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Biomedical subjects

W C Randall

Publications and source records attributed to W C Randall.

At least 19 recordsLinked to original sources
PubMed1992

4-substituted thiophene- and furan-2-sulfonamides as topical carbonic anhydrase inhibitors.

A series of 4-substituted thiophene- and furan-2-sulfonamides was prepared and was found to possess nanomolar-level potency for inhibition of human carbonic anhydrase II in vitro. Selected examples from this group were further evaluated for their potential to act as topically effective ocular hypotensive agents in the ocular normotensive albino rabbit and the ocular alpha-chymotrypsinized rabbit. Solubility studies in water and pH 7.4 buffer were carried out to estimate the ability of compounds to be formulated in solution. The sensitization potential of key representative structures was determined by in vitro glutathione reactivity studies and guinea pig maximization testing.

Animals↗
PubMed1992

Thieno[2,3-b]furan-2-sulfonamides as topical carbonic anhydrase inhibitors.

Novel 5-[(alkylamino)methyl]thieno[2,3-b]furan-2-sulfonamides were prepared and evaluated in vitro for inhibition of human carbonic anhydrase II (CA II) and ex vivo for their ability to inhibit Ca II in the albino rabbit eye after topical administration. Compound 11a was found to lower intraocular pressure (IOP) in both the alpha-CT ocular hypertensive albino rabbit and the normal albino rabbit, but was ineffective at lowering IOP in a hypertensive, pigmented monkey model. Since 11a was highly bound to ocular pigment, a series of less basic analogs was prepared. Examples in this series were both less extensively bound to ocular pigment and more active at reducing IOP in pigmented rabbits after topical dosing. Key examples displayed moderate reactivity toward glutathione.

Administration, Topical↗
PubMed1992

Gross and microscopic anatomy of the vagal innervation of the rat heart.

Intrinsic cardiac ganglia and their vagal innervation are described from gross and microscopic dissections and functional studies in the anesthetized, open-chest, adult rat. Dissecting microscope sketches of the ventral and dorsal aspects of the rat heart provide gross descriptions of the anatomical course of the vagal cardiac nerves. Histological sectioning of adipose tissue packets surrounding the terminal endings of vagal branches distributed to the roots of the great cardiac vessels (aorta, pulmonary artery, precaval veins) revealed clusters of autonomic ganglia. These packets or "fat pads" were located: (1) along the dorsal surface of the right precava and extending medially toward the aortic root, (2) deep to the aortic arch, (3) in the angle between the root of the left precava and the pulmonary artery on the superior-dorsal surface of the left atrium, and (4) in the rostro-dorsal interatrial septum. Vagal distributions of small terminal branches were traced to each of these pads, which contained numerous autonomic ganglia. Electrical excitation of right or left cervical vagus elicited varying degrees of sinus slowing, slowing of A-V conduction, and suppression in atrial contractile force. Very small quantities (0.5 mg in 10 microliters saline) of the ganglionic blocking agent, hexamethonium (C6) were injected selectively into a single fat pad, followed by repetition of right or left vagal stimulation, with careful analysis of changes in heart rate (paced and unpaced), A-V conduction, and contractile force.

Adipose Tissue↗
PubMed1992

A faculty research and training program for undergraduates in the sciences.

Faculty enthusiasm, with actual hands-on involvement, is a critical factor in establishing student research interest and excitement in a university or college science environment. Such faculty involvement is infectious to students and therefore key to restoring United States leadership in science and technology in the next decades. Most scientists acknowledge that they were initially attracted into scientific careers through one or two notable teachers who served as role models. However, with the introduction of so-called "big science" and its distraction of university faculty away from meaningful, direct student contacts, and with associated withdrawal of funding from "little science" in the college teacher's laboratory, research languishes in nearly all undergraduate teaching institutions. The inspiring college science teacher seems essentially gone, tired or burnt out, unable to keep pace with the rigorous demands of an active research lab while simultaneously meeting the exhausting load of 15-18 (or more) contact teaching hours per week. With all of the associated lecture preparations, student counseling, and Dean's committee assignments, the teacher has little or no scholarly "think time" or opportunity to inspire even the bright students. Without the teacher's honest and evident involvement and deep commitment, the student fails to experience the essential impact of a convincing role model. It is therefore necessary to restore the college science teacher's opportunity and aspirations to be personally involved in research. This can only be accomplished by providing time, facilities, incentives, and encouragement to do what originally attracted the teacher into a career in science and teaching in the first place.(ABSTRACT TRUNCATED AT 250 WORDS)

