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Biomedical subjects

M G Ziegler

Publications and source records attributed to M G Ziegler.

At least 145 records · Page 8Linked to original sources

Episodic catatonia, hypertension, and tachycardia: elevated plasma catecholamines.

We studied autonomic function in a 34-year-old woman who had episodes of catatonia, hypertension, and tachycardia. In one of these episodes, epinephrine and norepinephrine levels were extremely high. Catecholamine clearance was normal. Platelet alpha 2-adrenergic receptors were normal in number and affinity. Results of the phenylephrine infusion test suggested that these episodes were due to central activation of the sympathetic nervous system.

Adult↗

Theophylline toxicity and the beta-adrenergic system.

After ingestion of 12 g of theophylline caused severe toxicity in a young woman, we developed an experimental canine model to study human theophylline toxicity. Our study involved four anesthetized dogs given theophylline in a continuous intravenous drip for 180 minutes in one of four protocols. The protocols included a low-dose infusion (400 mg/h), a high-dose infusion (1000 mg/h), a high-dose infusion with beta-blockade induced by propranolol at 125 minutes after infusion, and a high-dose infusion while maintaining beta-blockade with propranolol throughout the experiment. Toxic levels of theophylline were associated with hypokalemia, hypophosphatemia, hyperglycemia, metabolic acidosis, and hypotension in both the patient and the experimental series. These effects were either prevented or partially reversed after induction of beta-blockade with propranolol. Very high levels of theophylline were associated with elevated levels of norepinephrine and epinephrine in the animals.

Acidosis↗

A new approach to determine rates of receptor appearance and disappearance in vivo. Application to agonist-mediated down-regulation of rat renal cortical beta 1- and beta 2-adrenergic receptors.

We have developed a method for the assessment of agonist-induced down-regulation of receptors in vivo in terms of rates of receptor appearance and disappearance. This method involves computer-assisted analysis of the kinetics of receptor loss during agonist infusion and of the recovery of receptor number upon the removal of the agonist. These kinetics are analyzed in terms of a steady state model that allows estimation of the rate constants for receptor appearance, kappa ap, and receptor disappearance, kappa dp. Several tests establish that the model can fit experimentally derived data very well. In testing this model, we examined the in vivo down-regulation and recovery of rat renal cortical membrane beta 1- and beta 2-adrenergic receptors in response to infusion of the agonist isoproterenol from subcutaneously implanted osmotic minipumps. During recovery from down-regulation, the beta 1-receptors have a t 1/2 of 45 hr and a kappa ap of 1.6%/hr, and the beta 2-adrenergic receptors a t 1/2 of 18 hr and a kappa ap of 3.9%/hr. During down-regulation, the t 1/2 for both receptors is 12 hr, while kappa ap for beta 1-receptors and beta 2-receptors are 3 and 2.3%/hr, respectively. To the extent that the kinetics of recovery from down-regulation reflect "basal" receptor metabolism, the data indicate that enhanced receptor clearance of both receptor subtypes from the plasma membrane contribute to down-regulation, but changes in rates of receptor appearance may occur as well. The use of this computer modeling technique for defining kinetics of changes in receptor number from one steady state level to another should provide a generally useful means to assess hormone and neurotransmitter receptor metabolism in vivo.

Animals↗

An examination of chronic angiotensin-converting enzyme inhibition in the rat.

We have examined the systemic and renal effects of 2 weeks' administration of angiotensin-converting enzyme inhibition (CEI) to both normal and chronic NaCl-depleted Munich-Wistar rats and focused particularly on the factors contributing to the significant hypotension observed during surgery and anesthesia and the response of renal glomerular hemodynamics under these conditions. At renal micropuncture, mean arterial pressure was decreased in rats receiving CEI on normal and NaCl-depleted diets (72 +/- 5 and 78 +/- 6 mm Hg, p less than 0.01) but nephron filtration rate (sngfr) was well maintained since plasma flow was not altered and glomerular capillary pressure only slightly decreased. Negative Na+ balance in NaCl-depleted CEI rats correlated with decreased awake blood pressures. Under surgery, plasma norepinephrine and epinephrine were not increased in CEI rats in spite of hypotension, and diminished adrenergic responses may contribute to systemic and renal effects observed. Nephron plasma flow and sngfr are remarkably well preserved during CEI in spite of hypotension due to marked afferent arteriolar dilation.

