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Biomedical subjects

M G Ziegler

Publications and source records attributed to M G Ziegler.

At least 19 recordsLinked to original sources
PubMed1992

Propranolol reduces rat dopamine-beta-hydroxylase activity and catecholamine levels.

Propranolol treatment (1 mg/kg i.p. twice daily for 8 days) reduced atrial dopamine-beta-hydroxylase (D beta H) activity by 60.5% and lung D beta H activity by 53.5% but did not alter ventricle D beta H activity. Propranolol also significantly reduced atrial noradrenaline (NA) by 66.3%, adrenaline (A) by 40%, dopamine (DA) by 72.4% and lung NA by 46.6% but did not change plasma or cardiac ventricle catecholamines. The addition of propranolol (10(-6) M) to cardiac and lung tissue homogenates in vitro did not inhibit tissue D beta H activities. The results suggest that chronic propranolol treatment inhibits NA synthesis and support the hypothesis of a centrally induced inhibition of sympathetic activity caused by beta-adrenoceptor blockade.

Animals↗
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↗
PubMed1979

Norepinephrine elevations in cerebrospinal fluid after d- and l-amphetamine.

We continuously collected cerebrospinal fluid (CSF) from the lateral ventricles of monkeys and gave them from 0.1 to 1.0 mg/kg d- or l-amphetamine intravenously. The norepinephrine (NE) content of their CSF had a small circadian rhythm and a large increase after amphetamine. 1.0 mg/kg amphetamine gave a four-fold rise in CSF-NE which remained elevated for 33 h, smaller doses gave proportionately lesser responses. Both d- and l-amphetamine caused similar NE elevations except for minor differences at the highest dose. If there are differences in behavioral effects of moderate doses of d- and l-amphetamine, they are probably not due to a general difference in central NE release from these stereoisomers.

Amphetamine↗
PubMed1979

Bromocriptine inhibits norepinephrine release.

Bromocriptine is a dopamine agonist that induces postural hypotension and can be used as an antihypertensive. The drug inhibits release of norepinephrine (NE) from an isolated artery by stimulating presynaptic receptors. In normotensive subjects it lowers both plasma and cerebrospinal fluid (CSF) levels of NE by 50% and lowers blood pressure moderately in standing subjects and slightly in recumbent subjects. Through central and peripheral mechanisms, bromocriptine inhibits sympathetic nervous discharge of NE.

Adult↗
PubMed1979

Hydrochlorothiazide-induced sympathetic hyperactivity in hypertensive patients.

Hydrochlorothiazide-induced diuresis and natriuresis is considered to be responsible for the antihypertensive effect of this drug. After short-term treatment there is decreased cardiac output and increased peripheral resistance which we have found to be attended by increased plasma norepinephrine (NE) levels. After longer treatment cardiac output returns to normal and peripheral resistance declines. At this time, plasma NE levels remain elevated, indicating that peripheral resistance reduction is not a consequence of a reduction of the elevated level of sympathetic activity. These results provide a rationale for the combined use of diuretics and drugs which diminish noradrenergic activity in the treatment of hypertension.

Adult↗
PubMed1979

Interactions of amphetamine, pimozide, and lithium on plasma norepineophrine and dopamine-beta-hydroxylase in schizophrenic patients.

The peripheral interactions of amphetamine with antipsychotic agents may elucidate some central mechanisms by which these drugs affect the behavioral responses to amphetamine. The authors studied the effects of intravenous amphetamine on plasma levels of norepinephrine (NE), dopamine-beta-hydroxylase (DBH), pulse rate, and blood pressure in schizophrenic patients. Amphetamine increased plasma NE, pulse rate, and blood pressure without significantly changing plasma DBH. DBH activity was similar in drug-free schizophrenic and normal subjects. Neither pimozide nor lithium altered these amphetamine effects nor changed any of the cardiovascular parameters measured in the drug-free subjects. Pimozide and lithium alter behavior and the behavioral effects of amphetamine, but neurotransmitters other than NE may be involved.

Adolescent↗
PubMed1979

Catecholamine metabolism in primary anorexia nervosa.

Abnormalities in neuroendocrine function and sympathetic nervous system activity appear to be present in primary anorexia nervosa. Hypothalamic catecholamines are involved in control of endocrine function and norepinephrine is released from sympathetic nerve endings. Because of possible abnormalities in catecholamine metabolism, plasma levels of norepinephrine and urinary excretion of homovanillic acid and 3-methoxy-4-hydroxyphenyl glycol were studied in female patients with primary anorexia nervosa before and after significant clinical improvement and compared with normal female volunteers. During the phase of the disease in which body weights were more than 20--25% below ideal, patients' blood pressures and pulse rates, plasma levels of norepinephrine, and 24-h urinary excretion of 3-methoxy-4-hydroxyphenol glycol and homovanillic acid were lower than those of a group of normal volunteers. After weight gain, these parameters increased to near-normal levels. At no time was plasma dopamine-beta-hydroxylase activity abnormal. The results suggest that abnormalities in catecholamine metabolism in primary anorexia nervosa are caused by starvation, and that neuronal functions dependent on aminergic neurotransmission may be altered as a result.