Education, Medical, Undergraduate↗
PubMed1992

Heart rate control in awake dog after selective SA-nodal parasympathectomy.

Selective surgical sinoatrial (SA)-nodal parasympathectomy (PSX) was used to distinguish the role of the cardiac autonomic nerves in heart rate (HR) control in awake dogs (n = 8) during rest and behavioral arousal. Resting HR increased from 85 +/- 9 beats (mean +/- SE) before surgery to 114 +/- 6 beats after denervation (P less than 0.05). Atrioventricular (AV)-nodal block occurred during the first 1-3 wk post-PSX, but subsequently resolved. Dogs were behaviorally conditioned by following a 30-s tone (CS+) by a 0.5-s shock. Before denervation the CS+ evoked an initial, rapidly developing tachycardia (phase 1), which was followed by a more slowly developing, but larger, phase 2 tachycardia. The selective SA-nodal parasympathectomy essentially abolished the phase 1 conditional HR response (magnitude: 23 +/- 5 vs. 5 +/- 2 beats, pre- vs. postdenervation, respectively). The phase 2 HR increase was similar before and after the denervation (magnitude: 44 +/- 6 vs. 33 +/- 6 beats; rate of increase: 5 +/- 1 vs. 6 +/- 1 beats/s, pre- vs. post-PSX). Beta-Blockade (propranolol, 1 mg/kg) after PSX decreased phase 2 (magnitude: 7 +/- 3 beats; rate of increase: 1 +/- 0.3 beats/s). These data reveal a sterotypic pattern of change in cardiac autonomic nervous drive during a sudden arousal from rest. Phases 1 and 2 appear to be selective and specific indexes of changes in SA-nodal parasympathetic and sympathetic tone, respectively. The selective denervation unmasks during stress a component of HR control that occurs in the absence of adrenergic or cholinergic mechanisms. These data suggest that multiple interactions occur within the intrinsic ganglion plexuses of the heart with respect to HR control.

Animals↗
PubMed1992

Epicardial sites for vagal mediation of sinoatrial function.

The posterior atrial fat pad (PAFP) has been described as the probable anatomic location of parasympathetic ganglia mediating sinoatrial (SAN) and atrioventricular nodal function in the mammalian heart. This contrasts with recent localizations of such control elements in the pulmonary vein fat pad (PVFP) and in fatty tissues overlying the junction of inferior vena cava-inferior left atrium (IVC-ILA), respectively. Short bursts (5-8 pulses/burst, 3 bursts/train) of electrical current (1-16 Hz, 400 ms, 1-5 mA) applied directly to the ventral right atrial epicardium via a concentric bipolar electrode (separation 0.3-0.6 mm) during the atrial muscle refractory period, activated subepicardial postganglionic pathways from PVFP and entering the SAN; identical stimulation of dorsal right atrial epicardium between PAFP and SAN excited few or no fiber pathways controlling SAN discharge rate or patterns. In a second series of experiments, injection of a neuronal marker (Fast Blue) into and around SAN, with time (5-10 days) allowed for retrograde transport, resulted in staining of many soma in PVFP but none in IVC-ILA or PAFP. These data strongly affirm the primary, and perhaps exclusive, localization of ganglia that mediate parasympathetic regulation of SAN function in PVFP of the dog's heart, with little or no such participation by ganglia within PAFP or IVC-ILA.

