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Biomedical subjects

W C Randall

Publications and source records attributed to W C Randall.

At least 55 records · Page 3Linked to original sources
PubMed1988

Differential autonomic control of SAN and AVN regions of the canine heart: structure and function.

Both anatomical and physiologic evidence for relatively rich autonomic innervation of sinoatrial (SAN) and atrioventricular (AVN) regions of the canine heart exist, with indication that SAN is especially responsive to parasympathetic, while AVN is preferentially sensitive to sympathetic regulation. The distribution of autonomic pathways are sufficiently separate and discrete that careful surgical intervention can selectively delete either parasympathetic or sympathetic nerve supplies to either (or both) SAN and AVN regions. Selective blockade by restricted injections of lidocaine (general neuronal blocker) or hexamethonium (ganglionic blocker) indicate that the vast majority (perhaps all) of vagal ganglia supplying SAN reside in the pulmonary vein fat pad and associated adipose tissues. In contrast, the vagal ganglia supplying AVN are found within a smaller fat pad overlying epicardium at the junction of inferior vena cava-inferior left atrium. These vagal pathways to either automatic cells of SAN or conductile tissues of AVN can be selectively interrupted without interfering with vagal regulation of the remaining intact system. Electroneurograms from large neurons situated within PVFP of the anesthetized, open-chest animal, reveal vigorous, phasic electrical activity associated with the cardiac and respiratory cycles, as well as with sensory stimulation of the heart, great vessels, and lungs. Spontaneous electrical activity of presently unknown origin is also observed. Direct neuronal stimulation, plus retrograde transport of fluorescent markers suggest that highly selective postganglionic intracardiac pathways may regulate discharge patterns of the sinus automatic cells.

Animals↗
PubMed1987

Pharmacological profile of a new potent and specific alpha 2-adrenoceptor antagonist, L-657,743.

L-657,743,(2S,12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12 b-octahydro-2H- benzo[b]furo[2,3-a]quinolizine)-2,4'-pyrimidin-2'-one, was tested in several in vitro and in vivo models for alpha 2-adrenoceptor antagonism. L-657,743 exhibited a high affinity (less than or equal to 1 nM) for alpha 2-adrenoceptors labelled by [3H] rauwolscine or [3H]clonidine with a 240-fold selectivity versus alpha 1-adrenoceptors labelled by [3H]prazosin. L-657,743 was a potent, selective, and competitive alpha 2-adrenoceptor antagonist in the rat isolated vas deferens (pA2 = 9.3 vs. clonidine; pA2 = 7.1 vs methoxamine). In vivo, L-657,743 potently blocked clonidine-induced mydriasis in the rat and stimulated cerebrocortical norepinephrine synthesis, two indices of central alpha 2-adrenoceptor antagonism. L-657,743 exhibited a comparatively low affinity for several monoamine receptor subtypes (D1, D2, 5-HT1, 5-HT2) in radioligand binding assays in vitro and a comparatively low potency to alter the synthesis of brain DA and 5-HT in vivo indicating a marked alpha 2-specificity versus other monoamine receptor mechanisms. Compared to yohimbine, L-657,743 had considerably higher alpha 2-antagonist potency and alpha 2/alpha 1 selectivity and was significantly more alpha 2-specific (i.e., vs. DA, 5-HT receptors).

Adrenergic alpha-Antagonists↗
PubMed1987

Vagal postganglionic innervation of the canine sinoatrial node.

Differential, selective distribution of parasympathetic, postganglionic innervation to the atrioventricular nodal (AVN) region of the canine heart was recently described. Ablation of parasympathetic pathways to the AVN by disruption of the epicardial fat pad at the junction of the inferior vena cava and inferior left atrium did not interfere with normal vagal control of the sinoatrial node (SAN) function. In sharp contrast, surgical dissection of the fat pad overlying the right pulmonary vein-left atrial junction interrupted the major right and left vagal inputs to the SAN region. The pulmonary vein fat pad (PVFP) in the dog heart is triangular in shape with roughly equilateral dimensions of approximately 1 cm, its base extending from superior to inferior veins, and its apex extending nearly to the sinus nodal artery as it courses rostrally in the sulcus terminalis. Careful dissection of smaller fat pads around the circumference of the pulmonary veins and particularly over the rostral-dorsal surfaces of the right superior pulmonary vein and adjacent right atrium, completed SAN parasympathetic denervation. Care in making these dissections left the vagal supply to the AVN region essentially intact, and preserved the sympathetic supplies to both SAN and AVN regions. Autonomic ganglia, varying in size from 1 or 2 cells to 80-100 cells, were found scattered throughout the ventral PVFP (overlying and surrounding the right pulmonary vein-left atrial junction). The ganglia were generally imbedded in fatty connective tissue, although they commonly rested very close to, or were loosely surrounded by epicardial muscle. Ganglia were also found in smaller fat pads on the dorsal surfaces of the atrium between the azygos and the right superior pulmonary vein.

