Biomedical subjects

W C Randall

Publications and source records attributed to W C Randall.

At least 73 records · Page 4Linked to original sources

PubMed1985

Selective parasympathectomy of automatic and conductile tissues of the canine heart.

From right thoracotomy (T4-T5), the canine heart was suspended in its pericardium to expose its major venous inputs. Vagal and sympathetic trunks were prepared for electrical stimulation (10-20 Hz, 5.0 ms, 3-5 V) before and after each separate denervation procedure. Vagal stimulation was instituted with and without concurrent atrial pacing. The following surgical interventions were performed. 1) The superior vena cava was cleared of connective and nervous tissues from the pericardial reflection caudally to the level of the right pulmonary artery. 2) The azygos vein was cleared, tied, and sectioned. 3) The right pulmonary veins were isolated and cleared intrapericardially. 4) The dorsal surface of the atria was dissected between the right and left pulmonary veins and painted with phenol. Each step in the procedure elicited successive stepwise deletion of parasympathetic influences on sinoatrial tissues of the canine heart with only minor ablation of sympathetic inputs. 5) Dissection of the triangular fat pad at the junction of the inferior vena cava and inferior left atrium eliminated the remaining parasympathetic efferent input to the heart with dramatic deletion of atrioventricular block during either left or right vagal stimulation, again with preservation of most of the sympathetic innervation. These experiments clearly demonstrate differential and selective inputs of parasympathetic pathways to sinoatrial (SAN) and atrioventricular (AVN) regions of the dog heart but relatively little interference with sympathetic distributions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Differential responses accompanying sequential stimulation and ablation of vagal branches to dog heart.

Electrical excitation of small thoracic vagal branches elicited highly localized responses in the canine heart. Specific pathways to the sinoatrial nodal (SAN) regions were identified from negative chronotropic responses to stimulation (20 Hz, 5.0 ms, 3.0-5.0 V) of these branches. Pathways to the atrioventricular nodal (AVN) region were determined from changes in A-H interval (His bundle electrogram) and incidence of heart block as vagal branches were stimulated during concurrent atrial pacing. A few small branches influenced a single cardiac function (atrial rate, contractile force, or AV conduction). More commonly, activation of such branches elicited simultaneous chronotropic and dromotropic effects. However, many branches failed to elicit any detectable cardiac change. The major outflow from the left vagus to SAN and AVN regions is by way of cardiac branches from the recurrent laryngeal nerve at its reflection around the aorta. Activation of the left recurrent nerve reduced atrial rate by 43% and doubled A-H interval 84 to 167 ms. The right thoracic vagus or its branches induced A-H prolongation from 78 to 131 ms. H-V intervals remained constant at a mean of 35 ms. Outflows from the right thoracic vagus to SAN and/or AVN regions originated just below the middle cervical ganglion and at all levels down to the azygos vein.

Animals↗

PubMed1985

Adverse effects of chronic cardiac denervation in conscious dogs with myocardial ischemia.

The extent to which total chronic cardiac denervation protects the ischemic myocardium was investigated in conscious dogs. The major hemodynamic difference after coronary artery occlusion was that left ventricular end-diastolic pressure rose significantly more, P less than 0.01, in the denervated group (12 +/- 1.5 mm Hg) than in the normal group (4.4 +/- 1.4 mm Hg). Blood flow (radioactive microspheres) in the ischemic endo- and epicardium fell to similar levels at 3-5 minutes after coronary occlusion, but was significantly less (P less than 0.01) in denervated dogs at 3 hours after occlusion in the endo- (0.05 +/- 0.01) and epicardium (0.30 +/- 0.02 ml/min per g), than in the endo- (0.13 +/- 0.03) and epicardium (0.42 +/- 0.05 ml/min per g) in the normal group. A subgroup of normal dogs was also studied, with left ventricular end-diastolic pressure increased by volume loading to levels similar to those observed in the denervated group after coronary occlusion; in these dogs, blood flow was similar to that in the other two groups 3-5 minutes after coronary artery occlusion, but, at 3 hours, was significantly more depressed (P less than 0.01) than that observed in normal dogs without volume loading in both endo- (0.03 +/- 0.01) and epicardial (0.25 +/- 0.03 ml/min per g) layers. Infarct size, as a fraction of the area at risk, was significantly greater (P less than 0.05) in the denervated group (60 +/- 4.3%) and in the subgroup of normal dogs with elevated left ventricular end-diastolic pressure (73 +/- 5.8%), compared with the normal group without volume loading (37 +/- 8.1%). Thus, in conscious dogs, total chronic cardiac denervation exerts an adverse effect on infarct size which may be related to the sustained elevation in left ventricular end-diastolic pressure and consequent impairment of collateral perfusion.

