the adult. These results are consistent with an age-related change in resting membrane K+ permeability which may result from a developmental change in the single-channel conductance properties of the inwardly rectifying K+ channel.

Action Potentials↗
PubMed1991

Calcium current and tension generation in immature mammalian myocardium: effects of diltiazem.

Single sucrose gap and isolated myocyte voltage-clamp techniques were used to study the effects of diltiazem on calcium current (ICa) and tension generation in isolated ventricular myocytes and right ventricular papillary muscles from neonatal New Zealand White rabbits. Diltiazem was shown to significantly shorten the duration of isolated myocyte action potentials with no effect on overshoot potential or resting membrane potential. Diltiazem blocked but did not completely abolish ICa in these neonatal cells. Addition of diltiazem to the solution bathing papillary muscles resulted in a similar reduction in action potential duration accompanied by a reduction in twitch tension. When the duration of depolarization was controlled employing the single sucrose gap voltage clamp, the decrease in tension development caused by diltiazem was abolished despite a significant decrease in twitch tension in the same muscles. In another series of experiments it was demonstrated that the magnitude of developed tension in neonatal papillary muscles is dependent upon the duration of depolarization. Taken together, the results of this investigation suggest that in neonatal myocardium when ICa is blocked by diltiazem, the resulting reduction in developed tension is caused in part by reduction of action potential duration. The calcium carried into the neonatal heart cell by ICa does not appear to be the only source of extracellular Ca2+ for excitation-contraction coupling. Finally, the action potential appears to act as a gate for calcium movement into the neonatal heart cell.

Action Potentials↗
PubMed1991

Calcium current measurements in acutely isolated neonatal cardiac myocytes.

Action potentials and voltage clamp-induced ionic currents were recorded in acutely isolated neonatal rabbit cardiac myocytes using the whole-cell voltage clamp technique. Time- and voltage-dependent Ca2+ currents in neonatal myocytes were elicited by depolarizations from a holding potential of -80 mV to various clamp potentials. The maximal measured inward Ca2+ current was 206 +/- 10 pA (mean +/- SEM, n = 51). The peak current occurred at a mean membrane potential of 7.8 +/- 1.3 mV (n = 51). The Ca2+ current voltage relation was shifted 26 mV in the positive direction when the external Ca2+ concentration was increased 10-fold. Ca2+ current rundown was observed with a half-time of approximately 20 min. Cells dialyzed with solution containing the Ca2+ chelating agent, EGTA (0.04 mM), had action potential durations similar to those previously reported in papillary muscle. In contrast, a higher concentration of EGTA (14 mM) prolonged the action potential duration. Control of the cell internal ionic composition was achieved by dialysis of the cell with a time constant for Na+ ions of 1.2 to 2.6 min. Tetrodotoxin (10 microM), included in some experiments to block Ca2+ entry via Na+ channels, was shown to be more than 98% effective. These results characterize the whole-cell voltage clamp technique as applied to immature heart cells.

Action Potentials↗
PubMed1991

L- and T-type calcium channels in acutely isolated neonatal and adult cardiac myocytes.

We have compared transsarcolemmal Ca2+ currents in acutely isolated neonatal (1- to 5-d-old) and adult rabbit cardiac myocytes prepared using similar enzymatic techniques. Time- and voltage-dependent inward Ca2+ currents were measured using the whole-cell voltage clamp technique. In neonatal myocytes, peak Ca2+ currents measured 114 +/- 10 pA (mean +/- SEM, n = 18) as compared with 2014 +/- 403 pA in adult myocytes (n = 5, p less than 0.001). Although adult myocytes had a larger surface area (estimated from cell capacitance) than neonatal cells (113 +/- 15 x 10(-6) versus 28 +/- 2 x 10(-6) cm2, p less than 0.001), the calculated peak current density was also significantly larger in adult cells (17.9 +/- 2.5 compared to 4.3 +/- 0.4 microA/cm2 for neonatal cells, p less than 0.001). The voltage dependence of the peak Ca2+ current was similar in neonatal and adult myocytes. Early transient (T-type) Ca2+ currents were also studied by comparing the current induced by depolarization to -20 mV from holding potentials of -40 and -80 mV. T-type Ca2+ channels were present in 91% of the adult cells but were evident in only 39% of the neonatal cells. In summary, voltage-gated Ca2+ current amplitude, current density, and T-type Ca2+ channel prevalence all increase with maturation. These data suggest that neonatal myocytes may be relatively deficient in Ca2+ channel activity when compared to adult myocytes.

Age Factors↗
PubMed1989

Description of a venous technique for selective coronary arteriography in newborns with d-transposition of the great arteries.

