Biomedical subjects

M G Ziegler

Publications and source records attributed to M G Ziegler.

At least 91 records · Page 5Linked to original sources

PubMed1992

Myocardial beta-adrenergic receptor expression and signal transduction after chronic volume-overload hypertrophy and circulatory congestion.

BACKGROUND: The volume-overload, high-output state induced by aortocaval fistula is unique because it is not generally associated with marked abnormalities of contractile function. Thus, changes in beta-adrenergic receptor (beta AR) expression should reflect more directly the influence of neurohumoral adrenergic tone, clarifying the manner in which peripheral (neurohumoral) versus primary myocardial factors are operative in decreased beta AR-dependent signal transduction. METHODS AND RESULTS: We examined the beta-adrenergic receptor-responsive adenylyl cyclase pathway in hearts from pigs subjected to volume-overload hypertrophy with circulatory congestion. Nine pigs underwent initial pharmacological and hemodynamic studies, and, 5 weeks after aortocaval fistula placement, when signs of circulatory congestion were evident, these measurements were repeated. Biochemical analyses of plasma and myocardium from these animals and seven normal animals were compared. Experimental animals showed signs of circulatory congestion (tachypnea, weight gain, pulmonary rales) within 3-4 weeks of fistula placement. Necropsy showed ascites and biventricular cardiac hypertrophy, but no fibrosis or inflammation was present on histological inspection. Heart rate responsiveness to beta AR stimulation was blunted, with ED50, for isoproterenol increased 133% (p less than 0.001) after development of circulatory congestion. Biochemical analyses of the beta AR-responsive adenylyl cyclase pathway showed uniform decreases in beta AR number in right atrium, right ventricle, and left ventricle (36-41% decreases, p less than 0.005). Downregulation was selective for beta 1-receptors, and remaining receptors in the right and left ventricles showed low-affinity agonist binding, suggesting an uncoupling from Gs. All measures of adenylyl cyclase activity were diminished significantly in membrane homogenates from the right atrium (mean reduction, 50 +/- 10%) and left ventricle (mean reduction, 44 +/- 8%) after volume overload. Finally, we found that amounts of cardiac Gs, as measured in reconstitution assays, were decreased in both the right atrium (p less than 0.02) and the left ventricle (p less than 0.01) of volume-overloaded animals but that levels of pertussis toxin substrate were unchanged. CONCLUSIONS: Biochemical findings occurred in the absence of myocardial inflammation or fibrosis and without pharmacological interventions, suggesting that circulatory congestion, with attendant elevation in plasma norepinephrine, may be a sufficient stimulus to induce such changes. The data are compatible with a catecholamine-driven beta AR pathway desensitization. Thus, a primary defect in intrinsic contractile function is not a necessary component for abnormalities of the myocardial beta AR-responsive adenylyl cyclase pathway.

Adenylyl Cyclases↗

PubMed1992

Myocardial adrenergic denervation supersensitivity depends on a postreceptor mechanism not linked with increased cAMP production.

BACKGROUND: Two major hypotheses have been proposed to explain catecholamine supersensitivity after myocardial denervation, but neither sufficiently explains certain features of the phenomenon. In addition, a nonsurgical method for long-term myocardial adrenergic denervation is desirable but has not been accomplished or described with respect to catecholamine supersensitivity. METHODS AND RESULTS: We have accomplished chronic myocardial adrenergic denervation by using 6-hydroxydopamine (6-OHDA). Sixteen weeks after 6-OHDA administration to newborn pigs, we found substantial myocardial adrenergic denervation associated with beta-adrenergic receptor (beta AR) downregulation. Despite decreased beta AR number, the dose of isoproterenol yielding 50% maximal heart rate change (ED50) was decreased, and heart rates during exercise showed increased responsiveness despite decreased circulating catecholamines. Thus, stimulation of fewer receptors yielded an increased response, implying improved signal transduction efficiency. Competitive binding studies with isoproterenol showed an increased proportion of beta AR with high-affinity binding in myocardial membranes from 6-OHDA pigs, suggesting that interaction between beta AR and cardiac G, may contribute to improved signal transduction efficiency. However, measures of adenylyl cyclase activity indicated marked reduction in beta AR-dependent and G2-dependent cAMP production in myocardial membranes from denervated animals despite a normal amount of cardiac Gs and decreased Gi. CONCLUSIONS: We have demonstrated that substantial, long-term myocardial adrenergic denervation is possible using 6-OHDA. Denervation supersensitivity in this model does not depend on enhanced cAMP stimulation but rather depends on postreceptor elements in the beta AR-responsive pathway that may be independent of Gs-activated adenylyl cyclase activity. In this model of adrenergic denervation supersensitivity, beta-receptors, through Gs, may be linked to an alternative effector that drives heart rate responsiveness.