Animals↗
PubMed1987

Thienothiopyran-2-sulfonamides: a novel class of water-soluble carbonic anhydrase inhibitors.

An attempt to develop a water-soluble carbonic anhydrase inhibitor focused on exploring structure-activity relationships in the thienothiopyransulfonamide class. The strategy to influence water solubility while retaining carbonic anhydrase activity involved the introduction of a hydroxyl moiety and adjusting the oxidation state of the sulfur on the thiopyran portion of the molecule. Compounds 4 and 17 best fit the criteria of aqueous solubility and inhibitory potency vs. human carbonic anhydrase II and are candidates for evaluation as topically effective antiglaucoma agents.

Carbonic Anhydrase Inhibitors↗
PubMed1987

Effects of myocardial ischemia on regional function and stiffness in conscious dogs.

The extent to which cardiac nerves influence responses of regional ventricular function to acute myocardial ischemia was investigated in conscious dogs with intact cardiac innervation (N) and dogs with chronic cardiac denervation (D). Following coronary artery occlusion (CAO) left ventricular (LV) end-diastolic pressure increased more (P less than 0.01) in D (18 +/- 3.2 mmHg) than in N dogs (3.4 +/- 0.7 mmHg), whereas heart rate increased more in N (32 +/- 4.8 beats/min) than in D dogs (16 +/- 3.0 beats/min). In nonischemic zones of D dogs there were greater increases, P less than 0.05, in end-diastolic segment length, systolic segment shortening, and velocity of shortening than in N dogs. In ischemic zones, significantly greater increases in end-diastolic segment length were also observed in the D group, but similar reductions in segmental shortening occurred in both N (-116 +/- 2.8%) and D (-108 +/- 5.2%) dogs. The time constant of isovolumic relaxation was not different in the two groups. However, in ischemic zones of N dogs myocardial stiffness constant (k) increased by 109 +/- 24 from 33 +/- 4.9 and end-diastolic stiffness (Eed) rose by 1527 +/- 310 from 253 +/- 34 mmHg, whereas k increased significantly less (P less than 0.05) in D dogs. Eed of ischemic zones also rose significantly less (P less than 0.05) in D dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of left circumflex coronary flow transducer implantation on posterior wall innervation.

To determine whether dissection around a coronary artery and implantation of a flow transducer resulted in partial regional denervation of the heart, the effects of bilateral stimulation of the ansae subclaviae were evaluated on regional left ventricular (LV) wall thickening (WT) and tissue norepinephrine content in four groups of dogs following 1) sham operations (n = 6),2) implantation of a Doppler flow transducer on the left circumflex coronary artery (n = 6), 3) selective circumflex coronary artery denervation with topical phenol application (n = 5), and 4) selective denervation of the posterior LV wall by extensive surgical stripping of the left circumflex coronary artery and local application of phenol (n = 6). One week later after anesthesia (chloralose 100 mg/kg) and a second thoracotomy for implantation of ultrasonic WT crystals, stimulation of the ansae subclaviae increased posterior WT by 67 +/- 9% in the sham group, 71 +/- 14% in the flow probe group, and did not increase systolic WT in the denervated group. In the posterior LV wall, norepinephrine levels were reduced (P less than 0.01) in the denervated group (6 +/- 4 pg/mg) but not in the flow probe group (629 +/- 4 pg/mg) compared with the sham group (589 +/- 88 pg/mg). Selective left circumflex coronary artery denervation did not result in either diminished norepinephrine levels in the posterior LV wall nor diminished response of WT to sympathetic nerve stimulation. Thus chronic instrumentation applied properly to the left circumflex coronary artery does not result in significant regional denervation of the posterior myocardium.

Animals↗
PubMed1987

Selective ganglionic blockade of vagal inputs to sinoatrial and/or atrioventricular regions.