Adipose Tissue↗
PubMed1991

Morphology of intracellularly labeled canine intracardiac ganglion cells.

The purpose of this study was to determine the morphological organization and structure-function correlation of mammalian intracardiac ganglion cells. Conventional intracellular microelectrode techniques were applied to the tissue whole mount preparation of canine intracardiac ganglia. Forty neurons were intracellularly recorded and labeled by means of horseradish peroxidase iontophoresis. Cell morphology was quantitatively analyzed by light microscopy and camera lucida technique. Somata were elongated (mean 62 x 40 microns) and had 2-12 primary dendrites restricted within the ganglion. Almost half of the neurons had either a short axon that was traced only within the ganglion or no axon distinguishable. These neurons may have perhaps been intraganglionically active neurons. The other cells had a long axon that either coursed out of the ganglion to peripheral cardiac tissue or exited the ganglion via interganglionic nerve to innervate more remote cardiac tissue or cells in other intracardiac ganglia. Interaction between neurons was suggested by the close proximity of processes from different neurons. Previously defined electrophysiological cell types (R-, S-, and N-cells), which were significantly different in their passive and active membrane properties, had different morphological features of the somata but not the axonal or dendritic processes. Intraganglionic or long axon neurons were not associated with a particular electrophysiological cell type. These findings provide the possibility of ganglionic modulation of vagal efferent activity in mammalian heart and also provide some morphological basis for the electrophysiological cell types.

Animals↗
PubMed1991

Intracellular recording of spontaneous activity of canine intracardiac ganglion cells.

Intracellular recordings were made from 302 canine intracardiac ganglion cells with intact synaptic connections. Fifty-two % of these cells exhibited spontaneous membrane potential changes consisting primarily of miniature excitatory postsynaptic potential (EPSP)-like depolarizations upon which an action potential or burst of action potentials was sometimes evoked. Most of the spontaneous potential changes are presumed to be synaptically mediated involving nicotinic mechanisms because they were blocked by low Ca2+/high Mg2+ and hexamethonium solutions.

Action Potentials↗
PubMed1991

Intracellular recordings from canine intracardiac ganglion cells.

Stable transmembrane potentials were recorded from 60 canine intracardiac ganglion cells taken from 10 dogs, which had intact synaptic connections: mean resting membrane potential, input resistance and time constant were 61.5 mV, 70 M omega and 3.3 ms. Action potentials could be evoked by intrasomal current injection and by orthodromic and antidromic stimulation of interganglionic nerves. Orthodromic action potentials were initiated by excitatory postsynaptic potentials and mediated by nicotinic receptors. All action potentials could be blocked by tetrodotoxin. Intracellular labeling revealed large cell bodies and long dendritic and axonal processes. Thus, the functional and anatomical properties of canine cardiac ganglion cells and their synaptic connections can be elucidated using this preparation.

Action Potentials↗
PubMed1991

Spinal mediation of thermally induced sweating.

The sweat responses of nine patients with physiologically complete lesions of the spinal cord (six cervical and three thoracic) were recorded by two different techniques while the patients were exposed to elevated environmental temperatures. Oral temperatures, heart rate and respiration were monitored throughout the observational periods. Oral temperature invariably rose during exposure to heat and both heart rate and respiration tended to increase. Sweating was detected on all of the test areas by both the iodine-starch-paper technique and the quinizarin technique, but it was of widely varying intensity in different portions of the body. In the patients with cervical lesions sweating was generally profuse on the head and neck and occurred in progressively decreasing intensity down to the level of the umbilicus. It was invariably present, but only in very low intensity, on the lower extremity. Sweating was frequently present as a result of manipulation of the patient during the initial preparations, but this generally declined or stopped before the heat was turned on. With application of heat, sweating was recruited on previously dry areas or increased in intensity on those areas in which it was previously present. After oral temperature had increased moderately, the heat was turned off and the doors of the chamber opened widely so that the heat stimulus was suddenly removed. Despite a continued rise in oral temperature, sweating stopped or decreased dramatically. These results are interpreted to indicate the direct mediation by the isolated spinal cord of reflex sweating responses to a heat stimulus applied to the skin. The general distribution of sweating was similar to that associated with distension of the urinary bladder, and careful attention was taken to avoid this complication. The distribution of sweating on the patients with lesions in the thoracic cord was quite different, being most obvious and profuse on the lower extremities and lower trunk and completely absent from the upper trunk, head and upper extremities.

