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Biomedical subjects

M G Ziegler

Publications and source records attributed to M G Ziegler.

At least 73 records · Page 4Linked to original sources
PubMed1995

Nonadrenal epinephrine-forming enzymes in humans. Characteristics, distribution, regulation, and relationship to epinephrine levels.

Animal studies indicate that nonadrenal tissues may synthesize epinephrine (E). Here we demonstrate phenylethanolamine N-methyltransferase (PNMT) and/or nonspecific N-methyltransferase (NMT) enzymatic activity in human lung, kidney, heart, liver, spleen, and pancreas. There was a significant overall correlation (r = 0.34) between tissue PNMT and E. PNMT and NMT in human tissues differed in substrate and inhibitor specificity, thermal stability, and antigenicity. By these criteria, PNMT in human lung and in human bronchial epithelial cells were indistinguishable from adrenal PNMT. PNMT and/or NMT activity were present in red blood cells (RBCs), and cancer cell lines. Human kidney, lung, and pancreas showed immunohistochemical staining with an antibody to adrenal PNMT. RBC PNMT activity was lower in males than females and was increased in hyperthyroidism and decreased in hypothyroidism. PNMT activity in a human bronchial epithelial cell line was dramatically increased by incubation with dexamethasone. E and 3H-E levels in plasma and urine during an intravenous infusion of 3H-E into humans indicated that kidney may synthesize half of urinary E. We conclude that PNMT and NMT are widely distributed in human tissues, that they may synthesize E in vivo and are influenced by glucocorticoid and thyroid hormones.

Adrenal Glands↗
PubMed1995

The effect of sleep apnea on plasma and urinary catecholamines.

Numerous studies have suggested an alteration of sympathetic nervous system functioning in sleep apnea. However, most of these studies did not control for confounding factors such as diet, obesity, hypertension and anti-hypertensive medications. We examined plasma and urinary catecholamines in 43 patients, including hypertensive and normotensive individuals with and without sleep apnea. Hypertensive patients were studied at least 3 weeks following tapering of anti-hypertensive medication. All patients consumed similar diets and were of similar age and level of obesity. Twenty-four-hour urinary norepinephrine levels were significantly higher in apneics (58.2 ng vs. 40.2 ng in nonapneics, p < 0.002). Urinary norepinephrine in apneics was increased during both day and night. Plasma norepinephrine levels were not significantly elevated in apneic patients but were elevated in hypertensive patients both during sleep and in the morning (p < 0.05).

Adult↗
PubMed1995

The effect of hypoxia on baroreflexes and pressor sensitivity in sleep apnea and hypertension.

Many persons with sleep apnea are hypertensive. Forty-two subjects of similar age and weight were divided into four groups of hypertensives and normotensives with and without sleep apnea. All subjects had heart rate, blood pressure (BP), baroreflex sensitivity and pressor sensitivity to phenylephrine measured while breathing room air or 15% oxygen. Hypoxia raised heart rate and lowered BP in all groups (p < 0.001), with the greatest hypotensive effect among hypertensives. Hypertensives had blunted baroreflex sensitivity, and breathing a hypoxic mixture lowered baroreflex sensitivity of all four groups (p = 0.008). The apneic subjects tended to lower their baroreflex sensitivity more in response to hypoxia and also had an enhanced pressor response to phenylephrine, whether breathing room air or 15% oxygen. Episodes of sleep apnea lead to hypoxia, an initial period of hypotension and a subsequent increase in sympathetic nervous activity. Our studies suggest that apneics could have an exaggerated pressor sensitivity to norepinephrine. They might also have difficulty returning BP to normal levels, because hypoxia impaired baroreflexes.

Adult↗
PubMed1994

Does chromostatin influence catecholamine release or blood pressure in vivo?

