Biomedical subjects

D Mendelowitz

Publications and source records attributed to D Mendelowitz.

32 records · Page 2Linked to original sources

PubMed1995

Acetylcholine activates a nicotinic receptor and an inward current in dorsal motor nucleus of the vagus neurons in vitro.

This study examines the effect of acetylcholine (Ach) on parasympathetic vagal neurons in the dorsal motor nucleus of the vagus (DMNX). Patch-clamp techniques were utilized to examine voltage and ligand-gated currents in visualized DMNX neurons in an in vitro slice. Ach (100 microM) activated an inward current, -196.4 +/- 56.9 pA at -80 mV (n = 15) that was accompanied by a decrease in membrane resistance of 48.6 +/- 9.2% in a population of DMNX neurons. The reversal potential for this ligand-gated current was -11.3 +/- 11.5 mV. The specific agonist nicotine (200 microM) elicited similar responses. Nicotine decreased membrane resistance by 60.9 +/- 4.3% and activated an inward current (-215.7 +/- 45.7 pA at -80 mV) that reversed at -12.7 +/- 20.4 mV (n = 16). Bethanecol (100 microM), a specific muscarinic agonist, had no effect. Neither Ach or nicotine had any effect on the voltage-gated sodium and outward potassium currents present in these neurons.

Acetylcholine↗

PubMed1995

Heterogeneous functional expression of calcium channels at sensory and synaptic regions in nodose neurons.

1. In the present study we have taken advantage of the unique anatomy of visceral sensory neurons that enabled us to isolate and examine the role of calcium channel subtypes at the soma, central synaptic terminals, and peripheral sensory endings. 2. N-type calcium channels dominated somatic currents (60%), with lesser (16% and 12%) contributions from P- and L-type channels, respectively, in patch-clamped dispersed nodose neurons using toxins selective for each calcium channel subtype. 3. These toxins also blocked the release of neurotransmitters from these visceral synaptic terminals in a brain stem slice. Similar to the profile at the soma, N-type calcium channels were most responsible for neurotransmission at this central glutamatergic synapse (57%), with P- and L-type channels making small contributions (12% and 11%, respectively). 4. In contrast to the soma and central synapses, these calcium channel toxins failed to affect the sensory transduction at aortic baroreceptor endings. 5. Therefore calcium channel subtypes have dramatically heterogenous distributions in sensory neurons that presumably subserve the specialized functions that occur at different cellular regions.

Animals↗

PubMed1994

A- and C-type rat nodose sensory neurons: model interpretations of dynamic discharge characteristics.

1. Neurons of the nodose ganglia provide the sole connection between many types of visceral sensory inputs and the central nervous system. Electrophysiological studies of isolated nodose neurons provide a practical means of measuring individual cell membrane currents and assessing their putative contributions to the overall response properties of the neuron and its terminations. Here, we present a comprehensive mathematical model of an isolated nodose sensory neuron that is based upon numerical fits to quantitative voltage- and current-clamp data recorded in our laboratory. Model development was accomplished using an iterative process of electrophysiological recordings, nonlinear parameter estimation, and computer simulation. This work is part of an integrative effort aimed at identifying and characterizing the fundamental ionic mechanisms participating in the afferent neuronal limb of the baroreceptor reflex. 2. The neuronal model consists of two parts: a Hodgkin-Huxley-type membrane model coupled to a lumped fluid compartment model that describes Ca2+ ion concentration dynamics within the intracellular and external perineuronal media. Calcium buffering via a calmodulin-type buffer is provided within the intracellular compartment. 3. The complete model accurately reproduces whole-cell voltage-clamp recordings of the major ion channel currents observed in enzymatically dispersed nodose sensory neurons. Specifically, two Na+ currents exhibiting fast (INaf) and slow tetrodotoxin (TTX)-insensitive (INas) kinetics; low- and high-threshold Ca2+ currents exhibiting transient (ICa,t) and long-lasting (ICa,n) dynamics, respectively; and outward K+ currents consisting of a delayed-rectifier current (IK), a transient outward current (I(t)) and a Ca(2+)-activated K+ current (IK,Ca). 4. Whole-cell current-clamp recordings of somatic action-potential dynamics were performed on enzymatically dispersed nodose neurons using the perforated patch-clamp technique. Stimulus protocols consisted of both short (< or = 2.0 ms) and long (> or = 200 ms) duration current pulses over a wide range of membrane holding potentials. These studies clearly revealed two populations of nodose neurons, often termed A- and C-type cells, which exhibit markedly different action-potential signatures and stimulus response properties. 5. Using a single set of equations, the model accurately reproduces the electrical behavior of both A- and C-type nodose neurons in response to a wide variety of stimulus conditions and membrane holding potentials. The structure of the model, as well as the majority of its parameters are the same for both A- and C-type implementations.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

Localization and retention in vitro of fluorescently labeled aortic baroreceptor terminals on neurons from the nucleus tractus solitarius.