Adolescent↗
PubMed1991

SA nodal parasympathectomy delineates autonomic control of heart rate power spectrum.

The purpose of this study was to quantify the relative roles of the canine cardiac parasympathetic and sympathetic nerves in controlling the distribution of power within the heart rate (HR) power spectrum using a highly selective surgical technique to parasympathectomize the SA node. DAta were recorded in awake dogs (n = 6) before and after the selective denervation; the animals were isolated from human contact and their behavior carefully monitored during the measurements. The average amplitude in the high-frequency (approximately 0.32 Hz) peak in the HR power spectrum decreased from a predenervation control of 2.68 +/- 1.54 (mean +/- SD, arbitrary units) to 0.07 +/- 0.06 (P less than 0.05). Corresponding resting HR increased from 80 +/- 9 to 106 +/- 16 beats/min (P less than 0.05). The low-frequency peak (approximately 0.02 Hz) also decreased from a control of 2.45 +/- 1.18 to a postparasympathectomy value of 1.25 +/- 0.92 (P less than 0.05). beta-Adrenergic blockade (propranolol, 1 mg/kg) further decreased the latter peak to 0.59 +/- 0.52 (P less than 0.05). These data directly demonstrate that the high-frequency peak of the HR power spectrum 1) results from parasympathetic control of SA nodal automaticity, while 2) the low-frequency peak reflects activity in both divisions of the autonomic nervous system.

Adrenergic beta-Antagonists↗
PubMed1991

Autonomic regulation of subsidiary atrial pacemakers during exercise.

Cardiac responses to graded treadmill exercise were compared in conscious dogs before and after excision of the sinoatrial node (SAN) and adjacent tissue along the sulcus terminalis. The chronotropic and dromotropic responses to dynamic exercise were compared with and without selective muscarinic (atropine) and/or beta-adrenergic (timolol) blockade. With the SAN intact, cardiac acceleration was prompt during onset of exercise and in proportion to work intensity. Immediately after SAN excision (1-7 days), pacemaker activity exhibited marked instability in rate and pacemaker location, with rapid shifts between atrial and junctional foci. Soon thereafter (1-2 wk), subsidiary atrial pacemakers (SAPs) assumed the primary pacemaker function. Although the SAP foci demonstrated stable heart rates and atrioventricular (AV) intervals at rest and during exercise, heart rates at rest and during steady-state exercise were reduced 34% from corresponding levels in the SAN-intact state, both with and without selective autonomic blockade. For control of dromotropic function, animals with SAP foci showed pronounced shortening in AV interval in conjunction with exercise that was further exacerbated by pretreatment with atropine. Eight weeks after excision of the primary SAN pacemakers, direct electrophysiological mapping localized the SAP foci to either the inferior right atrium along the sulcus terminalis or the dorsal cranial right atrium (in or near Bachmann's bundle). Animals with SAPs localized to the inferior right atrium had a more marked suppression in heart rate with a corresponding greater decrease in AV interval during exercise than dogs with SAP foci identified within the dorsal cranial right atrium.

Animals↗
PubMed1991

Surgical interruption of postganglionic innervation of the sinoatrial nodal region.