Vagal postganglionic neurons to sinoatrial (SAN) and atrioventricular (AVN) nodal regions of the canine heart have been localized surgically around the right pulmonary vein-atrial fat pad and in the fat pad overlying the epicardium at the inferior vena cava-inferior left atrial junction, respectively. Local ganglionic blocking doses (total of 5 mg per injection) of hexamethonium were injected into the pulmonary vein-atrial fat pad to block selectively right and left vagal inputs to the SAN region without interrupting vagal inputs to AVN. Conversely, hexamethonium injected into the inferior vena cava-inferior left atrial pad selectively blocked vagal control of arteriovenous conduction without interfering seriously with vagal control of SAN function. Vagal ganglia situated in pulmonary vein-atrial fat pad also exercise moderate but incomplete control of right atrial contractile force. Lesser vagal control of atrial inotropism is localized in the inferior vena cava-inferior left atrial fat pad. Ganglia situated in a large fat pad on the dorsal epicardial surface of the left atrium (left atrial fat pad) appear to play little or no role in SAN or AVN regulation, although some left preganglionic axons may pass through it en route to the AVN region. Vagal stimulation is associated with prompt and profoundly negative chronotropic and dromotropic responses, but in response to the same stimulation, a negative change in atrial contractile force is much slower in development and is much longer lasting. Such precise anatomical localization and differentiation of the intrinsic vagal regulation of SAN, AVN and contractile force opens new avenues of research on the neural regulation of cardiac performance.

Animals↗
PubMed1986

Functional anatomy of the major cardiac nerves in cats.

In recognition of the extensive use of the cat as an experimental model of cardiac innervation, the effects of electrical stimulation of stellate ganglia, thoracic vagosympathetic complexes, and individual feline cardiopulmonary nerves on heart rate, blood pressure, and contractility in all four cardiac chambers were analysed and correlated with the anatomy of the thoracic autonomic nervous system. The right and left stellate ganglia in cats are relatively large and globular. Distinct dorsal and ventral ansae subclavia arise from these ganglia, connecting with the relatively small, spindle-shaped middle cervical ganglia situated in the apices of the thoracic cage bilaterally. A cranial pole nerve arises from each of the middle cervical ganglia and courses cranially to unite with the ipsilateral superior cervical ganglia. On each side, the major cardiopulmonary nerves arise from the middle cervical ganglion, the relatively large vagosympathetic trunk, and the stellate ganglion. On the right side these nerves consist of a very small right stellate cardiac nerve, a recurrent cardiac nerve, a group of craniovagal nerves and a group of caudovagal cardiopulmonary nerves. On the left side are the left stellate cardiac, ventrolateral, ventromedial, and innominate cardiopulmonary nerves. All of these nerves contain efferent parasympathetic and/or sympathetic fibers which modify cardiac chronotropism and/or inotropism. Some contain afferent fibers. These results indicate that specific cardiopulmonary nerves exist in cats, which when stimulated, modify the cardiovascular system in specific fashions.

Animals↗
PubMed1986

L-654,284 a new potent and selective alpha 2-adrenoceptor antagonist.

L-654,284 [(2R, 12bS)-N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]-furo[2,3-a] quinolizine-2-yl)-N-methyl-2-hydroxyethanesulfonamide) was tested in several in vitro and in vivo models for alpha 2-adrenoceptor antagonist activity and compared to several reference agents. In vitro L-654,284 completed for the binding of 3H-clonidine or 3H-rauwolscine (Ki's 0.8 nM, 1.1 nM) and blocked the presynaptic effects of clonidine in the rat isolated vas deferens (pA2, 9.1). L-654,284 exhibited marked alpha 2-vs. alpha 1-adrenoceptor selectivity in vitro, inhibiting 3H-prazosin binding with a Ki of 110 nM and blocking the effects of methoxamine on the vas deferens with a pA2 of 7.5. In vivo L-654,284 at 22 nmoles/kg i.v. doubled the ED50 of clonidine to produce mydriasis in rats. Given orally, the potency of L-654,284 in this test was reduced by a factor of 5.5. L-654,284 also potently increased cerebrocortical NE turnover in the rat, another in vivo index of alpha 2-adrenoceptor blockade in the central nervous system. In the periphery, L-654,284 demonstrated alpha 2-adrenoceptor selectivity by preferentially blocking the pressor effects of UK 14304 versus those of methoxamine in the pithed rat. Overall, L-654,284 was generally a more potent alpha 2-adrenoceptor antagonist than RX 781094 with comparable alpha 2/alpha 1 selectivity and was several times more potent and alpha 2-selective than WY 26703 or yohimbine. In addition, L-654,284 had better (5-6 times) oral bioavailability than RX 781094 or WY 26703.