Although the structure of chromogranin A (CgA) is now known, its ultimate physiological role remains elusive. Recently, an interior fragment of CgA [CgA(124-143)], also called chromostatin, was reported to suppress catecholamine release from chromaffin cells in vitro. We therefore explored chromostatin's biological actions when administered in vivo to anesthetized rodents with normal (Wistar-Kyoto rats) or elevated blood pressure (spontaneously hypertensive rats). Neither mean arterial pressure nor plasma epinephrine concentrations were significantly altered following either chromostatin or vehicle administration. Plasma norepinephrine, on the other hand, tended to rise throughout all studies, with the rise reaching statistical significance only in the SHR subgroup receiving chromostatin. We conclude that, unlike its actions in vitro, chromostatin does not appear to suppress catecholamine release or modulate blood pressure in vivo.

Animals↗
PubMed1994

Plasma norepinephrine variations correlate with peripheral vascular resistance in resting humans.

Plasma levels of norepinephrine (NE) vary rhythmically in humans and animals with an ultradian (shorter than 1 day) periodicity. We repeatedly measured plasma NE levels, blood pressure, cardiac output, and total peripheral resistance in nine normal resting subjects over 5 h. Plasma NE correlated with total peripheral resistance (Z = 0.322, P < 0.0002) and inversely with cardiac output (Z = -0.276, P < 0.0002) for the nine subjects overall. The correlations were strongest in subjects with the most spontaneous variability in total peripheral resistance. These findings suggest that spontaneous oscillations in plasma NE levels reflect alterations in sympathetic nervous activity to resistance blood vessels. The negative correlation between cardiac output and plasma NE levels may result from the very minor cardiac NE spillover into plasma and the inverse relationship between cardiac output and total peripheral resistance.

Activity Cycles↗
PubMed1994

Deficient noradrenergic response to oral glucose in hypertensives.

The blood pressures of hypertensives lower more following a meal than those of normotensives; the reason for this difference is not known. We gave an oral glucose tolerance test to 33 normotensives and 16 hypertensives matched for age, sex, race, height, and weight. The hypertensives had slightly higher glucose levels and similar insulin levels. The diastolic blood pressures of hypertensives decreased by approximately 10 mmHg, more than twice as much as those of normotensives, but their heart rates did not change. Glucose increased the normotensives' heart rates by approximately 5 beats/min. The hypertensives' plasma norepinephrine responses to a glucose meal were less than one-half of normal. These findings suggest that hypertensives have a large drop in blood pressure following glucose because of a deficient sympathetic nervous response to eating. This may reflect both impaired baroreflexes and deficient insulin-mediated stimulation of the sympathetic nervous system.

Administration, Oral↗
PubMed1994

Cyclic AMP export from lymphocytes in hypertension.

While the importance of receptor-mediated intracellular cyclic AMP in blood pressure regulation is well documented, few studies have evaluated the physiologic relevance of cyclic AMP exported from cells. We report evidence of a relationship between blood pressure and the transport of intracellular cyclic AMP from lymphocytes. Twenty-eight hypertensive and 56 normotensive white and black volunteers (mean age 40 years) were studied. Both intra- and extracellular concentrations of cyclic AMP were determined in lymphocytes following incubation with 10(-5) M isoproterenol. Compared to normotensives, hypertensives (p = 0.001), particularly white hypertensives (p = 0.023) had higher levels of exported cyclic AMP. These values were independent of intracellular concentrations of cyclic AMP, which were similar across the groups. Exported cyclic AMP was independent of both sodium excretion and beta-adrenergic receptor sensitivity, the latter being lower in white hypertensives (p = 0.024). Across all subjects, exported cyclic AMP was correlated with MAP (r = .39, p < 0.001). These findings indicate that the active transport of cyclic AMP may be enhanced in hypertension and suggest a possible pathway which might explain existing data of increased cyclic AMP levels in hypertension.

Adult↗
PubMed1994

Does lipophilicity of angiotensin converting enzyme inhibitors selectively influence autonomic neural function in human hypertension?

