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Biomedical subjects

S B Jones

Publications and source records attributed to S B Jones.

At least 127 records · Page 7Linked to original sources

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↗

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↗

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↗

Plasma catecholamines in rats during rewarming from induced hypothermia.

The present study sought to quantitate the levels of plasma catecholamines [norepinephrine (NE), epinephrine (E), and dopamine (DA)] during induction and rewarming from hypothermia. Male rats (317 +/- 8 g) were made hypothermic by exposure to 0.9% halothane at -10 to -15 degrees C while blood pressure (carotid artery), heart rate, and colonic temperature (Tc) were monitored. Anesthesia was discontinued when Tc reached 28 degrees C. Tc continued to fall but was held at 20-20.5 degrees C for 30 min. Rewarming was then initiated by raising ambient temperature to 22 degrees C. Arterial blood samples were taken 1) before cooling, 2) just before rewarming, 3) when Tc reached 22 degrees C during rewarming, and 4) when Tc reached 27 degrees C during rewarming. Plasma was assayed radioenzymatically for catecholamines using both phenylethanolamine-N-methyltransferase and catechol-O-methyltransferase procedures, and hypothermic induction resulted in significant increases in NE, E, and DA above control levels (P less than 0.01). With rewarming to Tc = 22 degrees C, all catecholamines increased above the level observed during hypothermia (P less than 0.01), and NE and DA increased still further (P less than 0.01) when Tc reached 27 degrees C. The levels of plasma catecholamines observed during hypothermia and during the rewarming phase indicate a role of the sympathoadrenal medullary system in the metabolic adjustments associated with hypothermia and recovery. During rewarming, the levels of E and NE attained exceed those at which both substances may be expected to act as circulating hormones.

Adaptation, Physiological↗

Plasma catecholamines in the conscious rat during endotoxicosis.

Blood pressure, heart rate, and plasma catecholamines were determined in conscious unanesthetized rats given intravenous saline or endotoxin (LPS from S. enteritidis). Rats were monitored for 6 hr and survival determined at 24 hr. Blood pressure and heart rate measurements were determined using implanted arterial cannulae. The first of two protocols involved surgical implantation of cannulae 24 hr prior to the administration of endotoxin (2.0 mg/kg) or saline. Significant hypotension during the first hour following endotoxin was observed but significant increases in heart rate were not observed until 3 hr. Plasma norepinephrine (NE) and epinephrine (E) were significantly elevated at 30 min. Norepinephrine remained elevated (6 times control) during 6 hr, whereas E was elevated (60 times control) at 30 min but was less elevated at 6 hr. The second protocol involved endotoxin or saline administration immediately following implantation of cannulae. In this group, 16.7 mg/kg of endotoxin or saline was given. All animals died and plasma catecholamines were elevated at higher levels than those of the first group. Results suggest marked elevations in plasma catecholamines during endotoxicosis. Additional data analysis suggests that plasma NE and E may provide an early index of impending circulatory shock.

Animals↗

alpha 2-Adrenergic receptor binding in human platelets: alterations during the menstrual cycle.

We studied the effect of several clinically important variables on the characteristics of alpha 2-adrenergic receptors in human platelet membranes. The number and affinity of the receptor binding sites were determined from radioligand binding experiments, with [3H]yohimbine being the radioligand of choice. Platelets from female subjects had a cyclic variation in the number of alpha 2-adrenergic receptors that coincided with their menstrual cycles. The number of alpha 2-receptors was highest at the onset of menses and dropped to 74% to 79% of that value during the middle of the cycle. In concurrent experiments we did not observe comparable cyclic changes in receptor binding sites in platelets from male subjects. There was no age-dependent alteration in receptor number in a sample of 39 subjects ranging in age from 8 to 80 yr, but the number of alpha 2-receptors in platelets from male and female subjects differed. We also tested the possibility of a circadian rhythm in alpha 2-receptor number but found no cyclic changes as a function of time of day. There was no alteration in alpha 2-adrenergic receptor binding in the platelets from five subjects with Parkinson's disease. Finally, there was no change in receptor affinity as a function of any of the variables tested. These data should apply to the design of further studies on the clinical importance of platelet alpha 2-adrenergic receptors.

Adolescent↗

Caffeine inhibition of aflatoxin production: mode of action.