Animals↗

PubMed1984

Local epicardial chemical ablation of vagal input to sino-trial and atrioventricular regions of the canine heart.

In open-chest, pentobarbitalized dogs, right and left cervical vagi were electrically stimulated (20 Hz, 5.0 ms, 4-6 volts) before and after carefully painting phenol (90%) over each of 6-8 narrow strips (2-3 mm width) and over restricted portions of the superior and inferior right atrium. Successive phenol strips were applied until the sino-atrial nodal (SAN) region had been completely surrounded, and also applied over a triangular fat pad at the junction of the inferior vena cava (IVC) and inferior left atrium (ILA). Electrical excitation of the autonomic trunks following each sequential epicardial phenol blockade resulted in successive deletion of cardio-inhibitory responses, a majority of sympathetic excitatory responses remaining intact. We conclude that most vagal fibers reach the SAN region via the superior-posterior right atrium (SVC and superior pulmonary veins) and these can be ablated leaving most vagal fibers to the atrioventricular nodal AVN region unimpaired. Phenol painting at the junction of IVC and ILA abolished vagal inhibition of conduction across the A-V junction. These studies illustrate distinct vagal distributions to the SAN and AVN regions of the canine heart. After all responses to vagal stimulation have been abolished, sympathetic alterations in heart rate and A-V conduction remain, thus revealing important differentiation in sympathetic fiber distribution to these key regions of automaticity and conduction.

Animals↗

PubMed1984

Alterations in subsidiary pacemaker function after prolonged subsidiary pacemaker dominance in the canine right atrium.

In vivo and in vitro techniques were used to study the functional characteristics of subsidiary atrial pacemaker activity 4 to 11 months after surgical excision of the sinoatrial node region of the dog heart. Characteristics of this long-term subsidiary atrial pacemaker activity were compared with those of sinoatrial node and short-term subsidiary atrial pacemaker activities. Extracellular bipolar electrodes were used to estimate the site of earliest activation and monitor spontaneous rate. Under both in vivo and in vitro conditions, long-term pacemaker activity was located in the same region of the inferior right atrium as was short-term pacemaker activity. Under in vitro conditions, long-term activity was characterized by a reduced sensitivity to acetylcholine and overdrive pacing and by a lack of dependence on beta-adrenergic stimulation compared with short-term activity. Furthermore, long-term pacemaker activity was more sensitive to acetylcholine and less sensitive to norepinephrine (greater than 10(-7) M) compared with sinoatrial node activity. It is concluded that the subsidiary atrial pacemakers that emerge soon after removal of the sinoatrial node are the same as those pacemakers that ultimately assume long-term control of the heart. In addition, after subsidiary atrial pacemakers assume dominant pacemaker function, their dependence on norepinephrine and their response to acetylcholine and overdrive pacing are reduced. These changes facilitate a more stable regulation of atrial pacemaker rhythm and, thereby, make subsidiary atrial pacemaker function more like that of the sinoatrial node.

Acetylcholine↗

PubMed1984

Adrenoceptor and tetrabenazine antagonism activities of some pyridinyltetrahydropyridines.

A series of pyridinyltetrahydropyridine derivatives was synthesized and evaluated as adrenoceptor and tetrabenazine antagonists. 4-(3-Fluoro-2-pyridinyl)-1,2,5,6-tetrahydropyridine proved to be the most potent and selective alpha 2-adrenoceptor antagonist of the series as measured in vitro by displacement of [3H]clonidine and [3H]prazosin from membrane binding sites of calf cerebral cortex and by antagonism of the effects of clonidine and methoxamine in the rat isolated, field-stimulated vas deferens. In addition, this compound, and the corresponding desfluoro derivative, blocked tetrabenazine-induced ptosis in the mouse.

Animals↗

PubMed1984

Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists.