Adenylyl Cyclases↗

PubMed1992

Plasma atrial natriuretic peptide is unstable under most storage conditions.

BACKGROUND: Atrial natriuretic peptide (ANP) is a hormonal regulator of cardiovascular fluid volume. More than 1,000 scientific articles were written about ANP between 1987 and 1991. Because some articles hinted at problems with storing ANP, this study examined the effect of numerous techniques for storing and processing human ANP samples. METHODS AND RESULTS: Samples were obtained repeatedly from three patients, treated, and stored under a variety of conditions. Experiment 1 evaluated the effects of different preservatives at 35, 21, 14, 10, and 7 days before assay. Experiment 2 evaluated nonspecific binding of ANP to different storage tubes during 28 days of storage. Experiment 3 evaluated the effect of storage at -20 degrees C, -80 degrees C, and -196 degrees C for 1 month. ANP was very unstable, degrading as much as 30% after 3 days of storage and by more than 50% in 1 month even when stored at -80 degrees C. Only storage at -196 degrees C (in liquid nitrogen) kept ANP stable for 1 month. Extraction and lyophilization of the samples before freezing and assay within 7 days of freezing only partially minimized the amount of degradation. All other processing techniques had little effect on slowing the degradation of ANP. CONCLUSIONS: These findings raise disturbing questions about the interpretation of the substantial literature on ANP.

Atrial Natriuretic Factor↗

PubMed1991

The effects of race on norepinephrine clearance.

Eighteen normotensive and 19 unmedicated hypertensive black and white male subjects were studied twice, during a 10 meq sodium diet for 5 days and a 200 meq sodium diet for 4 days. The subjects received an infusion of 3H-norepinephrine (3H-NE) during both low and high sodium diets to measure NE clearance. Dietary sodium and blood pressure classification had no effect on 3H-NE clearance. Infusion of pressor doses of NE also failed to alter 3H-NE clearance. Both normotensive and hypertensive blacks had increased 3H-NE clearance rates (p less than .001). The increased rate of 3H-NE clearance among blacks was not affected by alterations in dietary sodium or by pressor doses of NE. Increased NE clearance by blacks may help explain observations that white hypertensives in the age range we studied (25-46 years) have elevated plasma NE levels, while blacks have normal NE levels.

Adult↗

PubMed1991

Disassociation between glomerular hyperfiltration and extracellular volume in diabetic rats.

The relationship of the development of glomerular hyperfiltration in diabetes to changes in extracellular fluid volume has not been previously examined. To accomplish this task, male Wistar rats were chronically cannulated in the bladder, femoral artery and vein. Control measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), extracellular fluid volume (ECF), and urinary sodium excretion were performed on two separate days prior to infusion of streptozotocin (65 mg/kg body wt i.v.). After infusion of streptozotocin, the IDDM rats were separated into two groups: untreated IDDM group of rats and IDDM rats treated with insulin at doses sufficient to normalize blood glucose (Ultralente, 2 to 8 IU/day). A third group of normal non-diabetic rats served as time controls. Measurements of renal function occurred at 1, 4, 7, 11, and 15 days after infusion of streptozotocin. Blood glucose in the non-diabetic measurement period averaged 137 +/- 30 mg/dl and increased from 412 +/- 55 after 24 hours in the untreated diabetic rats to 533 +/- 33 mg/dl after 15 days of IDDM. The time controls and the insulin-treated diabetic rats did not differ in blood glucose values at the time measurements were performed. Glomerular filtration rate increased from 1.0 +/- 0.1 to 1.7 +/- 0.1 ml/min/100 g body wt by day 15 in the untreated diabetic rats with significant increases in GFR within 24 hours. GFR of both time controls and the insulin-treated IDDM rats did not significantly vary during the time of the study. The increase in GFR in the untreated IDDM group was associated with a concomitant increase in RPF.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Epinephrine synthesis by rat arteries.