Adolescent↗
PubMed1979

Studies of experimental cervical spinal cord transection. Part II: Plasma norepinephrine levels after acute cervical spinal cord transection.

Plasma concentrations of norepinephrine (NE) were measured by a radioenzymatic assay technique before and serially after laminectomy at the C-6 level in 14 anesthetized dogs. In half the animals, no further procedures were carried out (control group); in the other dogs, cervical cord transection was performed in addition to laminectomy (experimental group). Mean plasma NE levels were similar in both groups after laminectomy and before cord interruption. In the control group, NE levels increased gradually for 2 hours after the procedure. In the group with cord transection, however, NE rose immediately after transection to 267% of the baseline value, then fell to 25% of the plasma NE level in the control group at 30 minutes, 29% at 60 minutes, and 15% at 120 minutes. Cervical spinal cord transection, therefore, results in an abrupt but short-lived increase in plasma NE concentrations. These changes in plasma NE levels may explain, at least in part, the hemodynamic alterations and the acute central hemorrhagic necrosis that occur after high spinal cord trauma.

Animals↗
PubMed1978

Plasma dopamine-beta-hydroxylase activity and norepinephrine levels during the human menstrual cycle.

Plasma samples obtained throughout the normal menstrual cycles of six women were analyzed for dopamine-beta-hydroxylase activity (DBH), norepinephrine (NE), follicle-stimulating hormone, luteinizing hormone, and prolactin. Neither DBH activity nor NE concentrations paralleled changes in plasma gonadotropins and prolactin. No consistent pattern of either plasma DBH activity or NE concentrations during the normal menstrual cycle was noted. Thus, an association between peripheral sympathetic nervous system activity and the midcycle surge in plasma gonadotropins reported by others was not reproducible in our study of normally menstruating women.

Dopamine beta-Hydroxylase↗
PubMed1978

The circadian variation of catecholamine metabolism in the subhuman primate.

Cerebrospinal fluid (CSF) was removed continuously in 2- or 3-h aliquots from the lateral and fourth cerebral ventricles of chronic chair restrained rhesus monkeys. Under conditions of 12 h light (06.00-18.00 h) and 12 h darkness (18.00-06.00 h) the concentrations of norepinephrine (NE) were found to describe a circadian pattern, with maximal concentrations occurring during the light hours and minimal concentrations occurring during the dark hours. The patterns were generally coincident with the circadian patterns of brain temperature and body activity. When assayed for 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA), samples of CSF collected over 3-4 days demonstrated no reproducible pattern of change. Fluctuation in the concentration of MHPG did not correspond in direction or magnitude to changes in the concentration of VMA. These random fluctuations may in part be accounted for by the influx of the metabolites from peripheral sources to the brain and CSF, and by the relatively slow movement of these metabolites as they diffuse from brain parenchyma to the CSF.

Animals↗
PubMed1978

Probenecid-induced norepinephrine elevations in plasma and CSF.

Probenecid administered in divided oral doses totaling 100 mg/kg increased levels of norepinephrine (NE) in plasma and cerebrospinal fluid (CSF). This technique is commonly used to measure the rate of accumulation of acidic metabolites of certain brain neurotransmitter biogenic amines in CSF after blockade of their transport into blood. Since levels of 3-methoxy-4-hydroxy-phenylethyleneglycol, a neutral metabolite of NE, are also elevated after high oral doses of probenecid, the increases of CSF and plasma NE levels may be directly related to probenecid-induced release of this amine from noradrenergic neurons. In patients who experienced nausea or vomiting there were lower levels of probenecid in CSF, probably secondary to diminished absorption of the medication. These patients also had lower levels of NE in plasma than did patients who remained asymptomatic.

Adolescent↗
PubMed1978

Phencyclidine: effects on motor activity and brain biogenic amines in the guinea pig.

Previous reports suggesting that the behavioral response of the guinea pig to phencyclidine (PCP) administration is more similar to the effects of PCP observed in higher animals than those observed in mice and rats prompted us to investigate the effects of PC on spontaneous motor activity and brain biogenic amine levels in the guinea pig. Doses of 2.5 and 5.0 mg/kg PCP were found to significantly elevate spontaneous motor activity; however, 7.5 mg/kg PCP produced highly variable results which were not significantly different from control. The concentrations of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and norepinephrine were measured in the forebrain and hindbrain of previously drug naive animals 30 min after administration of 5 mg/kg PCP. As compared to saline injected control animals, PCP was observed to have no effect on any of the neurochemical determinants measured. Contrary to previous reports, these data suggest that PCP produces behavioral effects in the guinea pig which are not unlike those observed in mice and rats. Furthermore, the effects which we report on spontaneous motor activity are not related to changes in the regional concentration of any of the neurochemical variables which were measured.

Animals↗