INTRODUCTION: Angiotensin II has both central nervous system and peripheral effects on autonomic function. Ramipril is among the more lipophilic angiotensin converting enzyme (ACE) inhibitors, and hence can penetrate the central nervous system readily. METHODS: We investigated whether rampiril has selective effects on autonomic control of the circulation in human hypertension, compared with the more hydrophilic ACE inhibitor enalapril. Blood pressure, hemodynamics and measurements of autonomic function were obtained in 13 essential hypertensive subjects after 10 days on placebo, and after crossover monotherapy with 10 days on enalapril versus 10 days on ramipril. RESULTS: Both enalapril and ramipril lowered systolic, diastolic and mean arterial blood pressures significantly, with no reflex increase in heart rate. Plasma renin activity increased substantially on each of the ACE inhibitors. There were no significant effects of either agent on plasma catecholamines (norepinephrine or epinephrine) or chromogranin A, biochemical indices of efferent sympatho-adrenal outflow. There were also no significant changes after either agent in baroreflex sensitivity (to high- and low-pressure stimuli), the response to cold stress or sympathetic (alpha-adrenergic) participation in blood pressure maintenance. There was a marginal effect of ACE inhibition on alpha 1-adrenergic pressor sensitivity, but the two compounds did not differ significantly in this respect. CONCLUSION: Autonomic control of circulatory function was maintained well after either lipophilic (ramipril) or hydrophilic (enalapril) ACE inhibitors, and the lipophilic compound ramipril had no additional effects on autonomic function beyond those shown by the hydrophilic agent enalapril.

Aldosterone↗
PubMed1994

Effects of an oral prostaglandin E1 agonist on blood pressure and its determinants in essential hypertension.

Arachidonic acid metabolites such as prostaglandins of the E series have well-documented effects on blood pressure (BP). Recently, a stable analogue of prostaglandin E1 (misoprostol) became available for oral use in humans, being primarily indicated for prevention of peptic disease induced by cyclo-oxygenase inhibitors. We hypothesised that misoprostol would exert antihypertensive actions and therefore performed a randomised, placebo-controlled clinical trial in 15 essential hypertensives to characterise the effects of a 400 micrograms oral dose of misoprostol on BP and its haemodynamic, autonomic and biochemical determinants. There was a modest (from 105.3 +/- 2.7 to 101.9 +/- 2.7 mmHg, P = 0.006) decrease in mean arterial pressure 20 minutes after the dose, accompanied by a decrease in systemic vascular resistance and a compensatory rise in cardiac output and heart rate. Baroreflex gain was unaltered by misoprostol, as were plasma renin activity, catecholamines and chromogranin A. Even this transient antihypertensive effect was abolished by cyclooxygenase inhibitor pretreatment. We conclude that oral misoprostol exerts a modest but transient antihypertensive effect that is unlikely to be of either therapeutic benefit or concern in essential hypertension.

Administration, Oral↗
PubMed1993

Sympathetic alterations after sodium restriction and short-term captopril administration.

OBJECTIVES: The purpose of this study was to examine the effects of short-term captopril therapy during sodium restriction on several markers of the sympathetic nervous system, including plasma norepinephrine, neuropeptide Y, beta-adrenergic receptors and cortisol. BACKGROUND: Recent studies suggest that the therapeutic effects of converting enzyme inhibitors involve not only the renin-angiotensin and prostaglandin systems but also the sympathetic system. METHODS: Twelve hypertensive and 20 normotensive men were studied after 2 5-day hospital stays during which they consumed a 10-mEq sodium diet and received captopril (25 mg twice daily) or placebo in a double-blind crossover study. RESULTS: Captopril decreased neuropeptide Y (p < 0.05) and angiotensin II (p < 0.01) and increased isoproterenol-stimulated cyclic adenosine monophosphate (AMP) in lymphocytes (p < 0.03), plasma norepinephrine (p < 0.02), cortisol (p < 0.05) and renin (p < 0.001) in both hypertensive and normotensive subjects. Hypertensive subjects had an increased beta-adrenergic receptor density (p < 0.02) and a greater decrease in diastolic blood pressure compared with normotensive subjects (p < 0.02). CONCLUSIONS: The results of this study suggest that the short-term therapeutic effects of captopril may involve concerted changes in key components of the sympathetic nervous system. These findings, such as decreased neuropeptide Y combined with increased norepinephrine and beta-adrenergic receptors, are compatible with the observation of increased cardiac output and decreased peripheral resistance after short-term angiotensin-converting enzyme inhibition.