Angiotensin-Converting Enzyme Inhibitors↗

The effects of dopamine agonists on human cardiovascular and sympathetic nervous systems.

We gave people four different dopamine agonists and monitored blood pressure, heart rate and circulating catecholamine levels. Bromocriptine decreased blood pressure and plasma norepinephrine levels. Dopamine increased pulse pressure, heart rate and circulating epinephrine (E) and norepinephrine (NE) levels. Dopamine agonists tend to diminish blood pressure by inhibiting sympathetic neuronal discharge of NE and, to a lesser extent, by stimulating dopamine vascular receptors. However, dopamine and L-dopa can be converted to NE and E, both of which have pressor effects. The complex cardiovascular effects of dopamine agonists are the result of stimulation of dopamine vascular and neuronal receptors and the production of NE and E.

Adult↗

Origins and terminations of descending noradrenergic projections to the spinal cord of monkey.

This report describes the distribution of noradrenergic cells in the brainstem and the pattern of terminal varicosities in the spinal cord of monkey using the immunocytochemical localization of dopamine-beta-hydroxylase (DBH). Using two separate and equally reliable techniques, retrograde transport of the antibody to DBH and a double-labeling method, the cells of origin of noradrenergic fibers in the spinal cord have been identified. The results of these studies indicate that 79% of all noradrenergic cells with axons projecting to the spinal cord are located in the nucleus subcoeruleus and nucleus locus coeruleus. Other pontine noradrenergic cell groups contribute the remainder of the fibers to the cord. No medullary cells contribute to the noradrenergic innervation of the spinal cord.

Animals↗

Angiotensin II in adrenergic-induced alterations in glomerular hemodynamics.

UNLABELLED: Micropuncture analysis of glomerular ultrafiltration (SNGFR) was conducted in Munich-Wistar rats to assess the functional responses to moderate-frequency (3-Hz) renal nerve stimulation. Angiotensin II inhibition (ANG II-inhib) was produced by the intravenous administration of [Sar1, Ala8] angiotensin II or MK 421 to investigate whether it modulates the effects of renal nerve stimulation. Micropuncture measurements were obtained before and during renal nerve stimulation. Renal nerve stimulation decreased SNGFR approximately 25% (from 49.9 +/- 2.3 to 38.0 +/- 1.4 nl X min-1 X g kidney wt-1), the result of decreased glomerular capillary hydrostatic pressure gradient and nephron plasma flow. These decreases were due to increased afferent (approximately 43%) and efferent (approximately 30%) arteriolar resistances, since the glomerular ultrafiltration coefficient remained unaffected. The effects of renal nerve stimulation during ANG II-inhib were less in magnitude than in renal nerve stimulation alone: SNGFR decreased from 48.0 +/- 1.5 to 44.8 +/- 2.0 nl X min-1 X g kidney wt-1 after renal nerve stimulation. The net renal production of norepinephrine was augmented by renal nerve stimulation but it was not influenced by ANG II-inhib. IN CONCLUSION: renal nerve stimulation can regulate glomerular ultrafiltration by altering vascular resistances, and angiotensin II appears to be a critical factor for the full functional expression of renal nerve stimulation at the glomerulus.

Angiotensin II↗

Gas exchange responses to bronchodilators following methacholine challenge in dogs.

To determine how and why different bronchodilators affect ventilation-perfusion (V/Q) relationships differently in experimental asthma, 10 anesthetized dogs were exposed 3 times each (2-1/2 h apart) to aerosolized 1% methacholine over 3 to 5 min. Mechanical, hemodynamic, gas exchange, and catecholamine concentration measurements were made before challenge, and 10, 20, 30, and 135 min after challenge. Fifteen min after challenge the dogs were exposed to aerosolized epinephrine, isoproterenol, salbutamol, or isotonic saline in random order. The worsened V/Q inequality after isoproterenol paralleled increased cardiac output (QT) and decreased pulmonary vascular resistance (PVR). Because of increased QT, arterial PO2 (PaO2) did not fall in spite of the increased V/Q inequality. After administration of isoproterenol, improvement in air-flow obstruction was always associated with significantly less increase in mean PaO2 and more V/Q inequality than after saline. After epinephrine and salbutamol a similar significant decrease in airflow obstruction was associated with only slightly more V/Q mismatching than after saline. The effects of epinephrine on low V/Q ratio areas, shunt, PaO2, QT, heart rate, and PVR were less and of shorter duration than those of isoproterenol. Salbutamol resulted in changes similar to but more persistent than those induced by epinephrine. All variables approached prechallenge values within 2 h after bronchodilator administration, regardless of agent used. These studies show that in a repeatable canine asthma model, randomized administration of epinephrine, isoproterenol, and salbutamol produce different gas exchange responses in spite of similar improvements in air-flow obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Central cholinergic stimulation causes adrenal epinephrine release.