An accurate description of the coronary anatomy is desired before anatomic correction of d-transposition of the great arteries. Two-dimensional echocardiography and aortic root angiography are occasionally unable to delineate the coronary arteries. In neonates, the arterial approach for selective coronary arteriography is difficult and may compromise visceral and lower limb perfusion. A venous technique was used in two newborns to define selectively the coronary origins and their distribution. The venous approach for selective coronary arteriography may be effective in the evaluation of newborns with d-transposition of the great arteries when echocardiography inadequately defines the coronary circulation.

Coronary Angiography↗
PubMed1986

Further characterization of the presynaptic alpha-1 receptor modulating [3H]ACh release from rat atria.

We have reported previously that norepinephrine (NE) and epinephrine reduce acetylcholine (ACh) overflow from superfused rat atria apparently through interaction with a presynaptic alpha-1 receptor. To characterize further this novel alpha-1-mediated effect, we tested the ability of a series of alpha antagonists and agonists to modulate ACh release in this preparation. The alpha-1 selective antagonists YM 12617 and WB 4101 blocked the inhibitory action of NE with IC50 values of about 0.1 and 1 nM, respectively, whereas the alpha-2 selective antagonists Wy 26703 and rauwolscine were much less potent. These data are consistent with the involvement of an alpha-1 receptor in the response to NE. ACh release was diminished by (-)-alpha-methyl-NE but similar concentrations of the alpha-2 selective agonists B-HT 920 and UK 14304 had no effect on ACh release. A number of alpha-1 selective agonists including amidephrine, cirazoline, St 587 and SK&F 89748 failed to inhibit [3H]ACh release or had only a small effect (phenylephrine). When tested as antagonists, however, phenylephrine, cirazoline and SK&F 89748 could block the inhibitory effect of NE at concentrations consistent with their affinities at alpha-1 receptors in other systems. These compounds thus bind to but do not activate the alpha receptor regulating ACh release, apparently due to their low efficacies compared to NE. Experiments carried out after alpha receptor inactivation with phenoxybenzamine demonstrate that there is little receptor reserve for the inhibition of ACh release by NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1985

Presynaptic modulation of acetylcholine release from cardiac parasympathetic neurons.

Acetylcholine can be released from parasympathetic nerve endings in rat atria by 57 mM K+ depolarization or by electrical field stimulation. We have studied the presynaptic modulation of [3H]acetylcholine release from superfused rat atria prelabeled with [3H]choline. Exogenous acetylcholine and the specific muscarinic agonist oxotremorine inhibit the stimulation-induced overflow of [3H]acetylcholine into the superfusion medium. The half-maximal inhibitory concentration (IC50) of oxotremorine is 0.3 microM. The cholinesterase inhibitor neostigmine also decreases K+-stimulated [3H]acetylcholine overflow, whereas the muscarinic antagonist atropine enhances the overflow of [3H]acetylcholine. These data suggest that acetylcholine release in atria is modulated through negative feedback by the endogenous transmitter. The sympathetic adrenergic neurotransmitter norepinephrine and the neurohormone epinephrine also inhibit the overflow of [3H]acetylcholine by approximately 60%. The IC50 values for the inhibitory effects of these catecholamines are 6.3 and 2.2 microM, respectively. The inhibitory effect of norepinephrine is blocked by the alpha-adrenergic receptor antagonist yohimbine but not by the beta-adrenergic receptor antagonist propranolol. We suggest that presynaptic muscarinic and alpha-adrenergic receptors participate in the physiological and pharmacological control of cardiac parasympathetic activity.

Acetylcholine↗
PubMed1985

Acetylcholine release from rat atria can be regulated through an alpha 1-adrenergic receptor.

Isolated superfused rat atria release [3H]acetylcholine when depolarized with 57 mM potassium. The depolarization-induced overflow of [3H]acetylcholine is markedly inhibited by micromolar concentrations of epinephrine and norepinephrine. The alpha 1-selective adrenergic agonist methoxamine also inhibits tritium overflow, but the alpha 2-selective adrenergic agonist clonidine and the beta-adrenergic agonist isoproterenol do not. Prazosin, an selective alpha 1-adrenergic antagonist, blocks adrenergic inhibition of [3H]acetylcholine overflow with a Ki of approximately 0.4 nM. Yohimbine has approximately one-hundredth the potency of prazosin for blocking adrenergic inhibition of [3H]acetylcholine overflow. [3H]Norepinephrine overflow from isolated rat atria is also inhibited by norepinephrine, but this effect is antagonized by yohimbine and not by prazosin. We suggest that the release of acetylcholine from cardiac parasympathetic neurons can be regulated through an alpha 1-adrenergic receptor, and that this mechanism may underly, at least in part, the relative lack of effects of prazosin on heart rate.