Carotid artery and aorta homogenates synthesized epinephrine (E) from norepinephrine (NE) in the presence of S-adenosylmethionine. Aorta synthesized epinine by the N-methylation of dopamine (DA) about 3 times as well as it synthesized E from NE. In contrast, adrenal homogenates which contain phenylethanolamine N-methyltransferase (PNMT) methylated DA only 1% as well as NE. The PNMT inhibitor SKF 29661 had no significant effect on methylation of NE by aorta but inhibited adrenal PNMT by 88%. N-Methylating activity in arterial homogenates was increased by dexamethasone and following catecholamine depletion by 6-hydroxydopamine (6-OHDA) and reserpine. Nine days after adrenal demedullation blood E levels collected at decapitation were less than 7% of levels found in sham operated controls but artery homogenate E was unchanged. Demedullated rats given 6-OHDA followed by reserpine for 4 days also had unchanged arterial E levels despite arterial NE levels that were less than 15% of controls. We conclude that arteries synthesize E in vitro and appear to synthesize E in vivo using an extraneuronal N-methyltransferase. This enzyme differs from adrenal PNMT in substrate and inhibitor specificity and its activity is enhanced by catecholamine depletion and by glucocorticoid treatment.

Animals↗

PubMed1991

Ultradian variations of chromogranin A in humans.

Chromogranin A (CgA) is an acidic soluble protein exocytotically released from virtually all neuroendocrine secretory vesicles. Here we examined spontaneous variations in CgA and catecholamine concentrations in humans. In normal subjects, basal CgA showed no day-to-day, week-to-week, or diurnal variability. Plasma CgA had significant ultradian variation in normotensives and hypertensives, and in bilaterally adrenalectomized subjects. Gender, but not age or blood pressure, influenced CgA variations, males having fewer (P less than 0.05) peaks per 8 h. Plasma catecholamines had significant ultradian variations in both controls and bilaterally adrenalectomized subjects. Within individuals, neither basal nor peak plasma CgA correlated with catecholamines, nor was there concordance between plasma CgA and catecholamine peaks. Somatostatin, a widespread inhibitor of nonsympathoadrenal neuroendocrine secretion, diminished both the frequency and amplitude of plasma CgA peaks. Thus spontaneous variations in basal CgA are not directly linked to alterations in sympathoadrenal catecholamine secretion. Furthermore, neuroendocrine secretion at sites other than the sympathoadrenal system contributes to spontaneous variations in CgA concentration.

Activity Cycles↗

PubMed1991

Cardiac epinephrine synthesis. Regulation by a glucocorticoid.

BACKGROUND: The heart can synthesize epinephrine. Homogenates of rat heart, which contain the enzymes phenylethanolamine N-methyltransferase (PNMT) and nonspecific N-methyltransferase (NMT), methylate norepinephrine to form epinephrine. The cardiac atrium contains primarily PNMT and the cardiac ventricle contains both PNMT and NMT. METHODS AND RESULTS: Rats were given the glucocorticoid dexamethasone at doses ranging from 0.2 to 20 mg/kg. Twenty-four hours later, cardiac atria, ventricle, skeletal muscle, and adrenal had increases in PNMT activity to as much as 230% of baseline. NMT activity was unchanged. Longer-term treatment with 1 mg/kg dexamethasone daily for 12 days increased cardiac PNMT activity about fivefold and also increased atrial epinephrine levels. Dexamethasone did not alter ventricular epinephrine levels but increased levels of both PNMT and catechol-O-methyltransferase, the major catabolic enzyme for epinephrine. After dexamethasone treatment, greater volumes of anti-PNMT antiserum were needed to decrease PNMT enzymatic activity, indicating that dexamethasone treatment resulted in greater amounts of PNMT and did not just activate existing PNMT molecules. Denervation of the masseter muscle of rats by unilateral superior cervical ganglionectomy markedly diminished tissue norepinephrine and epinephrine levels but had no effect on masseter PNMT or NMT levels. We have previously shown that chemical sympathectomy with 6-hydroxydopamine increases cardiac PNMT levels. These findings suggest that PNMT is an extraneuronal enzyme in both cardiac and skeletal muscle. CONCLUSIONS: Glucocorticoids have several cardiovascular effects, including increased cardiac output and blood pressure. Enhanced cardiac epinephrine synthesis may mediate some of these glucocorticoid effects.

