Biomedical subjects

R J Parmer

Publications and source records attributed to R J Parmer.

At least 55 records · Page 3Linked to original sources

PubMed1996

Vesicular monoamine transport inhibitors. Novel action at calcium channels to prevent catecholamine secretion.

Vesicular monoamine transport (VMAT) inhibitors, such as reserpine and tetrabenazine, impair vesicular catecholamine storage in chromaffin cells and sympathetic neurons, thereby lowering blood pressure. Here we describe a novel action of VMAT inhibitors-blockade of L-type voltage-gated calcium channels-that may also influence catecholamine release from both PC12 rat pheochromocytoma cells and bovine adrenal chromaffin cells. When given alone, VMAT inhibitors acutely release catecholamines from chromaffin cells in a dose-dependent fashion. However, VMAT inhibitors block catecholamine secretion stimulated by either nicotinic cholinergic agonists or cell membrane depolarization, each of which rely on the opening of L-type channels; the inhibition was more potent after long-term exposure to VMAT inhibitors (IC50 < 100 nmol/L). Reserpine blocked nicotinic-stimulated catecholamine release from neurite-bearing PC12 cells. Reserpine also antagonized catecholamine release triggered by combined membrane depolarization and the dihydropyridine L-type channel agonist Bay K8644, and reserpine blocked cellular uptake of extracellular 45Ca2+ in response to nicotine. Taken together, these results indicate that VMAT inhibitors are also antagonists at L-type voltage-gated calcium channels. Classic L-type channel antagonists (verapamil or nifedipine) also exhibited the reciprocal actions; acutely, they released norepinephrine from chromaffin cells, and chronically, they depleted cellular catecholamine stores, albeit with inferior molar potency to reserpine (IC50 < 1 nmol/L). We conclude that VMAT inhibitors and L-type calcium channel antagonists exert reciprocal inhibitory actions on each other's more classic pharmacological targets. Furthermore, these novel actions are seen at concentrations of these compounds frequently taken to be specific in vitro and likely to occur during antihypertensive treatment in vivo.

Adrenal Glands↗

PubMed1996

Arterial compliance by cuff sphygmomanometer. Application to hypertension and early changes in subjects at genetic risk.

Abnormalities of the arterial pulse waveform reflect changes in cardiovascular structure and function. These abnormalities may occur early in the course of essential hypertension, even before the onset of blood pressure elevation. Previous studies of cardiovascular structure and function have relied on invasive intra-arterial cannulation to obtain the arterial pulse wave. We evaluated arterial structure and function using a noninvasive cuff sphygmomanometer in hypertensive (n = 15) and normotensive (n = 36) subjects stratified by genetic risk (family history) for hypertension. Using a simple physical model in which the aorta was assumed to be a T tube and the brachial artery a straight tube, we determined vascular compliance and peripheral resistance by analyzing the brachial artery pulsation signal from a cuff sphygmomanometer. Essential hypertensive subjects tended to have higher peripheral resistance (P = .06) and significantly lower vascular compliance (P = .001) than normotensive subjects. Vascular compliance correlated with simultaneously determined pulse pressure in both groups (n = 51, r = .74, P < .0001). Higher peripheral resistance (P = .07) and lower vascular compliance (P = .04) were already found in still-normotensive offspring of hypertensive parents (ie, normotensive subjects with a positive family history of hypertension) than in normotensive subjects with a negative family history of hypertension. Multivariate analysis demonstrated that both genetic risk for hypertension (P = .030) and blood pressure status (P = .041), although not age (P = .207), were significant predictors of vascular compliance (multiple R = .47, P = .011). However, by two-way ANOVA, genetic risk for hypertension was an even more significant determinant (F = 7.84, P = .007) of compliance than blood pressure status (F = 2.69, P = .089). Antihypertensive therapy with angiotensin-converting enzyme inhibitors (10 days, n = 10) improved vascular compliance (P = .02) and reduced resistance (P = .003) significantly; treatment with calcium channel antagonists (4 weeks, n = 8) tended to improve vascular compliance (P = .07) and significantly reduced peripheral resistance (P = .006). We conclude that arterial vascular compliance abnormalities detected by a noninvasive cuff sphygmomanometer reflect treatment-reversible changes in vascular structure and function. Early changes in vascular compliance in still-normotensive individuals at genetic risk for hypertension may be a heritable pathogenetic feature of this disorder.