Recent experiments have revealed synapses that selectively mediate right and left vagal regulation of sinoatrial function in the fat pad overlying and surrounding the right pulmonary vein complex. However, precise vagal postganglionic pathways to the sinoatrial region have remained obscure. Such pathways, including critically important neural inputs to sinoatrial and atrioventricular nodal regions, may be vulnerable to surgical approaches to atrial or intracardiac repair. The present experiments seek to delineate specific autonomic pathways to the sinoatrial region of the canine heart. The distal ends of the cut right and left cervical vagi and the right and left ansae subclaviae were electrically stimulated (10 to 20 Hz, 1 msec, 2 to 3 V) before and after surgical incisions were placed. Cut No. 1 was made longitudinally along the ventral caval surface from the pericardial reflection caudally to the pulmonary vein fat pad, cut No. 2 was made from the caudal end of cut No. 1 transversely across the sulcus terminalis to a point midway across the anterior (ventral) surface of the right atrium. Each incision was closed with 4-0 silk, with care being taken to avoid injury to either the sinoatrial nodal or the pulmonary fat pad regions. In four of seven animals, these two incisions totally interrupted vagal input to the sinoatrial node, whereas in the remaining three dogs a residual inhibitory influence remained. These residual fibers were surgically ablated by excision of globular fat pads situated on the rostrodorsal surfaces of the right superior pulmonary vein, suggesting a dorsorostral route into the interatrial septum and thence to the sinoatrial node. There was little or no interruption of either right or left vagal input to the atrioventricular nodal region; sympathetic supplies to both sinoatrial nodal and atrioventricular nodal regions remained essentially intact after the two incisions. Thus the major parasympathetic postganglionic projections to the sinoatrial node in the dog heart are by way of the free wall of the right atrium and are vulnerable to surgical interventions in this portion of the heart.

Animals↗
PubMed1990

Hands-on laboratory experience in teaching-learning physiology.

Reactivation of several model 5 (vacuum tube) Grass polygraphs for active hands-on laboratory experiments by small student groups, in contrast to demonstrations and pretaped illustrations of physiological principles, resulted in remarkable rejuvenation of interest and excitement for learning in premed and introductory science classes at Taylor University. Accurate and perceptive observations were performed on the students themselves, each recording his own electrocardiogram, for example, as well as direct recordings from the pithed frog, the turtle heart, the anesthetized rabbit, and noninvasive recordings from students subjects during exercise. In the latter experiment, sweat recruitment patterns were recorded initially on the lower extremities, followed by successive appearances on thigh and abdomen and with final occurrence on the upper extremities and face. To our knowledge, this is the first report of such recruitment patterns during exercise. Results of actual student participation, with organized group discussions, convince us that laboratory teaching remains the premiere mechanism for teaching and learning organ-system physiology.

Animals↗
PubMed1990

Parasympathetic postganglionic pathways to the sinoatrial node.

Vagal ganglia that innervate the canine sinoatrial node (SAN) have been localized to a fat pad overlying and surrounding the right pulmonary vein complex (PVFP). The ventral epicardial surface of the right atrium was mapped in seven dogs anesthetized with alpha-chloralose after beta-blockade (timolol) and cardiac sympathetic and parasympathetic decentralization. A small, concentric bipolar exploring electrode was used to stimulate (during the atrial refractory period and using trains of five to eight stimuli per beat) systematically in the epicardial regions between the PVFP and the SAN. Changes in SAN rate with stimulation were measured, and the anatomic location was identified on a 150-point grid fitted to conform to size and shape of the atrium. Mapping was performed before and after local (PVFP) and systemic ganglionic blockade (hexamethonium). Data reveal that the primary vagal postganglionic pathways to the sinoatrial nodal region are subepicardial and adjacent to the SAN artery along the sulcus terminalis. Hexamethonium in the PVFP abolishes SAN inhibition during preganglionic vagal excitation, without interrupting vagal suppression of atrioventricular conduction. However, SAN slowing (with varying attenuation) continued to occur after hexamethonium (either PVFP or systemically) when the exploring electrode was applied directly over intramural postganglionic fibers between PVFP and sinus node. Attention is directed to existence of a very few synapses closer to SAN, probably in isolated ganglia immersed in fatty connective tissues along the sulcus terminalis.