Adrenal Medulla↗

PubMed1991

Hypertensives' pressor response to norepinephrine. Analysis by infusion rate and plasma levels.

After 5 days of a 10 mEq sodium diet or 4 days of a 200 mEq sodium diet, 15 hypertensives and 11 normotensive control subjects received pressor doses of intravenous norepinephrine (NE). Analysis of pressor responses to the rate of NE infusion showed that the high salt diet sensitized subjects so that they needed less NE to raise systolic blood pressure (SBP) 20 mm Hg (P = .005). There was a complex interaction of salt intake, black race, and hypertension on NE pressor sensitivity (P = .03). Hypertensives attained lower plasma NE levels during the stepwise NE infusion, so we reanalyzed NE sensitivity in terms of the changes in plasma NE levels. This analysis also showed that during the high salt diet, subjects initiated a pressor response at lower plasma NE levels (P = .017) and raised SBP 20 mm Hg at lower NE levels (P = .007). The reanalysis showed that hypertensives initiated a pressor response at lower plasma NE levels (P = .03) and raised SBP 20 mm Hg at lower NE levels (P = .002). Plasma NE levels should provide a better guide to the concentration of NE at cardiovascular receptors than the rate of NE infusion. Analysis of pressor responses to plasma NE levels demonstrated that the hypertensives had an exaggerated pressor response to NE.

Black People↗

PubMed1991

What do plasma and urinary measures of catecholamines tell us about human response to stressors?

Because of the complex physiology of the sympathetic nervous system, venous and urinary catecholamine levels in response to stressors may serve as approximations of sympathetic nervous system activity in the heart and vasculature. Furthermore, the sympathetic nervous system does not respond in a homogeneous fashion to stressors; instead, there is differential activation at various sites of the sympathetic nervous system. Despite these limitations, numerous studies document that peripheral venous samples reflect sympathetic nerve firing and are related to cardiovascular pathophysiology. Although arterial norepinephrine levels may be more sensitive than venous levels, venous levels do respond to stressors when attention is given to the time course of sampling, the imprecision of assays (and thus the requirement for larger sample sizes), and the selection of appropriate tasks. In addition to catecholamines, there are other compounds that may be used to index sympathetic nervous system responses to stressors. Chromogranin A, as measured in antecubital blood, responds to large-scale perturbations of the sympathetic nervous system but appears relatively insensitive to short-term behavioral challenge. In response to stressors, diastolic blood pressure is better predicted by plasma levels of renin than of norepinephrine.

Cardiovascular Physiological Phenomena↗

PubMed1990

Relation between motor asymmetry and direction of rotational behaviour under amphetamine and apomorphine in rats with unilateral degeneration of the nigrostriatal dopamine system.

The study examines whether in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra, the direction of amphetamine- and apomorphine-induced rotations is determined by a bias to step more frequently with one hindleg. Results show that there is a strong asymmetry in usage of hindlegs under apomorphine but a weak one under amphetamine. Moreover, under apomorphine, virtually all steps are backward. Under amphetamine, however, steps are directed both backward and forward, although backward steps are relatively more prevalent when striatal dopamine depletion is nearly total. The different styles of rotation reflect the activation of pure turning under apomorphine, and turning combined with forward progression under amphetamine. It is suggested that presence of forward progression during turning depends on the capacity to modulate striatal activation. Moreover, the different styles of rotation are inconsistent with the hypothesis that a bias in leg usage sets the direction of turning. Instead, it seems that unilateral striatal activation sets the directionality of turning, independent of any hindlimb motor asymmetries.