Adrenergic alpha-Antagonists↗
PubMed1986

Cardiac responses to exercise in the dog before and after destruction of the sinoatrial node.

Chronotropic and dromotropic responses to treadmill exercise were compared in conscious dogs prior to and following excision of the sinoatrial node (SAN). The initial junctional rhythm accompanying removal of the SAN region was replaced within hours to days by subsidiary atrial pacemaker (SAP) foci located in the inferior right atrium along the sulcus terminalis. With SAN intact, cardiac acceleration was immediate at onset of exercise and the tachycardia was directly proportional to work intensity. Atrioventricular (AV) conduction concurrently accelerated during exercise as manifest by shortening in P-R and atrioventricular (A-V) intervals. Following SAN excision, subsidiary atrial pacemaker foci likewise demonstrated prompt tachycardias during exercise, although heart rate was significantly reduced at rest and during steady state exercise. In the SAP state, tachycardia during exercise was related to work intensity and was mediated by changes in cardiac autonomic nerve activity. Combined propranolol-atropine blockade increased heart rate at rest in the SAP state, and significantly attenuated the tachycardia accompanying treadmill exercise. Following SAN excision the P-R (A-V) interval was significantly reduced in the resting animal. In response to exercise, AV conduction time decreased in the SAP state, though the absolute levels during steady state exercise were not significantly different from prior control runs with SAN intact. Blood pressure response to exercise was similar during both SAN and SAP states. We conclude that following an initial unstable period, SAP foci maintain adequate heart rate increases in response to dynamic exercise, primarily mediated via autonomic nerve regulation.

Adrenergic beta-Antagonists↗
PubMed1986

Parasympathetic ganglia innervating the canine atrioventricular nodal region.

Surgical disruption of the small (approximately 0.7 x 1.0 cm) epicardial fat pad situated at the junction of the inferior vena cava (IVC) and inferior surface of the left atrium (ILA) interrupts both right and left vagal input to the atrioventricular nodal (AVN) region of the canine heart. This intervention eliminates AV block during supramaximal stimulation of both cervical vagi, without interfering with sinus bradycardia normally associated with sinoatrial nodal (SAN) suppression. Independent modulation of SAN and AVN activities by the parasympathetic system is thereby revealed. Histology of the excised IVC-ILA fat pad reveals multiple well organized autonomic ganglia. These ganglia range from 2 to 80 cells per cluster and are associated with numerous nerve trunks. Individual ganglia are commonly surrounded by fatty connective tissue closely adjacent to epicardial muscle. They have not been found imbedded within atrial muscle and have been been found in or close to endocardial muscle layers. Other ganglia, imbedded in the fat pad overlying the posterior surface of the left atrium or in the atrioventricular groove, do not directly modulate A-V conduction. Surgical dissection around the extreme left or middle segments of the great cardiac vein and the coronary sinus failed to interrupt either left or right vagal input to the AVN region. Parasympathetic, preganglionic pathways to these AVN synapses do not, therefore, course from left to right along the atrioventricular groove. However, dissection around the extreme right portion of the coronary sinus at its penetration of the inferior interatrial septum, did interrupt vagal influences upon A-V conduction. Thus, numerous autonomic ganglia have been localized in the canine heart which serve as synaptic stations mediating both right and left vagal regulation of A-V conduction.

Adipose Tissue↗
PubMed1986

Functional anatomy of the canine mediastinal cardiac nerves located at the base of the heart.