A series of tricyclic oxazines, namely, the 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, have been synthesized and assayed for dopamine agonist activity. One of the members of this series, compound (+)VII-15, was found to be a remarkably potent agonist in vivo when tested in the standard 6-hydroxydopamine lesioned rat assay. The absolute configuration of the compound corresponds to that found in the active isomer of apomorphine. Its activity at the alpha 2 receptor (vs. [3H]clonidine) is relatively low. It also failed to stimulate the synthesis of cAMP in the carp retina assay, thus giving the compound a highly selective profile in favor of the D2 receptor.

Animals↗

PubMed1984

Conformational modifications of cyclic hexapeptide somatostatin analogs.

A model for the bioactive conformation of the highly active cyclic hexapeptide somatostatin analog cyclo-(Pro-Phe-D-Trp-Lys-Thr-Phe) has been proposed. As a test of this model, several compounds containing lactam and N-Me amino acid conformational modifications in the Thr-Phe-Pro-Phe beta turn were synthesized. The N-Me alanine and sarcosine substitutions for proline gave highly active analogs, while lactam dipeptides in place of Phe-Pro decreased potency. 1H n.m.r. and CD spectra of these analogs illustrate the conformational effects in solution of these modifications. The results provide additional support for the proposed conformational model.

Animals↗

PubMed1984

Parallel baroreceptor control of sinoatrial rate and atrioventricular conduction.

The vagal efferent limb of baroreceptor reflexes was studied in 10 anesthetized (alpha-chloralose) dogs to determine its differential regulatory significance on sinoatrial (SA) rate and antegrade atrioventricular (AV) conduction. The arterial pressure stimulus for these reflexes was produced by intra-aortic balloon inflation (increase) and hemorrhage (decrease); the efferent sympathetic reflex was blocked by spinal cord transection. The dromotropic response to arterial pressure changes was studied over a physiological range of arterial pressures (60-150 mmHg) with the chronotropic response intact, with atrial pacing to prevent the chronotropic response, and after atropine or bilateral vagotomy. In all animals, the chronotropic response to arterial pressure changes balanced the dromotropic response to preserve 1:1 AV conduction over most arterial pressures. If the chronotropic response was prevented with atrial pacing, an unbalanced and independent vagal regulation of AV conduction was "unmasked" with resultant high-grade second-degree AV block. The independent regulations of SA rate and AV conduction were further found to be finely matched to produce an equilibrium of chronotropic-dromotropic changes as arterial pressure varied. Clinical conditions arising from disruption of this equilibrium are discussed.

Animals↗

PubMed1984

Influence of cardiac denervation on subsidiary atrial pacemaker stabilization.

Overdrive suppression was determined by measuring cardiac cycle lengths after rapid atrial pacing in nine alert conscious dogs sustaining total intrapericardial denervation. Rapid atrial pacing was performed at 125-400% of spontaneous heart rate for 30 s and at 200% spontaneous rate for 30, 60, 120, and 180 s, with and without cholinergic (atropine 0.2 mg/kg iv) or adrenergic blockade (propranolol 0.5 mg/kg iv). Corrected recovery time (CRT) was defined as the first recovery cycle length minus average control cycle length. To compare responses of the intact sinoatrial node (SAN) and subsidiary atrial pacemakers, CRT was measured in the conscious animal before and after SAN excision. Immediately after SAN excision, a junctional rhythm was frequently observed, but within a short time (min-h), subsidiary atrial pacemaker dominance was established with well-formed P waves and P-R interval averaging 85.3 +/- 3.4 ms. CRT before SAN excision ranged from 100 to 300 ms. Following pacing at 125-400% of spontaneous heart rate soon after SAN excision, CRT was markedly prolonged, ranging up to 6,000 ms. Atropine and propranolol did not influence CRT in the denervated preparation. CRT of subsidiary atrial pacemakers in the normally innervated dog heart returned to control pre-SAN excision values in 1-2 wk. In the denervated heart complete autonomic denervation exaggerated time required for return to control CRT values to 5-8 wk.

Animals↗

PubMed1983

Multiple central alpha 2 adrenoceptors of avian and mammalian species.

Although equilibrium binding experiments indicated that calf cerebral membranes contained two classes of clonidine receptors and that chicken cerebral membranes might have contained only one, experiments investigating the kinetics of binding and the effects of GppNHp clearly indicated that the cerebral membranes of both species contained two subtypes of receptor, with the avian high affinity receptor having been present at too low a density to be readily detected in equilibrium binding studies. For both species 10 microM GppNHp sharply reduced or eliminated both the high affinity binding site and the slow steps of association and dissociation without changing the low affinity site and its related rapid association and dissociation steps. The high affinity sites from both species had similar specificities since the relative affinities of the avian binding site for a series of clonidine analogues closely reflected the relative affinities of the calf binding site. The properties of the chicken and calf alpha 2 subtypes resembled those reported for rat brain.