Animals↗

PubMed1990

Epinephrine synthesis in rat skin by an N-methyltransferase.

Homogenates of rat skin N-methylated norepinephrine to form epinephrine. In the brain and adrenal medulla the enzyme phenylethanolamine-N-methyltransferase synthesizes epinephrine, but the skin epinephrine forming enzyme was an N-methyltransferase distinct from phenylethanolamine-N-methyltransferase. Skin N-methyltransferase was not inhibited by the phenylethanolamine-N-methyltransferase inhibitor SKF 29661. Unlike phenylethanolamine-N-methyltransferase, skin readily methylated dopamine to form epinine. Sympathetic denervation by superior cervical ganglionectomy had no effect on skin N-methyltransferase levels. Procedures that reduced skin norepinephrine levels to 2% of control left skin epinephrine levels at 38% of control even when plasma epinephrine levels were very low. Skin contains an extraneuronal enzyme that synthesizes epinephrine in vitro and appears to synthesize part of the epinephrine normally present in skin. The enzyme can synthesize epinephrine and epinine, both of which can regulate epidermal proliferation, skin blood flow, and atopic responses.

Animals↗

PubMed1990

Epinephrine synthesis by an N-methyltransferase in rat liver.

We investigated if liver can synthesize epinephrine in vitro and in vivo. Homogenates of rat liver readily synthesized [3H]epinephrine from [3H]S-adenosylmethionine and norepinephrine. Liver homogenates also N-methylated dopamine at more than twice the rate that they N-methylated norepinephrine. In contrast, adrenal homogenates, which N-methylate norepinephrine to form epinephrine using the enzyme phenylethanolamine-N-methyltransferase (PNMT), methylated dopamine only about 1% as well as norepinephrine. Synthesis of epinephrine by liver homogenates was not significantly inhibited by the PNMT inhibitor SKF 29661 at a concentration that inhibited adrenal homogenate epinephrine synthesis by nearly 90%. These findings indicate that liver can synthesize epinephrine in vitro using an enzyme other than PNMT. Adrenal demedullation of rats reduced plasma epinephrine levels to 7% of control values, but left liver epinephrine and epinephrine-forming enzyme levels unchanged. Treatment of demedullated rats with 6-hydroxydopamine plus reserpine also resulted in dramatically reduced plasma epinephrine levels but no change in hepatic epinephrine and N-methylating enzyme levels. We conclude that the liver synthesizes its own epinephrine.

Animals↗

PubMed1990

A more sensitive and specific radioenzymatic assay for catecholamines.

This modification of the catechol-O-methyltransferase (COMT) based radioenzymatic assay for norepinephrine (NE) and epinephrine (E) improves sensitivity, selectivity and eliminates many inhibitors of COMT. Prior to assay, samples are extracted into heptane with diphenylborate, then into dilute acetic acid. This extraction procedure has an efficiency of 78% for NE but less than 2% for S-adenosylmethionine (SAM). The extraction procedure also excludes calcium and other COMT inhibitors present in urine, plasma and every tissue tested. This eliminates the requirement for individual standardization of tissue and urine samples. Sensitivity of the assay for NE and E is 10 and 6 pg/ml respectively in 1 ml of plasma. The intraassay coefficients of variation for NE and E are 4 and 13% and the interassay coefficients of variation for NE and E are 10 and 16% in a human plasma sample containing low catecholamine levels. The assay permits quantitation of plasma E levels that were undetectable in prior assays.

Animals↗

PubMed1990

Norepinephrine clearance, chromogranin A and dopamine beta hydroxylase in renal failure.

Plasma norepinephrine (NE) levels are normal or elevated in patients with renal failure even though uremia often damages the sympathetic nerves that release NE. We infused 3H-NE into subjects with normal, mildly depressed, or absent renal function. 3H-NE clearance was depressed 20% in mild renal failure and 40% in patients on hemodialysis. The calculated rate of NE release into plasma was low in uremics even though their plasma NE was normal. Dopamine beta hydroxylase (D beta H) and chromogranin A are released from sympathetic nerve endings along with NE. D beta H levels were low in uremia and D beta H levels doubled following hemodialysis. Chromogranin A levels were very high in uremics and increased slightly following hemodialysis. Plasma clearance of both NE and chromogranin A appears low in renal failure. The calculated rate of NE release is diminished in uremics, which is in accord with reports of autonomic neuropathy in these patients.