Animals↗
PubMed1989

Selective vagal postganglionic innervation of the sinoatrial and atrioventricular nodes in the non-human primate.

The distribution of parasympathetic postganglionic nerves to the atrioventricular (AVN) and sinoatrial nodal (SAN) regions was investigated in the non-human primate heart. Eight male monkeys (Macaca fascicularis) weighing 5.5-7.0 kg. were anesthetized (alpha-chloralose, 50 mg/kg and urethane, 500 mg/kg) and instrumented to measure arterial pressure, electrocardiogram, atrial and ventricular electrograms. The cervical vagi were electrically stimulated (20 Hz, 4 V, 2 ms) before and after selective denervation (D) of the AVN and/or SAN. Vagal stimulation was repeated during atrial pacing to assess parasympathetic modulation of AVN conduction. Ablation of parasympathetic pathways to the AVN, accomplished by the disruption of the epicardial fat and surface muscle layer at the junction of the inferior vena cava and inferior left atrium eliminated (P less than 0.01) the dromotropic effects of vagal stimulation without affecting the heart rate response (right vagus, before D, paced: atrial rate 218.0 +/- 6.3, ventricular rate 67.1 +/- 23.7; after D: atrial rate 210.3 +/- 6.4, ventricular rate 210.3 +/- 6.4 beats/min, means +/- S.D.). In sharp contrast, surgical dissection of the fat pad overlying the right pulmonary vein-superior vena cava junction significantly (P greater than 0.01) attenuated negative chronotropic effects of vagal stimulation (left vagus, before D the R-R interval increased by 832.7 +/- 146.4 ms, 209.5% increase; after D 37.4 +/- 18.0 ms, 8.8% increase). These data demonstrate discrete vagal efferent pathways innervate both the SAN and AVN regions of the non-human primate heart.

Animals↗
PubMed1989

Chemical synthesis of echistatin, a potent inhibitor of platelet aggregation from Echis carinatus: synthesis and biological activity of selected analogs.

Echistatin, a polypeptide from the venom of the saw-scaled viper, Echis carinatus, containing 49 amino acids and 4 cystine bridges was synthesized by solid-phase methodology in 4% yield. In the final step, air oxidation of the octahydroderivative was found to be optimal at pH 8. The synthetic product was shown to be physically and biologically indistinguishable from native material. It inhibits fibrinogen-dependent platelet aggregation stimulated by ADP with IC50 = 3.3 x 10(-8) M and also prevents aggregation initiated by thrombin, epinephrine, collagen, or platelet-activating factor. Reduction of purified synthetic echistatin to octahydroechistatin with dithiothreitol followed by air oxidation regenerated homogeneous echistatin in quantitative yield. This highly specific refolding strongly suggests that the linear sequence of octahydroechistatin contains all of the information that is required for the proper folding of the peptide. The sequence Arg24-Gly-Asp of echistatin occurs also in adhesive glycoproteins that bind to the platelet fibrinogen receptor--a heterodimeric complex composed of glycoproteins IIb and IIIa. In an effort to evaluate the role of this putative binding site we have synthesized analogs of echistatin with substitution of Arg-24. Replacement with ornithine-24 (Orn-24) resulted in an analog having a platelet aggregation inhibitory activity with IC50 = 1.05 x 10(-7) M. Substitution with Ala-24 gave IC50 = 6.1 x 10(-7) M. The inhibitory activity of the corresponding short sequence analogs Arg-Gly-Asp-Phe (IC50 = 6 x 10(-6) M), Orn-Gly-Asp-Phe (IC50 = 1.3 x 10(-4) M), and Ala-Gly-Asp-Phe (IC50 = 5.0 x 10(-4) M) was also determined. These results suggest that arginine plays a more important role in the binding of the tetrapeptide than in that of echistatin.

Amino Acid Sequence↗