The major canine cardiopulmonary nerves which arise from the middle cervical and stellate ganglia and the vagi course toward the heart in the dorsal mediastinum where they form, at the base of the heart dorsal to the pulmonary artery and aorta, the dorsal mediastinal cardiac nerves. In addition, the left caudal pole and interganglionic nerves project onto the left lateral side of the heart as the left lateral cardiac nerve. These nerves contain afferent and (or) efferent axons which, upon stimulation, modify specific cardiac regions and (or) systemic pressure. In addition, with the exception of the left lateral cardiac nerve, stimulation of each of these nerves produces compound action potentials in the cranial ends of the majority of the major cardiopulmonary nerves demonstrating that axons in each dorsal mediastinal cardiac nerve interconnect with axons in the majority of the cardiopulmonary nerves. Axons in the left lateral cardiac nerve connect primarily with axons in the left caudal pole and left interganglionic nerves. The dorsal mediastinal nerves project distally onto the heart as coronary nerves accompanying the right or left coronary arteries. These innervated the ventricular myocardium which is supplied by their respective vessels. The left lateral cardiac nerve projects directly onto the lateral epicardium of the left ventricle. The dorsal mediastinal and left lateral cardiac nerves are the major sympathetic cardiac nerves. Thus, the cardiac nerves located in the mediastinum at the base of the heart are not simple extensions of cardiopulmonary nerves, but rather have a unique anatomy and function of their own.

Action Potentials↗
PubMed1986

Functional interdependence of discrete vagal projections to SA and AV nodes.

Dynamic modulation of chronotropic and dromotropic function was evaluated in anesthetized dogs before and after selective parasympathectomy of the atrioventricular (AV) node. Vagal and cardiac sympathetic efferent nerves were decentralized, and the distal cut ends of the cervical vagi were stimulated at frequencies from 1 to 25 Hz with step-wise voltage changes. To investigate parasympathetic modulation of AV conduction, stimulations were performed with and without atrial pacing. After determination of chronotropic and dromotropic responses, in the intact state, selective AV node parasympathectomy was performed as previously described [Am. J. Physiol. 248 (Heart Circ. Physiol. 17): H61-H68, 1985]. Stimulation protocols were then repeated. Control results in intact animals reveal a parallel and finely balanced vagal regulation of chronotropic and dromotropic responses over a wide range of frequency stimulations. Conversely, selective parasympathectomy of the AV node interrupts extrinsic vagal modulation of AV conduction without affecting parasympathetic control of chronotropic function. The dynamic balance of chronotropic and dromotropic function, modulated by extrinsic vagal input, reflects the parallel activation of functionally and anatomically distinct parasympathetic projections to the sinoatrial (SA) and AV nodal tissue. Thus present experiments allow a more detailed examination of vagal innervation of the SA and AV nodes, the importance of their balance through neuroregulation, and progress toward understanding the pathophysiology of disturbances to this balance.

Animals↗
PubMed1986

Selective vagal innervation of sinoatrial and atrioventricular nodes in canine heart.

Parasympathetic pathways mediating chronotropic and dromotropic responses to cervical vagal stimulation were determined from sequential, restricted, intrapericardial dissection around major cardiac vessels. Although right cervical vagal input evoked significantly greater bradycardia, supramaximal electrical stimulation of either vagus produced similar ventricular rates, both with and without simultaneous atrial pacing. Dissection of the triangular fat pad at the junction of the inferior vena cava-inferior left atrium (IVC-ILA) invariably eliminated all vagal input to the atrioventricular (AV) nodal region. Yet IVC-ILA dissection had minimal influence on evoked-chronotropic responses to either cervical vagal or stellate ganglia stimulation. Respective intrapericardial projection pathways, from either right or left vagi, are sufficiently distinct to allow unilateral parasympathetic denervation of the sinoatrial (SA) and atrioventricular (AV) nodal regions. Left vagal projections to the SA and AV nodal regions course primarily along and between the right pulmonary artery and left superior pulmonary vein. Right vagal projections to the SA and AV nodal regions are somewhat more diffuse but concentrate around the right pulmonary vein complex and adjacent segments of the right pulmonary artery. We conclude there are parallel, yet functionally distinct, inputs from right and left vagi to the SA and AV nodal regions.

Animals↗
PubMed1985

Rebound cardiovascular responses following stimulation of canine vagosympathetic complexes or cardiopulmonary nerves.

Electrical stimulation of a canine vagosympathetic complex or a cardiopulmonary nerve can elicit a variety of negative chronotropic and inotropic cardiac responses, with or without alterations in systemic arterial pressure. In the period immediately following cessation of such a stimulation "rebound" tachycardia, increased inotropism above control values in one or more regions of the heart, and (or) elevation in systemic arterial pressure can occur. These "rebound" phenomena are abolished by propranolol or ipsilateral chronic sympathectomy. It is proposed that "vagal" poststimulation "rebound" of the canine cardiovascular system is primarily the result of activation of sympathetic neural elements present in the vagosympathetic complexes or cardiopulmonary nerves.

Animals↗