Animals↗

PubMed1983

Piperazinylimidazo[1,2-a]pyrazines with selective affinity for in vitro alpha-adrenergic receptor subtypes.

Regioselective syntheses of alkyl- and halogen-substituted piperazinylimidazo[1,2-a]pyrazines by novel oxidation-dehydration of [(beta-hydroxyalkyl)amino]pyrazines are described. Lanthanide shift reagent studies allowed correction of literature assignments of NMR chemical shifts and coupling constants for the imidazo[1,2-a]pyrazine ring system (e.g., J5,8 greater than J6,8). Equilibrium constants for displacement of specifically bound [3H]clonidine and [3H]prazosin from calf cerebral cortex homogenates in vitro are tabulated for reference and title compounds, and structure-affinity relationships for alpha 2- vs. alpha 1-adrenergic receptors are considered. Compound 2a, 8-(1-piperazinyl)imidazo[1,2-a]pyrazine, is equipotent with mianserin on the clonidine receptor (alpha 2) but ca. 70 times as selective as mianserin for this alpha 2-adrenergic receptor. Reduction of the imidazo ring (2,3-dihydro) lowers affinity for the alpha 2 receptor without affecting alpha 1-receptor affinity. Computer-assisted molecular modeling techniques are applied to the estimation of conformational energies of 2a and its 5-position isomer in relation to the semirigid molecule mianserin.

Animals↗

PubMed1983

Synthesis of (7R)-7H-indolo[3,4-gh][1,4]benzoxazines, a new class of D-heteroergolines with dopamine agonist activity.

Synthesis of several members of the 9-oxaergoline ring system is presented. Both the C/D cis and the C/D trans isomers of 4,6,6a,8,9,10a-hexahydro-7-ethyl-7H-indolo[3,4-gh] [1,4]benzoxazine were prepared, and the C/D trans isomer was resolved into its optical isomers. The enantiomer having the highest affinity for the [3H]apomorphine binding site, (-)-trans-6-ethyl-9-oxaergoline [(-)-6b], was shown to have the same absolute configuration as the natural ergolines, namely, 6aR, 10aR. In vivo and in vitro pharmacological evaluation shows these 9-oxaergolines to possess potent dopamine agonist properties.

Animals↗

PubMed1983

Antihypertensive beta-adrenergic blocking agents: N-aralkyl analogues of 2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine.

An interest in dual-acting antihypertensive agents, specifically those related to (S)-2-[3-(tert-butylamino)-2-hydroxypropoxy]-3-cyanopyridine (1), led us to probe the contribution of the side-chain amino substituent in this series. The ability of 1 and its various analogues to displace radiolabeled alpha 1 (WB-4101 and prazosin) and beta (dihydroalprenolol) adrenergic receptor ligands was assessed by receptor-binding techniques. Most of the compounds exhibited high beta-adrenoceptor binding affinities, but only the N-aralkylamino-substituted compounds showed high alpha 1-adrenoceptor affinities. Therefore, the vasodilation shown by 1 was not due to an interaction with the alpha 1 adrenoceptor. The aralkylamino analogues of 1 in spontaneously hypertensive rats and anesthetized dogs exhibited antihypertensive activity and alpha 1-adrenoceptor blocking properties. Unlike the preference shown by beta-adrenoceptors for S enantiomers in this oxymethylene class of beta blockers, the chirality at the secondary hydroxy center made only a minor contribution to the affinity for the alpha 1-adrenoceptor and even less of a contribution to the observed antihypertensive effects. This lack of chiral influence at the hydroxy center confirmed what had been previously observed in more limited studies with the isomers of both labetalol and medroxalol.

Adrenergic beta-Antagonists↗

PubMed1983

Inhibitors of glycolic acid oxidase. 4-Substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives.