Adult↗

PubMed1996

Activities of nitric oxide in normal physiology and uremia.

Nitric oxide (NO) generated from arginine exerts a variety of renal and extrarenal physiological and pathophysiological effects. NO is generated by two types of nitric oxide synthases: acutely responsive, constitutive NOS and slower, more persistent inducible NOS (iNOS). The latter is transcriptionally dependent, often stimulated by cytokines. NO regulates glomerular ultrafiltration, tubular reabsorption, and intrarenal renin secretion; many of these renal effects are mediated by interactions with angiotensin II and adrenergic (alpha 2) activity. Decreased NO activity also enhances tubuloglomerular feedback activity, which could contribute to renal vasoconstriction, NaCl retention, and elevated blood pressure. Loss of renal function could influence NO activity via: (1) endothelial dysfunction; (2) decreased arginine synthesis by kidney; (3) responses to arginine analogs that act as NOS inhibitors; (4) increased cytokine activity; and (5) altered oxidation:reduction status of cells, etc. For example, platelet dysfunction in uremia may be caused by cytokine-induced iNOS activation. Moreover, acutely responsive, constitutive NOS activity may be depressed in progressive loss of renal function. Decreased NO activity might contribute to baroreceptor dysfunction observed in hypertension and progressive renal disease. Studies of the impact of uremia suggest that iNOS may be chronically stimulated by cytokines, whereas acutely responsive, constitutive NOS activity may be concurrently depressed.

Animals↗

PubMed1995

Factitious pheochromocytoma: novel mimickry by Valsalva maneuver and clues to diagnosis.

Factitious pheochromocytoma usually occurs in patients surreptitiously ingesting adrenergic medications. We encountered a case of factitious pheochromocytoma where in the subject mimicked hemodynamic (profound hypertension) and biochemical (plasma catecholamine elevation) manifestations of the illness by consciously altering autonomic function with Valsalva maneuver. Clues to this presentation included visible performance of Valsalva maneuver, marked disparity between blood pressures recorded in the presence and absence of the subject's knowledge, normal urinary catecholamine and metabolite excretion, and normal plasma chromogranin A. We reproduced, in part, the hemodynamic and biochemical manifestations of this presentation with Valsalva maneuver in healthy subjects.

Adrenal Gland Neoplasms↗

PubMed1995

Plasma chromogranin A marks emesis and serotonin release associated with dacarbazine and nitrogen mustard but not with cyclophosphamide-based chemotherapies.

Chromogranin A (CgA) is present in high concentrations in enterochromaffin cells, where it is co-localised with serotonin in the storage granules. Plasma CgA has been reported to mark emesis and serotonin release associated with cisplatin treatment. However, it is not known whether plasma CgA could be an indicator of emesis and of serotonin release in patients receiving non-cisplatin chemotherapies. Therefore, in this study we evaluated, in cancer patients, the temporal relationships between the increases in plasma CgA and urinary 5-hydroxyindoleacetic acid (5-HIAA) and the development of vomiting following dacarbazine, nitrogen mustard and cyclophosphamide treatments. Metoclopramide was used as antiemetic. With dacarbazine, nitrogen mustard and cyclophosphamide the median time to the onset of emesis was 2.3, 2.8 and 5.3 h and the duration of intense emesis was 3, 2 and 6 h respectively. Plasma CgA and urinary 5-HIAA increased after dacarbazine- and nitrogen mustard-based chemotherapies, with maximal increases between 4 and 6 h after initiation of drug infusion. The time course for the increases in plasma CgA paralleled that of urinary 5-HIAA and the period of intense emesis. A highly significant (P = 0.0009) positive correlation (r = 0.68) was found between the increases in plasma CgA and in urinary 5-HIAA. Cyclophosphamide treatment was not associated with increases in plasma CgA and in urinary 5-HIAA, despite inducing emesis; this indicates that the increases in CgA and 5-HIAA after dacarbazine and nitrogen mustard are not due to the act of vomiting per se. In summary, plasma CgA is a marker of serotonin release (most likely from enterochromaffin cells) after dacarbazine and nitrogen mustard-based chemotherapies, exocytosis being the most likely mechanism for the release of serotonin. Serotonin released from enterochromaffin cells seems to trigger the emetic response to dacarbazine and nitrogen mustard; however, cyclophosphamide may release serotonin from a different pool (enteric serotonin neurons and/or CNS serotonin?).