Evaluation of caffeine and a number of related methylxanthines indicated that the ability of the compound to inhibit growth and aflatoxin production by Aspergillus parasiticus is highly specific and does not involve an inhibition of cyclic AMP phosphodiesterase. Supplementation of the culture medium with purine bases, nucleosides, and nucleotides suggested that the inhibition of fungal growth could be partially overcome by adenine or guanine but that the purines had little effect on the inhibition of aflatoxin production. Likewise, increasing the levels of trace minerals did not overcome the inhibition of toxin production. Electron microscopic evaluation of caffeine-treated and -untreated cultures indicated that the compound produced observable changes in the ultrastructure of the fungus.

3',5'-Cyclic-AMP Phosphodiesterases↗

Cardiac and splenic norepinephrine turnovers in endotoxic rats.

Although sympathetic hyperactivity has been implicated in the pathogenesis of endotoxin shock, methodologies employed to assess the activity have been indirect in nature and results have been equivocal. The present experiments quantitated postganglionic sympathetic activity by measuring norepinephrine (NE) turnovers in hearts and spleens of fasted male Holtzman rats injected intravenously with Salmonella enteritidis lipopolysaccharide (2 mg/300 g rat; 5.7-6.7 mg/kg). NE turnovers were measured over 12 h by the [3H]NE decay method. Cardiac NE turnovers were increased in endotoxic rats (0.075 micrograms X g-1 X h-1) compared with controls (0.009). Similarly, NE turnovers in spleens of endotoxic rats (0.099 micrograms X g-1 X h-1) were increased compared with control rats (0.033). Because NE reuptake is depressed in spleens of severely shocked endotoxic rats, the singular effect of reduced reuptake (desmethylimipramine treatment, 20 mg/kg) on NE turnovers was evaluated in spleens of a separate group of control rats. Desmethylimipramine had no effect on the slopes of the NE decay lines compared with untreated rats (-0.015 +/- 0.008 vs. -0.015 +/- 0.029, respectively). Thus these experiments support the concept of heightened sympathetic activation during endotoxicosis as assessed quantitatively in a noninvasive, unanesthetized rat model.

Animals↗

Characterization of [3H]yohimbine binding to putative alpha-2 adrenergic receptors in neonatal rat lung.

In contrast to the adult rat lung, which lacks alpha-2 adrenergic receptor binding sites, the neonatal rat lung had a high density of [3H]yohimbine binding sites. The binding of this alpha-2 antagonist was saturable, reversible and stereospecific. Steady-state binding was reached by 15 min at 23 degrees C, and the association and dissociation rate constants were 0.17 min-1nM-1 and 0.30 min-1, respectively. From saturation experiments, a Bmax of 304 fmol/mg of protein and a KD of 1.53 nM were calculated. Surprisingly, no appreciable specific binding was observed in this tissue for the alpha-2 agonists [3H]clonidine, [3H]paraminoclonidine and [3H]epinephrine. Inhibition experiments indicated that the binding site had the characteristics of an alpha-2 adrenergic receptor although yohimbine was only 5 times more potent than prazosin. The Ki for epinephrine was decreased 4-fold by 100 microM guanyl-5'-6'-imidodiphosphate suggesting that the receptor binding site may be coupled to adenylate cyclase. Ethanol inhibited the [3H]yohimbine binding with an IC50 of 200 mM. This inhibition was "competitive-like" as increasing concentrations of ethanol resulted in an increased KD, but not a decrease in Bmax. The presence of high density [3H]yohimbine binding sites in early life may have a developmental importance which is not yet understood.

Animals↗

Contribution of depressed reuptake to the depletion of norepinephrine from rat heart and spleen during endotoxin shock.

