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Biomedical subjects

D S Gann

Publications and source records attributed to D S Gann.

At least 19 recordsLinked to original sources
PubMed1995

Cell swelling and depolarization in hemorrhagic shock.

Although an increase in intracellular water volume (IWV) in hemorrhagic shock has been inferred from measured changes in transmembrane potential, it has not been measured directly. We have described the presence of a circulating protein that appears in hemorrhagic shock [circulating shock protein (CSP) 70] that depolarizes numerous cell types. To determine if this substance produced a concurrent increase in intracellular water, cells were incubated with CSP 70. Then we measured IWV as the difference between the 3H water space and the [14C]mannitol space. CSP 70 increased IWV 9% in rat red blood cells (RBCs) (n = 8, p < 0.05), 22% in rat H9c2 cells (n = 7, p < 0.05), 11% in dog RBCs (n = 10, p < 0.005), and 31% in dog white blood cells (n = 8, p < 0.005). The results indicate that a protein that circulates in hemorrhagic shock depolarizes cells and increases intracellular water. This suggests that the changes in transmembrane potential observed in hemorrhagic shock are accompanied by movement of extracellular fluid into cells and may account for the inability to restore blood volume after large hemorrhage.

Animals↗
PubMed1995

Plasminogen activator inhibitor-1 rises after hemorrhage in rats.

Large hemorrhage leads to hypercoagulability, a phenomenon that has never been well explained. Because an elevation of plasminogen activator inhibitor (PAI)-1 increases procoagulant activity, we have determined whether plasma PAI activity and tissue PAI-1 mRNA are elevated after hemorrhage. Sprague-Dawley rats were bled (20 or 15 ml/kg) 4 days after cannulation. Plasma PAI activity was determined by the capacity of plasma to inhibit tissue-type plasminogen activator activity. Changes of PAI-1 mRNA in various tissues were detected by high-performance liquid chromatography after reverse transcription and polymerase chain reaction. Hemorrhage (20 ml/kg) significantly elevated plasma PAI activity at 0.5, 1, 2, 4, 6, and 8 h after hemorrhage and PAI-1 mRNA in liver at 1, 2, 4, and 6 h after hemorrhage. The PAI-1 message was also significantly elevated in lung, heart, and kidney at 4 h after hemorrhage. The increases of PAI-1 mRNA after 20 ml/kg hemorrhage were significantly greater than those after 15 ml/kg hemorrhage. These findings indicate that large hemorrhage can induce the increases in PAI activity and PAI-1 message and suggest that induction of PAI-1 may be involved in the thrombogenic responses observed after large hemorrhage.

Animals↗
PubMed1995

Responses of immunoreactive ACTH and bioactive ACTH to large hemorrhage and resuscitation in conscious dogs.

We studied the effect of fluid resuscitation on immunoreactive adrenocorticotropic hormone (irACTH) and bioactive ACTH (bioACTH) after hemorrhage in conscious dogs. Animals (n = 7) were bled 30% (approximately 25 ml/kg) over 3 min and 30 min later were either resuscitated [43.3 ml/kg 0.9% NaCl (1.8 times hemorrhage volume) over 10 min] or not. Blood was reinfused after 210 min. Animals had both treatments (> 4 days apart). irACTH, bioACTH, cortisol, angiotensin II, and aldosterone increased rapidly after hemorrhage. Resuscitation increased blood volume and cardiac output to resting values, but arterial hypotension persisted. bioACTH and irACTH decreased 40-90 min after hemorrhage in both groups, but each decreased more rapidly after resuscitation. The elimination half-life of bioACTH was shorter than that of irACTH, but neither was affected by resuscitation. The ratio of bioACTH to irACTH followed the same pattern with or without resuscitation. Angiotensin II and aldosterone remained increased without resuscitation but decreased promptly after resuscitation. In conclusion, 1) saline infusion at 1.8 x hemorrhage volume provides effective cardiovascular resuscitation, with resolution of hormonal responses to hemorrhage; 2) although ACTH responses resolved with or without resuscitation, resuscitation produced more rapid resolution without changing the parameters of ACTH elimination; 3) the dynamics of the resolution of the ACTH response to hemorrhage are similar whether induced by stimulus removal or feedback inhibition.

Adrenocorticotropic Hormone↗
PubMed1995

Role of intestinal fluid in restitution of blood volume and plasma protein after hemorrhage in awake rats.