Adult↗

PubMed1995

Divergent effects of dihydropyridine and phenylalkylamine calcium channel antagonist classes on autonomic function in human hypertension.

Calcium channel antagonists differ by class in reported frequency of side effects that suggest reflex sympathoadrenal activation. Do such differences result from differential effects on autonomic and baroreflex function? The present study compared acute and chronic effects of two classes of calcium channel antagonists, the dihydropyridine type (felodipine) and the phenylalkylamine type (verapamil), on efferent sympathetic outflow and baroreflex slope in 15 essential hypertensive subjects. Blood pressure, heart rate, hemodynamics, and biochemistries were determined at baseline and after acute (first dose) and chronic (4 weeks) administration of the drugs versus placebo. Acutely, felodipine caused a greater decrease in blood pressure associated with a larger decline in systemic vascular resistance than the corresponding effects produced by verapamil. Chronically, there were similar, significant declines in blood pressure (P = .001) and systemic vascular resistance (P = .001) after each drug. Acutely, increased sympathetic activity after felodipine was suggested by reflex tachycardia (from 69 +/- 3 to 74 +/- 2 beats per minute, P = .014) and elevation of plasma norepinephrine (from 264 +/- 25 to 323 +/- 25 pg/mL, P = .037), whereas after verapamil the corresponding changes were closely similar to those after placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗

PubMed1995

Chromogranin A in human hypertension. Influence of heredity.

Multiple heritable traits are associated with essential (genetic) hypertension in humans. Because chromogranin A is increased in both human and rodent genetic hypertension, we examined the influence of heredity and blood pressure on chromogranin A in humans. In estimates derived from among- and within-pair variance in monozygotic versus dizygotic twins, plasma chromogranin A displayed significant (F15,18 = 2.93, P = .016) genetic variance (sigma 2 g), and its broad-sense heritability was high (h2B = 0.983). Plasma chromogranin A was increased in essential hypertension (99.9 +/- 6.7 versus 62.8 +/- 4.7 ng/mL, P < .001) but was influenced little by genetic risk for (family history of) hypertension (in normotensive or hypertensive subjects), by race, or by several antihypertensive therapies (angiotensin-converting enzyme inhibitor, diuretic, or beta-adrenergic antagonist). In normotensive subjects at genetic risk for essential hypertension, neither basal nor sympathoadrenal stress-evoked chromogranin A differed from values found in subjects not at risk. In established essential hypertension, plasma chromogranin A responses to adrenal medullary (insulin-evoked hypoglycemia) or sympathetic neuronal (dynamic exercise) activation were exaggerated, whereas responses to sympathoadrenal suppression (ganglionic blockade) were diminished, suggesting increased vesicular stores of chromogranin A and an adrenergic origin of the augmented chromogranin A expression in this disorder. We conclude that plasma chromogranin A displays substantial heritability and is increased in established essential hypertension. Its elevation in established hypertension is associated with evidence of increased vesicular stores of the protein and with adrenergic hyperactivity but is influenced little by customary antihypertensive therapies. However, the chromogranin A elevation is not evident early in the course of genetic hypertension.

Adrenal Medulla↗

PubMed1995

A functional cyclic AMP response element plays a crucial role in neuroendocrine cell type-specific expression of the secretory granule protein chromogranin A.