Adult↗

PubMed1990

Elevated insulin, norepinephrine, and neuropeptide Y in hypertension.

To investigate the relationship between insulin and sympathetic activity, plasma norepinephrine, neuropeptide Y, serum glucose and insulin concentrations were measured in ten age-, weight-, and sex-matched normotensive and untreated hypertensive subjects at fasting and 2 h following ingestion of a 75 g oral glucose dose. Hypertensives had higher fasting serum insulin (27 +/- 6 v 12 +/- 2 microU/mL; P = .02) and plasma norepinephrine (356 +/- 38 v 235 +/- 35 pg/mL; P = .03) concentrations than normotensives. Glucose load increased serum insulin (P less than .001) and plasma norepinephrine concentrations (P = .001) in both groups and hypertensives had still higher postglucose insulin (P = .003) and norepinephrine levels (P = .003) than normotensives. Fasting neuropeptide Y was higher in hypertensives than in normotensives (P = .03) and correlated with age in both groups (r = 0.7; r = 0.77). Postglucose serum insulin correlated positively with plasma norepinephrine (r = 0.75; P = .013) in normotensives, but these parameters correlated negatively in hypertensives (r = -0.7; P = .036). We hypothesize that elevated plasma norepinephrine and neuropeptide Y levels reflect an increased level of sympathetic nervous activity in hypertensives, which in turn may be responsible for the abnormal relationship between plasma NE and insulin levels.

Blood Glucose↗

PubMed1990

Cardiac atria and ventricles contain different inducible adrenaline synthesising enzymes.

STUDY OBJECTIVE - The aim of the study was to investigate adrenaline synthesis in atrial and ventricular homogenates. DESIGN - The study involved the use of a new assay which measures the rate at which tissue homogenates convert noradrenaline into adrenaline, or dopamine into N-methyldopamine. This was coupled with a sensitive assay for tissue catecholamines in an investigation of ventricular and atrial homogenates from rats exposed to adrenal demedullation and chemical depletion of cardiac catecholamines. MEASUREMENTS and RESULTS - Atrial and ventricular homogenates from 12 male Sprague-Dawley rats were investigated. Atrial adrenaline forming activity resembled adrenal phenylethanolamine-N-methyltransferase (PNMT) in its relatively high affinity for noradrenaline, substrate specificity for noradrenaline over dopamine, and inhibition by the PNMT inhibitor SKF 29661. Ventricular tissue nonspecifically methylated both noradrenaline and dopamine, and was less inhibited by SKF 29661. Adrenal demedullation induced activity of ventricular adrenaline forming enzyme. CONCLUSIONS - The cardiac atria and ventricles contain different inducible adrenaline forming enzymes. About one third of cardiac adrenaline may be synthesised by the heart itself. The ventricular enzyme can synthesise adrenaline from noradrenaline, and N-methyldopamine from dopamine.

Animals↗

PubMed1990

Catecholamine and thyroid hormones in traumatic injury.

During hyperthyroidism, hypothyroidism, and severe stress there is often an inverse relationship between plasma norepinephrine (NE) and thyroid hormones. We evaluated this relationship in patients who were severely burned, patients who had injury to both brain and body, patients with head injury, and patients receiving high dose barbiturates for head injury. Head-injured patients had a low thyroxine (T4), low triiodothyronine (T3), and high reverse T3. Phenytoin for control of seizures lowered T3 and T4 and increased thyroid-stimulating hormone. Burned patients had a strong negative correlation between NE and T3 (r = -.88, p less than .001). Patients with injury to both brain and body had a weak negative correlation between NE and T3 (r = -.5, p = .06). Patients with head injury showed no correlation between NE and T3. Severely injured patients had a close inverse relationship between elevated NE levels and depressed T3 levels. This relationship appears to depend on an intact CNS, as the relationship was disrupted by head injury and barbiturates.

Adolescent↗