To determine whether food and/or water in the gastrointestinal tract affects restitution of blood volume and plasma protein after hemorrhage, fed and 24-h-fasted awake rats received a 20 ml.kg-1 x 3 min-1 hemorrhage, and restitution of blood volume was measured by Evans blue dye and dilution of hematocrit. Restitution of blood volume and plasma protein in fed rats was complete by 2-4 h. In contrast, restitution was severely attenuated in fasted rats and was not complete by 24 h. Because initial blood volume was significantly lower in the fasted rats (55.4 +/- 1.7 vs. 64.9 +/- 2.5 ml/kg in fed), the percent blood lost during hemorrhage was significantly greater (36 vs. 31%). However, the attenuated restitution was not the result of the larger hemorrhage, as fed rats receiving a 36% hemorrhage also restored blood volume completely by 4 h. In fasted rats, complete restitution of blood volume did occur when either water or food and water were given 4 h after hemorrhage. Gastrointestinal water content fell (from 65.5 +/- 4.8 to 47.9 +/- 1.6 ml/kg) 2h after hemorrhage in fed but not in fasted rats (33.5 +/- 2.4 to 30.6 +/- 2.5 ml/kg). These data suggest that gastrointestinal fluid is essential for complete restoration of blood volume in the awake rat.

Animals↗
PubMed1995

Changes in regional vascular resistance and blood volume after hemorrhage in fed and fasted awake rats.

To determine whether fasting alters the response of blood flow to hemorrhage, blood flow was measured by radiolabeled microspheres before and after a 20 ml.kg-1.3 min-1 hemorrhage in fed and fasted chronically cannulated male Sprague-Dawley rats. Restitution of blood volume, as determined by dilution of hematocrit, was attenuated in fasted rats, although the responses of arterial blood pressure, heart rate, cardiac output, and total peripheral resistance were not significantly different. Fasting only affected resting blood flow in the bronchial artery and fat and had no effect on resting vascular resistance in any organ studied. In both fed and fasted rats, hemorrhage led to a significant fall in blood flow to the stomach, small intestine, cecum, colon, spleen, pancreas, kidney, bronchial artery, thymus, and muscle and a rise in blood flow to the adrenals. However, fasting did not significantly alter the response of flow or vascular resistance to these organs. Fasting did alter the blood flow response to hemorrhage in bone, fat, and the hepatic artery. These results demonstrate that 24 h of fasting does not affect the responses of blood flow and vascular resistance to hemorrhage in most organs, even though restitution of blood volume is attenuated.

Animals↗
PubMed1995

Adrenal cortical carcinoma with adenosquamous differentiation. Report of a case with immunohistochemical and ultrastructural studies.

We report the case of an adrenal cortical carcinoma with glandular and squamous differentiation, demonstrated by light and electron microscopy as well as by immunohistochemical studies. The patient was a 63-year-old man presenting with a large adrenal mass and markedly increased 24-hour urine metanephrine, initially suggesting the diagnosis of pheochromocytoma. Upon histological examination of the surgically excised tumor, the presence of adenosquamous differentiation was most consistent with a metastasis to the adrenal gland. No other primary tumor was later found at autopsy, however. It thus becomes evident with this case that squamous and glandular differentiation can be observed in primary adrenocortical carcinomas, and therefore the conventional approach to the immunohistochemical and ultrastructural features of these tumors is challenged. This type of aberrant morphology in adrenocortical carcinomas makes the differentiation from a metastatic carcinoma particularly difficult for the surgical pathologist. Clinical correlation is absolutely necessary for an accurate diagnosis, and occasionally, as was the case with this patient, only with postmortem studies can another primary be ruled out with certainty.

Adrenal Cortex↗
PubMed1994

A circulating shock protein that depolarizes cells in vitro depresses myocardial contractility and rate in isolated rat hearts.

Previously, we identified the presence of a circulating shock protein (CSP) in the plasma of hemorrhaged rats that depolarizes a variety of cells in vitro. In isolated perfused rat hearts, partially purified CSP produced dose-dependent decreases in contractility and heart rate associated with an increase in coronary perfusion pressure (CPP). Electrical pacing failed to prevent the negative inotropic effects. Preventing the coronary vasoconstriction with nitroglycerin or attenuating it with a cyclooxygenase inhibitor also failed to prevent the inotropic or chronotropic effects of CSP. Carbocyclic thromboxane A2 (50ng/min) caused a similar increase in CPP to CSP but had no effect on contractility or rate during the first minute of infusion. These data indicate that the protein that appears in rat plasma after hemorrhage produces negative inotropic and chronotropic effects on the isolated heart that are independent of changes in CPP. Vasoactive arachidonic acid metabolites elicited by CSP are partially responsible for the increase in coronary vascular resistance.