Chromogranin A, a soluble acidic protein, is a ubiquitous component of secretory vesicles throughout the neuroendocrine system. We reported previously the cloning and initial characterization of the mouse chromogranin A gene promoter, which showed that the promoter contains both positive and negative domains and that a proximal promoter spanning nucleotides -147 to +42 bp relative to the transcriptional start site is sufficient for neuroendocrine cell type-specific expression. The current study was undertaken to identify the particular elements within this proximal promoter that control tissue-specific expression. We found that deletion or point mutations in the potential cAMP response element (CRE) site at -68 bp virtually abolished promoter activity specifically in neuroendocrine (PC12 chromaffin or AtT20 corticotrope) cells, with little effect on activity in control (NIH3T3 fibroblast) cells; thus, the CRE box is necessary for neuroendocrine cell type-specific activity of the chromogranin A promoter. Furthermore, the effect of the CRE site is enhanced in the context of intact (wild-type) promoter sequences between -147 and -100 bp. DNase I footprint analysis showed that these regions (including the CRE box) bind nuclear proteins present in both neuroendocrine (AtT20) and control (NIH3T3) cells. In AtT20 cells, electrophoretic mobility shift assays and factor-specific antibody supershifts showed that an oligonucleotide containing the chromogranin A CRE site formed a single, homogeneous protein-DNA complex containing the CRE-binding protein CREB. However, in control NIH3T3 cells we found evidence for an additional immunologically unrelated protein in this complex. A single copy of this oligonucleotide was able to confer neuroendocrine-specific expression to a heterologous (thymidine kinase) promoter, albeit with less fold selectivity than the full proximal chromogranin A promoter. Hence, the CRE site was partially sufficient to explain the neuroendocrine cell type specificity of the promoter. The functional activity of the CRE site was confirmed through studies of the endogenous chromogranin A gene. Northern mRNA analysis showed that expression of the endogenous chromogranin A gene was stimulated seven- to eightfold by cAMP in PC12 cells, whereas no induction occurred in the NIH3T3 cells. Similar cAMP induction was obtained with the transfected chromogranin A promoter in PC12 cells, and abolition of the CRE site (by deletion or point mutation) eliminated the induction. Thus, the CRE site in the chromogranin A proximal promoter is functional and plays a crucial, indeed indispensable, role in neuroendocrine-specific expression of the gene. These results also provide insight into transcriptional mechanisms governing acquisition of the neuroendocrine secretory phenotype.

3T3 Cells↗

PubMed1995

Plasma chromogranin A: a marker of serotonin release and of emesis associated with cisplatin chemotherapy.

PURPOSE: Emesis is a common side effect of cancer chemotherapy. Serotonin released from gastrointestinal enterochromaffin cells (ECC) may mediate chemotherapy-induced emesis. Since chromogranin A (CgA) is colocalized in ECC storage granules with serotonin, we tested the hypothesis that plasma CgA could mark emesis and serotonin release from ECC. PATIENTS AND METHODS: The relationships between plasma CgA, serotonin release, and the development of vomiting following the first course of cisplatin chemotherapy were evaluated in 60 patients. RESULTS: CgA levels increased in 59 of 60 patients (245% +/- 18% increase above baseline levels, P < .001). The time course of the increase in plasma CgA matched that of emesis and of urinary 5-hydroxyindoleacetic acid (5-HIAA). Significant (P < .001) positive correlations were found between the dose of cisplatin and the increases in plasma CgA, and between the changes in plasma CgA and urinary 5-HIAA after cisplatin (r = .54, n = 39, P < .001). The increase in plasma CgA after cisplatin did not correlate with changes in serum lactic dehydrogenase (LDH) activity, a marker of cell toxicity or lysis. CONCLUSION: Plasma CgA marks emesis and serotonin release induced by cisplatin. Since both CgA and serotonin are costored in ECC granules, we suggest that the source of release of each may be the ECC. Increases in plasma CgA are not explained by drug cytotoxicity. Exocytosis appears as the main mechanism by which cisplatin releases serotonin. This work further supports the role of serotonin as a mediator of emesis associated with cisplatin and suggests that plasma CgA level is a valuable tool in studies of chemotherapy-induced emesis.

Adolescent↗

PubMed1994

Dopamine beta-hydroxylase immunoreactivity in human cerebrospinal fluid: properties, relationship to central noradrenergic neuronal activity and variation in Parkinson's disease and congenital dopamine beta-hydroxylase deficiency.