Cholinergic drugs administered into the cerebral ventricles of animals selectively stimulate the adrenal medulla. However, the effects of central cholinergic stimulation on the sympathoadrenal system have not been studied in man. We stimulated central cholinergic activity in man by administering the cholinesterase inhibitor physostigmine to subjects pretreated with peripheral cholinergic blocking agents. A dose of 0.022 mg/kg physostigmine dramatically increased plasma epinephrine levels and slightly increased norepinephrine levels, which is consistent with selective adrenomedullary stimulation. A smaller dose of physostigmine increased epinephrine but did not alter norepinephrine levels. Subjects had increased pulse rates and blood pressures, and felt anxious while they had high plasma epinephrine levels.

Adrenal Medulla↗

Pressor response to beta-blocking drugs.

A patient with essential hypertension had a prolonged period of uncontrollable high blood pressure during therapy with the nonspecific beta-blocker nadolol. A subsequent challenge with the beta1-blocker atenolol caused a pressor response associated with diminished catecholamine release, impaired catecholamine clearance, loss of baroreflex response, and bradycardia. Beta-blocking drugs can lead to hypertension by causing fluid retention, reversal of catecholamine vasodilatation, or a direct pressor effect.

Adrenergic beta-Antagonists↗

Autonomic degeneration and altered blood pressure control in humans.

The study of patients with partial or total defects of their sympathetic nerves can help clarify the role of the sympathetic nervous system in blood pressure control. Denervation supersensitivity of both beta and alpha receptors develops in humans and is proportional to the degree of sympathetic withdrawal. Although alterations in beta-receptor sensitivity are familiar responses to beta agonists or antagonists, patients with decreased norepinephrine (NE) levels appear to develop alpha-receptor supersensitivity of greater hemodynamic importance. When beta supersensitivity is marked, there may be a pressor response to beta blockade even when circulating levels of NE and epinephrine are very low. Indomethacin blocks prostaglandin synthesis and causes an increase in blood pressure in patients with partial autonomic neuropathies. The drug increases blood pressure by enhancing alpha- and diminishing beta-receptor sensitivity to NE, so it is effective only in patients who have some residual NE release.

Autonomic Nervous System Diseases↗

Effect of antihypertensive therapy on sympathetic nervous system activity in patients with essential hypertension.

The sympathetic nervous system (SNS) plays a major role in blood pressure regulation. Although the exact relationship of the SNS to the etiology of hypertension remains undetermined, many of the agents used to treat hypertension interfere with this system. Clonidine, methyldopa, guanethidine, and reserpine decrease SNS tone whereas hydralazine, minoxidil, and hydrochlorothiazide increase it. Most evidence suggests that beta-adrenergic blocking agents decrease SNS activity. The effect of prazosin and captopril on the SNS requires further study. The appropriate use of these antihypertensive agents requires a knowledge of their sites of action and the physiological reflexes they induce. Efficacy, toxicity, and effective drug combinations can be predicted based on their mechanism of action and effect on SNS activity.

Antihypertensive Agents↗

Use of beta-blockade and hemoperfusion for acute theophylline poisoning.

Five adults were treated successfully for severe theophylline poisoning due to intentional overdosage. Clinical features included nausea, tremor, delirium, hypotension and cardiac arrhythmias, metabolic acidosis, hyperglycemia, hypokalemia and hypophosphatemia. No seizures or deaths occurred despite very high serum theophylline concentrations (between 96 and 194 mug per ml). Extreme elevations of plasma catecholamines were documented and are implicated in the toxicity. beta-Blockade with intravenous administration of propranolol hydrochloride was the most effective therapy for theophylline-induced hypotension. All patients were treated with resin hemoperfusion, which resulted in significant clinical improvement and rapid lowering of the serum theophylline level.

Adolescent↗

Plasma catecholamine levels in normal subjects and in patients with secondary hypertension.