The anterograde fluorescent tracer DiA was used to visualize baroreceptor fibers and synaptic terminals both in living and fixed tissue. Baroreceptor fibers labeled with DiA terminated as a dense synaptic field in the medial nucleus tractus solitarius (NTS), making synaptic contact on the soma, as well as processes of neurons that they innervated. A similar distribution and morphology was observed in baroreceptor fibers and terminals labeled with horseradish peroxidase. DiA also identified baroreceptor terminals and the neurons receiving these synaptic contacts in vitro. NTS neurons were dissociated from their surrounding tissue and identified by attached baroreceptor terminals that retained the fluorescent dye. These results will enable us to study the electrophysiological properties of dispersed neurons that receive identified baroreceptor synaptic terminals.

Animals↗

PubMed1992

Bradykinin-activated calcium influx pathway in bovine aortic endothelial cells.

Clusters of electrically coupled endothelial cells were used to characterize a bradykinin (BK)-activated Ca2+ influx pathway. Spatial voltage control of clusters containing three to eight cells, evaluated as the ratio of the voltage response in one cell to a voltage pulse in the most distant cell of the cluster, was 0.96 at a holding potential of 0 mV in normal saline bath and 0.88 in the presence of BK. BK activated an inward current that was carried by either Na+ or Ca2+ when the membrane potential was held at -60 mV. Current was activated within 3 s of application of BK and peaked within 1 min. With Ca2+ as the permeable extracellular ion the current was stable for 1-3 min and then declined over a period of 5-8 min in the continued presence of BK. However, when Na+ carried the current it was sustained over a 10-min test period. The reversal potential of the BK-activated current was near 0 mV, suggesting activation of a nonspecific cation channel(s). The inward current at -60 mV averaged 13 +/- 4.5 pA (n = 9)/cell in Ca2+ and 12.2 +/- 9.3 pA (n = 5)/cell in Na+. Both Na+ and Ca2+ currents were blocked by 200 microM lanthanum.

Animals↗

PubMed1992

Characterization of calcium currents in aortic baroreceptor neurons.

1. Calcium currents in identified rat aortic baroreceptors were characterized with the perforated patch whole-cell voltage-clamp technique. Aortic baroreceptors were distinguished from other neurons by the presence of a fluorescent tracer that was previously applied to the aortic depressor nerve. The diversity of calcium currents in unidentified neurons dissociated from neonatal rat nodose ganglia were also examined. 2. A population of aortic baroreceptors (63%, 7 of 11) possessed a low-threshold, also referred to as a T-type, calcium current. This current was typically less than 100 pA in 2 mM Ca [72.7 +/- 20.9 (SE) pA, n = 7], had a rapid activation and inactivation, and inactivated completely at conditioning voltages positive to -50 mV. 3. All aortic baroreceptors possessed high-threshold calcium currents that were activated at voltages positive to -30 mV, with typical maximum amplitudes of 600-1,000 pA (826 +/- 79 pA, n = 11). 4. The high-threshold current inactivated with three exponential rates of decay of tau = 10.7 +/- 2.2 ms, 138 +/- 14.6 ms, and a third tau greater than 3 s. It was not possible to separate the kinetic components of inactivation with conditioning voltages (voltage-dependent inactivation), activation thresholds, deactivation kinetics, or calcium-channel antagonists. 5. The voltage-dependent inactivation of high-threshold calcium currents began at voltages positive to -70 mV and became steeply voltage dependent between -60 and -10 mV. Unexpectedly, the three decay constants were present after all conditioning voltages. There were no conditioning voltages that excluded any component.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Identification and dissociation of cardiovascular neurons from the medulla for patch clamp analysis.

This study describes a preparation that will enable us to study, using voltage clamp techniques, ionic currents from dissociated cardiovascular neurons that have retained their anatomical and functional identity of the intact animal. To identify dispersed preganglionic cardiac motoneurons various fluorescent dyes (rhodamine, fluorogold, microspheres, bizbenzimide and dextrans) were examined to determine which can be absorbed by preganglionic cardiac motorneuron nerve terminals (without surgical penetration of cardiac tissue), transported retrogradely to their soma in the medulla and retained during dissociation of the neurons. Rhodamine fulfilled these criteria. Dissociated preganglionic cardiac motorneurons had resting membrane potentials of -52.4 +/- 3 mV and input resistances of 236 +/- 71 M omega (mean +/- S.E.M., n = 10). Depolarizing voltage steps to -50 mV or above evoked a tetrodotoxin (TTX) sensitive inward sodium current followed by a biphasic outward current.