Analysis of Variance↗
PubMed1993

Decreased angiotensin II response but unaltered cardiovascular pressor response to infused norepinephrine after sodium restriction and converting enzyme inhibition.

Although studies indicate that converting enzyme inhibitors such as captopril influence beta-adrenergic physiology, the data on alpha-adrenergic physiology is inconsistent. This study therefore examined the effects of captopril (50 mg/day for 5 days) during sodium restriction on the pressor response and on angiotensin II and neuropeptide Y levels to infused norepinephrine (0.01 to 0.1 micrograms/kg/min) in 17 hypertensive and 27 normotensive subjects. Angiotensin II increased significantly in response to infused norepinephrine during placebo administration (p < 0.001) but not during captopril administration (p = 0.15). Neuropeptide Y levels decreased in response to captopril (p = 0.02). Despite these changes the pressor response to infused norepinephrine was unchanged with captopril. These data support the conclusion that the antihypertensive action of captopril is unrelated to alterations in norepinephrine-mediated alpha-adrenergic pressor regulation. The finding of a decrease in neuropeptide Y levels may have relevance to the therapeutic effects of captopril.

Adult↗
PubMed1993

Temporal stability of task-induced cardiovascular, adrenergic, and psychological responses: the effects of race and hypertension.

This study examined the test-retest reliability of task-induced responses of blood pressure, heart rate, norepinephrine, epinephrine, anger, and anxiety in 98 black and white normotensive and hypertensive individuals. Subjects completed three laboratory tasks (standing, mental arithmetic, and cold pressor) on two occasions 10 days apart. For all subjects, all baseline and test-retest correlation coefficients were significant (rs = .23-.71; median = .58). Baseline-adjusted (residual scores) reactivity test-retest correlation coefficients were consistently smaller (rs = .02-.55; median = .36). In contrast to the white hypertensives, white normotensives, and black normotensives, the black hypertensives showed no significant baseline-adjusted test-retest correlation coefficients (rs = -.21-.40; median = .12). Epinephrine responses revealed a significant session by race interaction; blacks had 20% higher mean values and whites had 10% lower mean values upon retesting. The data suggest that race and hypertension may interact to affect the temporal stability of task-induced responses to stressors.

Adrenergic Fibers↗
PubMed1993

Glucocorticoid elevation of mRNA encoding epinephrine-forming enzyme in lung.

The epinephrine-forming enzyme phenylethanolamine N-methyltransferase (PNMT) is present in lung and its activity is increased by the glucocorticoid dexamethasone. Chronic administration of dexamethasone (0.5 mg/kg twice daily) doubled levels of mRNA coding for PNMT in rat lung. Administration of the glucocorticoid antagonist RU 486 after 7 days of dexamethasone treated reduced PNMT mRNA by about two-thirds within 24 h. Lung epinephrine (E) levels correlated with lung PNMT activity in these dexamethasone-treated and control rats. In a separate experiment, lung PNMT mRNA levels were nearly tripled 6 h after dexamethasone (1 mg/kg sc). In a third experiment chronic administration of the PNMT inhibitor SKF 64139 (50 mg/kg twice daily) reduced in vitro lung PNMT activity in chronically dexamethasone-treated adrenalectomized rats by approximately 96% and reduced lung E levels by approximately 75%. We conclude that glucocorticoids increase lung PNMT activity by increasing levels of mRNA coding for this enzyme. The data also suggest that a substantial fraction of lung E is locally synthesized. We speculate that enhanced lung E synthesis may participate in glucocorticoid-induced dilation of the bronchioles.

Adrenal Glands↗
PubMed1993

Glucocorticoid hypertension and nonadrenal phenylethanolamine N-methyltransferase.