Norepinephrine content (microgram/g) was depressed in hearts and spleens of fasted male Holtzman rats treated intravenously with Salmonella enteritidis lipopolysaccharide (14-17 mg/kg). To investigate the mechanism of norepinephrine depletion during endotoxicosis, in vivo norepinephrine reuptake was evaluated in control and severely shocked rats using the incorporation of 3H-norepinephrine into hearts and spleens. Incorporation of 3H-norepinephrine into spleens of endotoxic rats was reduced 88%, i.e., from a control of 2309 +/- 224 dpm/gm to 270 +/- 69 dpm/gm after endotoxin. In contrast, cardiac tissue incorporation of 3H-norepinephrine was not significantly impaired, i.e., control of 11838 +/- 845 dpm/gm versus severe shock of 17783 +/- 2904 dpm/gm. In vitro analysis of total norepinephrine retained in cardiac and splenic tissue slices incubated with 3H-norepinephrine yielded results consistent with in vivo experiments: Splenic norepinephrine reuptake was significantly decreased on the order of 50% in preparations from endotoxic rats, while myocardial norepinephrine reuptake was the same in both groups. The results indicate that depression of norepinephrine reuptake is a mechanism of norepinephrine depletion in spleens but not hearts of endotoxic rats.

Animals↗

Sinoatrial node artery distribution and its relation to hierarchy of cardiac automaticity.

The sinoatrial node (SAN) artery (SANA) was cannulated in dogs anesthetized with chloralose (7 dogs) or pentobarbital (1 dog). Intra-SANA injection of acetylcholine (ACh) with edrophonium (EPh) produced a transient junctional rhythm (JR) when the cannula tip lay near SANA origin. However, when ACh-EPh was injected while the cannula tip lay within SAN region, a slower P wave rhythm, rather than a JR, developed. To determine visually the injected ACh-EPh distribution, an equal volume of dye was injected under similar conditions. Dye-distribution patterns were consistent in all atria. These averaged 44 +/- 2% of the total endocardial surface, indicating that SANA distribution is not discrete, but widespread. Dye extended cranially, caudally, and laterally and included documented subsidiary pacemaker sites. Dye approached, but never trespassed, the coronary sinus ostium. Results suggest that cholinergic drug injection into the proximal SANA may suppress not only the SAN, but subsidiary atrial pacemakers as well. In this situation, junctional pacemakers probably emerge, not because of inherently greater automaticity, but after default of subsidiary atrial pacemakers.

Acetylcholine↗

Myocardial norepinephrine turnover during induced hypothermia and rewarming.

Norepinephrine (NE) turnover in myocardial tissue was measured in male golden hamsters (Mesocricetus auratus) during 1) continuous hypothermia, 2) rewarming from hypothermia initiated by exposure to 22 degrees C ambient, and 3) normothermic control state. Hypothermia was induced by exposure to 80% He-20% O2 atmosphere at 0 to -10 degrees C. At sequential periods after tritiated norepinephrine ([3H]NE) infusion, hamsters were killed by cervical transection and hearts were removed and analyzed for NE and [3H]NE content. Rate constants, turnover times, and turnover rates were determined from regression analysis of [3H]NE/micrograms NE tissue decay. Myocardial concentrations of NE were constant during NE-turnover measurements in each group. However, myocardial NE levels were reduced by 37% in both continuous hypothermia and rewarming from hypothermia compared with normothermic controls. NE turnover was highest during rewarming from hypothermia (0.34 micrograms.g-1.h-1), but no decay in myocardial [3H]NE was detectable during continuous hypothermia. Control animals had turnover values of 0.15 micrograms.g-1.h-1. Turnover data indicate severe depression in myocardial sympathetic nerve activity during hypothermia but a significant increase above normothermic control levels during rewarming from hypothermia.

Adrenergic Fibers↗

Hierarchy of supraventricular pacemakers.

Definitive subsidiary atrial pacemakers (SAPs) exist within the crista terminalis and in the atrial free wall tissue at the junction of the inferior vena cava and the inferior right atrium. These pacemakers are capable of maintaining cardiac rhythm at a rate intermediate between that of the sinoatrial (SA) nodal and atrioventricular (AV) junctional pacemakers upon default of the normal SA nodal cells. The conventional concept of a single (junctional) escape mechanism needs to be updated by recognition of these SAP sites, which are under comprehensive autonomic regulation. A great variety of clinically important cardiac syndromes require understanding of the SAPs, not only for diagnostic significance but also for therapeutic consideration. SAPs differ from the SA pacemakers in that they possess intrinsically slower spontaneous rates and are less stable. There is early competition among them for instantaneous dominance. They are more responsive to both sympathetic and parasympathetic control, and they are initially more susceptible to underdrive stimulation by another pacemaker (whether artificial or natural) than are pacemakers with the SA node.

Atrial Function↗