Animals↗
PubMed1994

Corticotropin-releasing hormone but not glutamate elicits hormonal responses from the parabrachial region in cats.

Corticotropin-releasing hormone (CRH)-containing processes were found by immunohistochemistry in the dorsal and lateral parabrachial nucleus extending medially over the dorsal aspect of the brachium and then along the lateral and medial aspects of the mesencephalic trigeminal tract. Reactivity of lesser density extended ventrally from the medial parabrachial nucleus into the locus ceruleus and subceruleus. To determine if CRH acts in these areas to modulate plasma adrenocorticotropic hormone (ACTH) and arginine vasopressin (AVP), acutely prepared, chloralose-anesthetized cats were tested with microinjections (100 nl/min, 2 min). Plasma ACTH increased significantly after injections of CRH (2 pmol) along the dorsal aspect of the brachium and in the locus subceruleus (P < 0.05 and P < 0.01, respectively). Plasma AVP increased significantly after injections of CRH into the medial parabrachial nucleus (P < 0.01). These responses of ACTH and AVP differed significantly from those to injections of either vehicle or glutamate at identical sites and from those to CRH injected in other areas. None of these latter responses was significant. CRH was without effect on arterial pressure even though glutamate (30 nmol) injected into the area ventral and medial to the brachium elicited a significant pressor response. We suggest that excitatory amino acids such as glutamate act in this area to activate neurons with descending projections that influence autonomic function. In contrast, CRH appears to activate other neurons with ascending projections that drive neuroendocrine release.

Adrenocorticotropic Hormone↗
PubMed1994

Management of the trauma victim with pre-existing endocrine disease.

The clinical course of individuals after trauma largely is determined by their pretraumatic state. The endocrine system plays a major role in the response to injury, surgery, and sepsis, and endocrine dysfunction places the trauma victim at risk of greater morbidity and mortality. Further, chronic endocrine disease usually is accompanied by multiorgan dysfunction, which may compromise the physiologic reserve of the critically injured patient. Among patients with pre-existing endocrine disease, the severe stresses of multisystem trauma can lead to a further, often subtle, decompensation in endocrine function (Fig. 1). In the management of trauma victims with pre-existing endocrine disease, the role of the critical care specialist is three-fold--(1) to maintain a high index of suspicion for endocrine disease in all trauma victims, (2) to anticipate and prevent endocrine organ decompensation, and (3) to rapidly diagnose and institute therapy in those suspected of having endocrine disease.

Addison Disease↗
PubMed1992

Hypocalcemia during sepsis. Relationship to resuscitation and hemodynamics.

The ionized calcium (IC) and parathyroid hormone response to polymicrobial intra-abdominal sepsis and the relationship between IC and hemodynamic alterations with and without crystalloid resuscitation were investigated. Thirty swine underwent cecal ligation and incision (n = 19) or sham laparotomy (n = 11), with seven animals that had cecal ligation and incision administered Ringer's solution (50 mL/kg) after each set of measurements recorded on days 0, 1, 2, 4, and 8. An early decrease in mean arterial pressure and cardiac index in animals that had cecal ligation and incision reversed with resuscitation. The IC also fell early and parathyroid hormone level increased in both the unresuscitated and resuscitated septic groups. However, correlation coefficients of mean arterial pressure and cardiac index with IC ranged from .034 to .287 in the septic animals and were lower in the group that had sham laparotomy. We conclude that polymicrobial intra-abdominal sepsis results in decreased IC and an elevated parathyroid hormone level. Hemodynamics do not correlate with IC levels, and resuscitation can be achieved without calcium administration.

Animals↗
PubMed1992

The hypothalamic-pituitary-adrenal-immune axis. A critical assessment.

The hypothalamic-pituitary-adrenal (HPA) system has been a model for neuroendocrine control of responses of organisms to stressors since the turn of the century. Despite this, the pathways by which infectious insults interact with the HPA system remained poorly defined. Recently, evidence has been presented suggesting that humoral mediators released by inflammatory cells (cytokines) may participate in two-way communication between the site of inflammation and the central nervous system. In this review, we detail the current understanding of the responses of the HPA system to the classic physiologic stimuli of hypovolemia and pain, with an emphasis on the cellular mechanisms and mediators discovered in recent years. We also examine the data substantiating a role of interleukin 1, interleukin 6, and tumor necrosis factor in the direct humoral activation of the HPA system and consider the evidence favoring a physiologic negative feedback relationship between the HPA and the immune systems. Such as interaction is an exciting concept with broad clinical implications. However, we believe that the temporal and quantitative aspects of experiments designed to evaluate this interaction must be carefully evaluated to assure that true physiologic stimuli are studied and that the responses observed are not due to pharmacologic effects of inflammatory mediators acting through "classic" neuroendocrine pathways.