We compared normal values for human venous norepinephrine (NE) and epinephrine (E) as reported in the literature with values determined in this laboratory and we measured and contrasted NE levels in patients with primary and secondary hypertension. Analysis of published data from many laboratories involving more than 800 supine, resting, healthy subjects indicated an average circulating level of venous NE of 260 pg/ml and of E, about 35 pg/ml. Supine levels of NE normally double when normal subjects stand for 5 min. This simple test provides one assessment of overall sympathetic nervous system integrity. Levels of catecholamines have been extensively studied in essential hypertension but much less so in secondary hypertension. Of the groups we studied with secondary hypertension (diabetes mellitus, primary hyperaldosteronism, polycystic kidney disease, chronic bilateral renal parenchymal disease, and unilateral renal arterial stenosis), only the group with renal parenchymal disease had supine NE levels significantly higher than the control group. Patients with essential hypertension and diabetes had a blunted increase in NE on standing. Plasma levels of NE do not reliably differentiate these groups of secondary hypertension from one another or from patients with primary hypertension.

Adolescent↗

Noradrenergic projections to the spinal cord of the rat.

Noradrenergic terminals were identified in the spinal cord of rats by immunocytochemical staining for dopamine-beta-hydroxylase. Although immunoreactive fibers and terminals were observed throughout the spinal grey matter, heavier accumulations of terminal labeling were observed in the marginal layer of the dorsal horn, in the ventral horn among motoneurons, and in the autonomic lateral cell columns of the thoracic and sacral spinal cord. Two specific retrograde transport techniques were employed to identify the origins of these noradrenergic terminations in the spinal cord. Cells of origin were observed in the locus coeruleus, the subcoeruleus, the medial and lateral parabrachial, and the Kölliker-Fuse nuclei, as well as adjacent to the superior olivary nucleus. These regions correspond to the A5-A7 cell groups of the pons. No spinally projecting noradrenergic cells were ever observed in the medulla. It was concluded that pontine noradrenergic cell groups are the sole source of noradrenergic terminals in the spinal cord.

Animals↗

Sympathetic nervous system function in XYY subjects.

Initial reports of males with the XYY sex chromosome anomaly indicated that these individuals excessively exhibit impulsive, aggressive, and criminal behavior. Central nervous system (CNS) defects, including low intelligence, in certain XYY subjects may be associated with these antisocial behaviors. The sympathetic nervous system (SNS) is activated in stressful conditions of "fight or flight" upon standing up from a supine posture, with physical exercise, and with aggressive behavior. Norepinephrine (NE) is the principal neurotransmitter of the SNS, and plasma levels of NE and dopamine-beta-hydroxylase are indices of SNS function. We questioned the integrity of SNS function in XYY subjects for two reasons: (1) their inferred propensity for aggressive behavior and the association of this behavior with increased NE levels; and (2) their potential for CNS dysfunction, which could be reflected in abnormal SNS regulation by the CNS. In the current study plasma levels of NE in XYY subjects are nonsignificantly higher than in normal volunteers. Additionally, XYY patients have a normal NE half-life indicating normal SNS activity and metabolism. Thus, we are unable to document with confidence any abnormality in SNS function in these XYY subjects.

Adolescent↗

Renal denervation in the rat: analysis of glomerular and proximal tubular function.

We examined 1) the potential modifications in both single nephron filtration rate (SNGFR) and the determinants of glomerular ultrafiltration, and 2) the alterations in peritubular capillary (PTC) "physical factors" that may contribute to changes in proximal tubular reabsorption (APR) after acute renal denervation (DNx). Micropuncture measurements were obtained in euvolemic Munich-Wistar rats with DNx or sham operation (sham). The content of norepinephrine in renal tissue homogenates was markedly reduced in DNx kidneys compared with sham kidneys (P less than 0.001). Mean arterial blood pressure, hematocrit, whole kidney GFR, and urinary flow rate were not different between the sham and DNx groups. Absolute urinary sodium excretion was 3 times greater in the DNx than in the sham group (P less than 0.01). SNGFR and its determinants were not statistically different in the two experimental conditions. APR was significantly reduced by approximately 25% in DNx (P less than 0.02). This reduction in APR was not accompanied by significant directional changes in peritubular capillary and renal interstitial pressures and the passive driving forces acting across the PTC-proximal tubular epithelium. These data demonstrate that elimination of renal innervation does not alter SNGFR or its determinants and suggest that the effect of denervation on APR is a primary epithelial event that occurs independent of changes in renal interstitial pressure and peritubular oncotic and hydrostatic pressures.

Absorption↗