Animals↗

PubMed1990

Pulsatile pressure can prevent rapid baroreflex resetting.

In a previous study [Am. J. Physiol. 255 (Heart Circ. Physiol. 24): H673-H678, 1988] we demonstrated that baroreflex responses decay (reset) to increased static sinus pressures, but with increased pulsatile pressure, responses are maintained. To determine more conclusively whether pulsatile pressure prevents rapid baroreflex resetting in this study we examined resetting as shifts of the baroreflex (sinus pressure-arterial pressure) curve. In seven anesthesized rabbits the left sinus was vascularly isolated and conditioned for 5 min to static or pulsatile pressures of 60, 100, or 140 mmHg mean pressure, 0 or 35-40 mmHg pulse pressure. The baroreflex curve was then determined by stepwise changing sinus pressure from 40 to 160 mmHg in 20-mmHg increments. Threshold, midpoint, and saturation sinus pressures shifted 25-39% with static conditioning pressures but did not shift significantly with pulsatile pressures. Also, the baroreflex responses to step increases in static sinus pressure decayed, as resetting occurred, but did not decay with pulsatile sinus pressure increases. Thus the baroreflex rapidly resets with static pressures, but there is minimal, if any, resetting with pulsatile pressures.

Animals↗

PubMed1989

Chronic exercise training protects aged cardiac muscle against hypoxia.

To test the hypothesis that chronic exercise may improve tolerance to hypoxia in aged hearts, we compared cardiac function of exercised rats to that of their age-matched, nonexercised controls. Right ventricular papillary muscles were removed from young adult (9 mo) and old (24-26 mo) male Fischer 344 rats that were chronically exercised on a rodent treadmill and from their age-matched, nonexercised controls. During isometric contraction, hypoxia depressed contraction and relaxation in all muscles, but to a lesser extent in the exercised groups. A significant exercise effect was observed in the following variables: the maximum developed tension, the maximum rate of tension development, the maximum rate of tension decline, and the time required for the hypoxia to reduce maximum tension by 20%. The maximum rate of tension decline was more sensitive to hypoxia than was the maximum rate of tension development in all groups. Exercise also had an effect on the temperature dependence of cardiac performance during hypoxia. Thus, chronic exercise results in the preservation of both contraction and relaxation during hypoxia for aged as well as young adult hearts.

Aging↗

PubMed1988

Pulsatile sinus pressure changes evoke sustained baroreflex responses in awake dogs.

A modified Stephenson-Donald preparation was used to control pressure in an isolated carotid sinus in conscious dogs with all other arterial baroreceptors denervated. Sinus pressure was changed from preisolation control levels to either an elevated static or an elevated pulsatile pressure for 5 min. These sinus pressure changes evoked similar initial decreases in arterial pressure. The elevated static sinus pressure (150 or 175 mmHg) caused an initial depressor response of -32.7 +/- 5.5 mmHg, which then decayed rapidly. Five minutes after the change in sinus pressure, the depressor response was abolished, as arterial pressure returned to control pressure. This decay of the response would be expected if resetting occurred. In contrast, when the sinus was exposed to elevated pulsatile pressures (125 or 150 mmHg mean, 50 mmHg pulse pressure) depressor responses were sustained throughout the sinus pressure change (-23.2 +/- 5.3 mmHg initial, -29.0 +/- 4.8 mmHg at 5 min; P greater than 0.4). These results demonstrate that while the reflex responses rapidly reset to elevated static sinus pressures, elevated pulsatile pressures elicit sustained reflex responses.

Animals↗

PubMed1986

Age-related differences in effect of exercise training on cardiac muscle function in rats.

To test the hypothesis that age may alter the effect of exercise training on myocardial function, we trained young adult (4-5 mo at study initiation) and old (21 mo at initiation) male Fischer 344 rats to run on a rodent treadmill 5 days/wk for 4.5 mo and compared their myocardial function with that of age-matched sedentary controls. Right ventricular papillary muscles were isolated from the young adult and aged animals and stimulated at the length at which developed isometric tension was maximal to contract isometrically at 12/min, bathed in oxygenated modified Krebs solution, and studied at 28 degrees, 32 degrees, 35 degrees, and 38 degrees C. In the absence of cardiac hypertrophy, exercise training significantly reversed the age-related prolongation of isometric contraction duration in the senescent rat (P less than 0.001). However, exercise training prolonged contraction duration in the young adult rat (P less than 0.05). The relaxation phase was more sensitive than the contraction phase to changes in temperature, especially in the aged rat (P less than 0.02). The ratio of developed tension to time-to-peak tension of the isometric twitch was not affected by exercise training. Because exercise training affects cardiac function in opposite directions from young adulthood to senescence, caution is advised in extrapolating results from exercise studies in young adult rats to populations of older animals.