Afferent Pathways↗
PubMed1992

Saline resuscitation after fixed-volume hemorrhage. Role of resuscitation volume and rate of infusion.

The authors have reported previously that small-volume resuscitation (1.8 x bled volume) with 0.9% NaCl restores blood volume and attenuates hormonal responses after large hemorrhage without correction of arterial hypotension. The authors studied the role of rate of infusion in this observation in chronically prepared dogs (aortic flow probe, right atrial pressure and volume, and arterial catheters) after 30% hemorrhage (24.1 +/- 0.4 mL/kg). After 30 minutes, subjects were observed either without treatment (no resuscitation) or with infusion of 43 mL/kg 0.9% NaCl over 3 hours by one of three protocols: (1) impulse infusion over 10 minutes, (2) variable rate infusion, bolus with tapering infusion, or (3) constant rate infusion. Significant improvement in cardiac output and in blood volume and significant decreases of vasopressin and arterial catecholamines were observed in all fluid-treated groups. This benefit was relatively independent of rate of infusion, although impulse infusion produced greater early improvement, which dissipated with time, and constant rate infusion produced better late results. In none of the fluid-treated groups were these improvements reflected in improved mean arterial pressure compared with the no resuscitation group. The authors conclude that small-volume, slow-rate saline infusion produces physiologic benefits that cannot be assessed by easily measured clinical parameters. Thus, early resuscitation after trauma could aid patients even if arterial pressure is unchanged. This benefit might be even greater in patients with uncontrolled bleeding because arterial pressure, and hence bleeding, may not be increased by resuscitation of this type. A reassessment of the value of prehospital fluid resuscitation in the injured patient is warranted.

Animals↗
PubMed1992

Identification of carotid vascular receptors that control adrenal catecholamine secretion in dogs.

The role of carotid sinus and thyrocarotid mechanoreceptors in the reflex control of adrenal medullary function was assessed in anesthetized dogs with adrenal vein catheters. Dogs underwent carotid sinus, thyrocarotid junction, combined carotid sinus and thyrocarotid junction, or sham denervation. On the day after surgery, catecholamine secretion was measured after carotid occlusion proximal to the thyrocarotid junction, cervical vagotomy, and repeat carotid occlusion, each separated by 90 min. After combined carotid denervation, baseline norepinephrine secretion was increased, resulting in a decreased epinephrine-to-norepinephrine ratio. Carotid occlusion before vagotomy did not change the secretion of catecholamines or the epinephrine-to-norepinephrine ratio. After sham carotid denervation, acute vagotomy did not affect catecholamine secretion. However, after denervation of the carotid sinus or thyrocarotid junction, vagotomy resulted in small increases in catecholamine secretion without changing the epinephrine-to-norepinephrine ratio; the magnitude of the response was augmented after combined denervation. At 90 min after vagotomy in dogs with intact carotid baroreceptors, carotid occlusion increased adrenal secretion of catecholamines and decreased the epinephrine-to-norepinephrine ratio. After denervation of carotid sinus or thyrocarotid junction receptors, carotid occlusion increased secretion of catecholamines without changing the epinephrine-to-norepinephrine ratio; the response was abolished by combined denervation. These results show that both carotid sinus and thyrocarotid receptors contribute to the adrenomedullary response to carotid occlusion and to acute vagotomy. Also, reduction in the activity of carotid sinus and thyrocarotid junction receptors chronically (by denervation) or acutely (by carotid occlusion) results in preferential secretion of norepinephrine over epinephrine.

Adrenal Glands↗
PubMed1992

Hypotensive hemorrhage elevates corticotropin-releasing hormone messenger ribonucleic acid (mRNA) but not vasopressin mRNA in the rat hypothalamus.