An extensive series of novel 4-substituted 3-hydroxy-1H-pyrrole-2,5-dione derivatives has been prepared and studied as inhibitors of glycolic acid oxidase (GAO). Compounds possessing large lipophilic 4-substituents are, in general, potent, competitive inhibitors of porcine liver GAO in vitro. Methylation of the nitrogen or the 3-hydroxy substituent reduced potency dramatically, indicating the requirement for the two acidic functions on the 1H-pyrrole-2,5-dione nucleus. In rat liver perfusion studies, with three representative compounds, concentration-dependent inhibition of the conversion of [1-14C]glycolate to [14C]oxalate was observed. Chronic oral administration to ethylene glycol fed rats of the 4-(4'-bromo[1,1'-biphenyl]-4-yl) derivative (83) was shown to effect a significant reduction in urinary oxalate levels over a 58-day period.

Alcohol Oxidoreductases↗

PubMed1983

Synthesis and receptor binding studies relevant to the neuroleptic activities of some 1-methyl-4-piperidylidene-9-substituted-pyrrolo[2,1-b][3]benzazepine derivatives.

The synthesis of a series of 1-methyl-4-(9-substituted-11H-pyrrolo[2,1-b]benzazepin-11-ylidene)piperidines (4a-f) and 1-methyl-4-(9-substituted-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-ylidene)piperidines (4g-l) is described. As with th e 3-substituted cyproheptadine compounds 1b-e, atropisomerism exists in 4b-f, but unlike the enantiomers of 1b-e, the pyrrolobenzazepine enantiomers racemize at room temperature. Thus, the bromo compound (+)-4b has a half-life of 128 +/- 1 min at 25 degrees C, while the chloro compound (-)-4c has a half-life of 114 +/- 9 min at 25 degrees C. Compounds 4a-l have been examined for receptor binding affinities in assays that have been recognized as predictive for antipsychotic activity. The displacement of specifically bound tritiated ligands, comprising the dopamine antagonist [3H]spiperone, the dopamine agonist [3H]apomorphine, the muscarinic cholinergic antagonist [3H]quinuclidinyl benzilate (QNB), the alpha-adrenergic antagonist [3H]prazosin, the alpha-adrenergic agonist [3H]clonidine, the serotonin-1 binding agent [3H]serotonin, and the mixed serotonin agonist-antagonist [3H]lysergic acid diethylamide (LSD), by 4a-l has been measured utilizing membrane preparations of mammalian brain. Certain of the features of the receptor binding of these compounds have been shown to be common to several of the receptor sites. Data from these binding studies have been compared to corresponding data previously obtained for a series of chiral 3-substituted cyproheptadine analogues, and the receptor binding data of the two classes of compounds are discussed with respect to their molecular geometries.

Animals↗

PubMed1983

Inhibitors of glycolic acid oxidase. 4-substituted 2,4-dioxobutanoic acid derivatives.

Fourteen new 4-substituted 2,4-dioxobutanoic acids have been synthesized. These compounds, all of which contain lipophilic 4-substituents, are potent inhibitors in vitro of porcine liver glycolic acid oxidase. The I50 value of the two most potent representatives, 4-(4'-bromo[1,1'-biphenyl]-4-yl)-2, 4-dioxobutanoic acid (8) and 4-[4'-[[(3,4-dihydro-3-hydroxy-2H-1, 5-benzodioxepin-3-yl)methyl]thio][1,1'-biphenyl]-4-yl]-2, 4-dioxobutanoic acid (13) is 6 X 10(-8)M.

Alcohol Oxidoreductases↗

PubMed1983

Pyridinylpiperazines, a new class of selective alpha 2-adrenoceptor antagonists.

A series of 1-(2-pyridinyl)piperazine derivatives was synthesized and evaluated for adrenergic activity. In vitro activity was assessed through the antagonism of clonidine's effect in the rat, isolated, field-stimulated vas deferens and by the displacement of [3H]clonidine from membrane binding sites of calf cerebral cortex. Antagonism of clonidine-induced mydriasis in the rat was used as an in vivo assay. Several members of the series proved to be potent, selective alpha 2-adrenoceptor antagonists. 1-(3-Fluoro-2-pyridinyl)piperazine was more potent than either yohimbine or rauwolscine in displacement of [3H]clonidine and had a higher affinity for this binding site (alpha 2) than for the [3H]prazosin site (alpha 1). In vivo, the 3-F derivative was more potent than the reference standards in reversing clonidine-induced mydriasis. None of the members of this series was more selective or potent than rauwolscine in antagonizing clonidine in the rat vas deferens.

Adrenergic alpha-Antagonists↗