Several drugs that block epinephrine synthesis by inhibiting phenylethanolamine N-methyltransferase (PNMT) lower blood pressure in hypertensive rats. We investigated the mechanism by which these drugs lower blood pressure in rats made hypertensive with the glucocorticoid dexamethasone. We performed adrenalectomy or sham operation on several rats and then gave them either dexamethasone chronically or vehicle. The dexamethasone-treated adrenalectomized rats also received either the centrally acting PNMT inhibitor SKF 64139 chronically or an equal dose of the primarily peripherally acting PNMT inhibitor SKF 29661. Both SKF 64139 and SKF 29661 reduced blood pressure by more than 25 mm Hg. SKF 64139 also reduced PNMT activity in hypothalamus, medulla oblongata, skeletal muscle, and cardiac atria and ventricles; SKF 29661 inhibited PNMT in muscle and heart tissue by 40-75%, did not inhibit PNMT in hypothalamus, and inhibited PNMT by only 29% in medulla oblongata. PNMT activity in peripheral tissues was also more highly correlated with blood pressure than was PNMT activity in the brain areas studied. Neither drug reduced tissue epinephrine levels, but SKF 64139 elevated dopamine or norepinephrine levels or both in several tissues. We conclude that the blood pressure-lowering action of PNMT-inhibiting drugs in glucocorticoid hypertensive rats may be due to inhibition of peripheral nonadrenal PNMT. We speculate that elevations in nonadrenal PNMT may mediate glucocorticoid hypertension.

Adrenalectomy↗
PubMed1993

Catecholamine secretory vesicles. Augmented chromogranins and amines in secondary hypertension.

Chromogranins A and B are major soluble proteins in chromaffin granules. Their adrenomedullary content is increased in the spontaneously (genetic) hypertensive rat. Is augmented catecholamine vesicular storage of the chromogranins a specific feature of genetic hypertension? To explore this question, we measured chromogranin A immunoreactivity, using a novel, synthetic peptide radioimmunoassay, in rat adrenal medullas 4-6 weeks after induction of the two-kidney, one clip Goldblatt model of renovascular hypertension and in unmanipulated control animals. We also measured messenger RNAs of chromogranins A and B and dopamine beta-hydroxylase by Northern blot. Immunoreactive adrenal chromogranin A was 3.3-fold higher (p < 0.01) in clipped rat adrenals. Adrenal catecholamine concentrations and phenylethanolamine-N-methyltransferase activity were also higher in clipped rats. Adrenal dopamine beta-hydroxylase activity (both membrane-bound and soluble forms) and corticosterone (glucocorticoid) concentration did not significantly differ between the groups. Adrenal medullary chromogranin A messenger RNA levels in clipped rats were 3.2-fold higher (p = 0.029) than those in the control group, and chromogranin B messenger RNA levels were 4.6-fold higher (p = 0.05). Dopamine beta-hydroxylase messenger RNA levels were 2.9-fold higher (p = 0.038). Thus, augmented synthesis and storage of adrenomedullary chromogranins A and B, catecholamines, and their biosynthetic enzymes appear to be characteristic of both acquired and genetic hypertension.

Adrenal Medulla↗
PubMed1993

Glucocorticoid induction of epinephrine synthesizing enzyme in rat skeletal muscle and insulin resistance.

Rat skeletal muscle contains two enzymes which can make epinephrine: phenylethanolamine N-methyltransferase (PNMT) and nonspecific N-methyltransferase. We studied the time-course and mechanism by which the glucocorticoid dexamethasone increases muscle PNMT activity. We also examined the hypothesis that increased muscle E synthesis may contribute to glucocorticoid-induced insulin resistance. Dexamethasone (1 mg/kg s.c. for 12 d) increased muscle PNMT activity seven-fold but did not change NMT activity. Immunotitration with an anti-PNMT antibody indicated that the PNMT elevation was due to increased numbers of PNMT molecules. Dexamethasone rapidly increased PNMT activity and this elevation was largely maintained 6 d after glucocorticoid treatment stopped. Muscle epinephrine levels were transiently elevated by dexamethasone. Dexamethasone-treated rats had elevated insulin levels after a glucose load, and chronic administration of the PNMT inhibitor SKF 64139 reversed this increase. Chronic SKF 64139 improved glucose tolerance in normal rats. Dexamethasone induced muscle synthesis of the epinephrine-forming enzyme PNMT. A PNMT inhibitor lowered insulin levels in glucocorticoid-treated rats and glucose levels in untreated rats. These findings are compatible with antagonism of insulin-mediated glucose uptake by epinephrine synthesized in skeletal muscle.

Adrenal Medulla↗
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↗