Acetylcholine↗
PubMed1983

Relationships between choline uptake, acetylcholine synthesis and acetylcholine release in isolated rat atria.

Isolated rat atria take up [3H]choline and synthesize [3H]acetylcholine (ACh). The uptake of [3H]choline has a high-affinity component with a Km of approximately 0.2 microM and a Vmax of approximately 6 fmol/min/mg wet wt. This high-affinity component of choline uptake is difficult to measure directly because it represents only a small portion of total [3H]choline uptake. However, the rate of synthesis of [3H] ACh from [3H]choline appears to reflect the activity of the high-affinity choline uptake system. Thus, [3H]ACh synthesis is most efficient at low choline concentrations and is inhibited in the presence of hemicholinium-3 and low NaCl medium. The neuronal localization of the [3H]Ach synthesized from [3H]choline is demonstrated by the finding that [3H]ACh is released from the atria by depolarization with 57 mM K+ medium. The release is Ca++ -dependent and there is a compensatory increase in the synthesis of [3H]ACh after depolarization-induced ACh release. These data suggest that [3H]choline can be specifically incorporated into a releasable pool of [3H]ACh localized in cardiac parasympathetic neurons. The synthesis of [3H]ACh is inhibited by blockade of high-affinity choline uptake and is regulated in response to neuronal activity. The application of these methods will provide a means for directly examining the physiological and pharmacological control of ACh synthesis and release from cardiac parasympathetic neurons.

Acetylcholine↗
PubMed1982

Activation and blockade of cardiac muscarinic receptors by endogenous acetylcholine and cholinesterase inhibitors.

Cholinesterase inhibitors are known to potentiate the effects of acetylcholine (ACh) and vagal stimulation on the myocardium. The studies presented here demonstrate that cholinesterase inhibitors (ChEI) also have activity in isolated atria in the absence of extrinsic cholinergic stimulation and that, depending on the ChEI, either indirect stimulation or direct blockade of cardiac muscarinic receptors can occur. Muscarinic agonists inhibit cyclic AMP formation in atria and the ChEIs physostigmine, neostigmine and echothiophate likewise produce a marked attenuation of isoproterenol-stimulated cyclic AMP accumulation The effect of physostigmine appears to result from muscarinic receptor activation by endogenous ACh as it is blocked by atropine. In contrast, the ChEI ambenonium does not stimulate but instead blocks muscarinic receptors coupled to cyclic AMP accumulation. Radioligand binding studies provide direct evidence that both ambenonium and demecarium are relatively potent muscarinic receptor antagonists, whereas physostigmine and other ChEI have little direct receptor activity. Physostigmine and ambenonium also have different effects on heart rate in vivo, the former potentiating and the latter apparently blocking vagal tone. The inhibition of cyclic AMP formation produced by physostigmine can be used as a measure of the concentration of endogenous ACh available at muscarinic receptor sites. Physostigmine blocks cyclic AMP formation in atria incubated in the absence of calcium or in the presence of tetrodotoxin, suggesting that endogenous ACh is spontaneously released in the absence of neuronal activity or depolarization-secretion coupling.

Acetylcholine↗
PubMedDate not supplied

Predictors of graft longevity in pediatric heart transplantation.

Given the volume of pediatric orthotopic heart transplants (OHTs) at several centers, it is now possible to generate pediatric-specific, single-center OHT survival data. The transplant experience for 152 pediatric OHT patients at our institution was reviewed. The following were noted for each patient: graft survival; immunosuppressant therapy; initial diagnosis; cause of graft failure; clinical status at time of transplant; donor and recipient blood type, sex, weight, and age; ischemic time; previous cardiac surgery; race; and immune status. A series of Kaplan-Meier survival curves were constructed. Univariate comparisons of survival curves were performed with the Breslow test to determine equality of each pair of curves. Only immunosuppression with tacrolimus and an initial diagnosis of noncongenital heart disease positively influenced survival in pediatric OHT patients (p < or = 0.021 and p < or = 0.03, respectively). The more recently transplanted patients, managed with tacrolimus, had less mortality early after OHT (acute rejection) and less mortality during the period 2 or 3 years after OHT. No other factors, including prior cardiothoracic surgery, sex matching, and race matching, significantly influenced survival. Recently transplanted patients managed with tacrolimus-based immunosuppression and patients with noncongenital cardiomyopathy have significantly superior graft survival.

Child↗