Aging↗

PubMed1986

Maintenance of carotid baroreflex function in advanced age in the rat.

To evaluate the influence of age per se on the carotid sinus baroreceptors in the absence of hypertension and atherosclerosis, we employed the Fischer 344 rat model. In 14 adult (A, 6-9 mo) and 9 senescent (S, 24-26 mo) normotensive male Fischer 344 rats the left carotid sinus region was vascularly isolated with sinus nerve intact and perfused with oxygenated modified Kreb's solution. Simultaneous measurements of intrasinus pressure and femoral arterial pressure response were obtained during linear pressure increases (20-200 mmHg) in the vascularly isolated sinus. There was no age difference in base-line arterial pressure or heart rate. Both age groups demonstrated similar positive relations between basal femoral arterial pressure and the magnitude of the femoral pressure response to equivalent carotid sinus pressures. There were similar estimated sinus volumes at onset of systemic response (39 +/- 1, A; 39 +/- 1 microliter, S), time to initial systemic pressure response (9 +/- 1, A; 7 +/- 1 s, S), mean rates of femoral pressure decline (1.8 +/- 0.3, A; 2.1 +/- 0.3 mmHg/s, S), and return to base line (1.5 +/- 0.3, A; 1.4 +/- 0.3 mmHg/s, S) as well as magnitudes of systolic (25 +/- 3, A; 26 +/- 4 mmHg, S) and diastolic (21 +/- 2 A; 22 +/- 4 mmHg, S) pressure drops. Thus, in the Fischer 344 rat model of aging, which differs from the human in that it is not complicated by hypertension or atherosclerosis, carotid sinus baroreflex function appears to be well maintained in senescence.

Aging↗

PubMed1985

Influence of age on cardiovascular reflex response in anesthetized rats.

To test the hypothesis that aging is associated with an altered hemodynamic response to physiological (nonpharmacological) stimuli, such as postural change and intravascular volume perturbations, we studied the adult (A, 6 mo) and senescent (S, 24 mo) Fischer 344 rat, a mammalian aging model not influenced by atherosclerosis or hypertension. Special emphasis was placed on the afferent limb of the baroreceptor reflex arc, an area not previously studied with respect to age. The base-line heart rate (HR), systemic arterial pressure (SAP), pulmonary arterial pressure (PAP), and carotid sinus nerve activity were not influenced by age. Following postural change (60 degrees upward tilt), the old animals demonstrated a greater drop in systolic pressure (-11 +/- 2, A; -21 +/- 4 mmHg, S; P less than 0.05), but there was no significant change in HR in either group. In response to a controlled withdrawal of 0.5 ml, the A had a greater reduction in systolic pressure (-29 +/- 4, A; -12 +/- 3 mmHg, S; P less than 0.01), whereas HR or PAP did not change; both groups showed a similar decrease in nerve activity. After infusions of 0.5 and 1.0 ml, the systolic and diastolic pressure changes were greater (P less than 0.02), and the changes in nerve activity appeared to be slightly more prolonged in the A compared with the S. Thus the response to changes in intravascular volume and posture are altered with age, and differences in volume-mediated venovasomotor reflex response may contribute to these age-related changes in the rat.

Aging↗

PubMedDate not supplied

Nicotine enhances presynaptic and postsynaptic glutamatergic neurotransmission to activate cardiac parasympathetic neurons.

Although peripheral cholinergic neurotransmission has long been known to play a pivotal role in the control of heart rate and blood pressure, recent evidence has suggested that central cholinergic mechanisms may be involved in the genesis of hypertension, anxiety, cardiorespiratory control, and, in particular, the respiratory modulation of heart rate. Yet, the sites, mechanisms, and receptor subtypes involved in the action of nicotine within the central nervous system are controversial. The present study demonstrates that nicotine has at least 3 sites of action to increase the activity of vagal cardiac neurons. Nicotine, but not muscarinic agonists, activates postsynaptic receptors and a depolarizing inward current in vagal cardiac neurons studied with the perforated patch-clamp technique in a visualized brain stem slice. In addition, nicotine acts at different presynaptic and postsynaptic sites to facilitate glutamatergic neurotransmission. Presynaptic nicotinic receptors increase the frequency of transmitter release and are sensitive to block by alpha-bungarotoxin. Nicotine also elicits a previously undescribed augmentation of postsynaptic non-NMDA currents. The presynaptic and postsynaptic receptors may prove to be future targets in the search for agonists to increase vagal cardiac activity and reduce the fatality associated with cardiac hyperexcitability and for antagonists to reduce cardiac vagal activity in pathological conditions associated with abnormally low heart rates and cardiac function such as sudden infant death syndrome.

6-Cyano-7-nitroquinoxaline-2,3-dione↗