We examined the effect of acute hypotensive hemorrhage on corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) messenger RNAs (mRNAs) in neurons of the rat hypothalamus. Sprague-Dawley male rats were cannulated (femoral artery and vein) and received a 15 ml/kg.3 min hemorrhage on the morning of the fourth day. Time controls received no hemorrhage. After light halothane anesthesia, the rats were decapitated at 1 or 4 h (six to nine rats per group). The hypothalami were removed, frozen, and sectioned at 12 microns. In situ hybridization was performed using two 48-base oligodeoxynucleotide probes for CRH and AVP message, respectively. Hemorrhage led to a fall in arterial blood pressure and heart rate that recovered by 1 h. Plasma ACTH, corticosterone, and AVP were elevated 20, 60, and 90 min after hemorrhage, but returned to near control levels by 4 h. CRH mRNA was significantly elevated 1 and 4 h after hemorrhage, as compared to time controls, in parvocellular neurons of the paraventricular nuclei. However, AVP mRNA was not different from controls at 1 or 4 h after hemorrhage in the magnocellular or parvocellular paraventricular nuclei, or in the supraoptic or accessory nuclei of the hypothalamus. AVP mRNA was also found in neurons of the suprachiasmatic nuclei, but there was no difference in the amount of mRNA between the 1-h hemorrhage and control groups. These data suggest that neural signals, originating for cardiovascular receptors activated by hemorrhage, up-regulate message for CRH but not for AVP in the paraventricular nuclei of the rat hypothalamus.

Adrenocorticotropic Hormone↗
PubMed1992

Alpha-adrenergic input in the locus coeruleus modulates plasma adrenocorticotropin in cats.

Previous evidence suggested that noradrenergic activity in the vicinity of the ventrorostral locus coeruleus (LC) increased in response to hemorrhage. To investigate the possible role of this response in the control of ACTH release, microinjections (100 nl/min for 2 min) of several agents were made at 59 sites in 35 cats anesthetized with chloralose. Injections were as follows: vehicle (all sites); 150 mM L-glutamate (GLU; 51 sites); an alpha 2-agonist, 1 mM clonidine (19 sites); an alpha 2-antagonist, 1 mM yohimbine (32 sites); an alpha 1-agonist, 1 mM phenylephrine (PE; 42 sites); and an alpha 1-antagonist, 0.05 mM prazosin (20 sites). Plasma ACTH was measured by RIA. Responses were tested statistically by repeated measures analysis of variance. GLU at 12 sites in the region of the ventrorostral LC facilitated plasma ACTH (P less than 0.01), whereas GLU at 6 sites in the caudal LC inhibited ACTH (P less than 0.05). Clonidine at 9 sites in an area that included the ventrorostral LC inhibited ACTH (P less than 0.05), and yohimbine at 7 sites within this latter area facilitated ACTH (P less than 0.01). PE within the ventrorostral LC had no effect on ACTH. However, PE at 10 sites within the caudal LC and along the ventromedial border of the ventrorostral LC facilitated ACTH. The responses for all of these areas to the respective agents differed from those to vehicle, whereas responses from other areas to the former agents or from all areas to prazosin did not. An increase in noradrenergic turnover in the LC may provide inhibitory alpha 2 modulation to the neurons in the LC that are activated by hemorrhage. This modulation and possible alpha 1 input in areas adjacent to the ventrorostral LC may influence the hemodynamic control of ACTH release.

Adrenocorticotropic Hormone↗
PubMed1991

A circulating factor(s) mediates cell depolarization in hemorrhagic shock.

Cell depolarization in hemorrhagic shock has been attributed to hypoperfusion, but the mechanism remains unclear. Suspensions of single cell lines loaded with the potential-sensitive fluorescent dye bis-(1,3-dibutylbarbiturioc acid) trimethine oxonal (DIBAC) and exposed for 30 minutes to rat plasma drawn either before or after hemorrhagic shock (bled 20 mL/kg: mean arterial blood pressure less than 40 mmHg) were studied. Plasma drawn after, but not before, hemorrhage led to partial depolarization regardless of cell type (rat H9C2 skeletal muscle, A-10 smooth muscle, C-9 liver, adrenal, kidney, red blood cell [RBC], white blood cell [WBC]) or species (cat, dog, pig RBC; cat WBC; mouse C2C12 skeletal muscle; and human intestinal smooth muscle [HISM]). Dialysis did not remove the factor(s), suggesting a molecular weight of more than 10,000 daltons. The factor appeared within 5 minutes of shock. The depolarization amplitude increased as a function of plasma concentration and demonstrated saturation kinetics indicating specific receptor binding. Cells were equivalently oxygenated, excluding hypoperfusion as a necessary condition for depolarization. Tumor necrosis factor or platelet activating factor alone or in combination were not effective in this system. Stable measurements can be obtained with this noninvasive system that avoids cell injury consequent to cell impalement with electrodes. This system provides a sensitive in vitro bioassay that should permit identification of the plasma factors mediating cell depolarization, as well as definition of the responsible intracellular mechanisms.

Animals↗