1. Dopamine beta-hydroxylase is stored and released with catecholamines by exocytosis from secretory vesicles in noradrenergic neurons and chromaffin cells. Although dopamine beta-hydroxylase enzymic activity is measurable in cerebrospinal fluid, such activity is unstable, and its relationship to central noradrenergic neuronal activity in humans is not clearly established. To explore the significance of cerebrospinal fluid dopamine beta-hydroxylase, we applied a homologous human dopamine beta-hydroxylase radioimmunoassay to cerebrospinal fluid, in order to characterize the properties and stability of cerebrospinal fluid dopamine beta-hydroxylase, as well as its relationship to central noradrenergic neuronal activity and its variation in disease states such as hypertension, renal failure, Parkinsonism and congenital dopamine beta-hydroxylase deficiency. 2. Authentic, physically stable dopamine beta-hydroxylase immunoreactivity was present in normal human cerebrospinal fluid at a concentration of 31.3 +/- 1.4 ng/ml (range: 18.5-52.5 ng/ml), but at a 283 +/- 27-fold lower concentration than that found in plasma. Cerebrospinal fluid and plasma dopamine beta-hydroxylase concentrations were correlated (r = 0.67, P = 0.001). Some degree of local central nervous system control of cerebrospinal fluid dopamine beta-hydroxylase was suggested by incomplete correlation with plasma dopamine beta-hydroxylase (with an especially marked dissociation in renal disease) as well as the lack of a ventricular/lumbar cerebrospinal dopamine beta-hydroxylase concentration gradient. 3. Cerebrospinal fluid dopamine beta-hydroxylase was not changed by the central alpha 2-agonist clonidine at a dose that diminished cerebrospinal fluid noradrenaline, nor did cerebrospinal fluid dopamine beta-hydroxylase correspond between subjects to cerebrospinal fluid concentrations of noradrenaline or methoxyhydroxyphenylglycol; thus, cerebrospinal fluid dopamine beta-hydroxylase concentration was not closely linked either pharmacologically or biochemically to central noradrenergic neuronal activity. 4. Cerebrospinal fluid dopamine beta-hydroxylase was not changed in essential hypertension. In Parkinson's disease, cerebrospinal fluid dopamine beta-hydroxylase was markedly diminished (16.3 +/- 2.9 versus 31.3 +/- 1.4 ng/ml, P < 0.001) and rose by 58 +/- 21% (P = 0.02) after adrenal-to-caudate chromaffin cell autografts. In congenital dopamine beta-hydroxylase deficiency, lack of detectable dopamine beta-hydroxylase immunoreactivity in cerebrospinal fluid or plasma suggests absent enzyme (rather than a catalytically defective enzyme) as the origin of the disorder. 5. We conclude that cerebrospinal fluid dopamine beta-hydroxylase immunoreactivity, while not closely linked to central noradrenergic neuronal activity, is at least in part derived from the central nervous system, and that its measurement may be useful in both the diagnosis and treatment of neurological disease.

Adult↗

PubMed1994

Sympatho-adrenal secretion in humans: factors governing catecholamine and storage vesicle peptide co-release.

1. In postganglionic sympathetic neurones and adrenal chromaffin cells, catecholamines are co-stored in vesicles with soluble peptides, including chromogranin A (CgA) and neuropeptide Y (NPY), which are subject to exocytotic co-release with catecholamines. 2. Plasma catecholamine, CgA and NPY responses to stimulators and inhibitors of sympatho-adrenal catecholamine storage and release were measured in humans. Short-term, high-intensity dynamic exercise, prolonged low-intensity dynamic exercise, and assumption of the upright posture, in decreasing order of potency, predominantly stimulated noradrenaline (NA) release from sympathetic nerve endings. Only high-intensity exercise elevated CgA and NPY, which did not peak until 2 min after exercise cessation. Stimulated NA correlated with plasma CgA 2 min after exercise, and with NPY 5 min after exercise. 3. Insulin-evoked hypoglycaemia and caffeine ingestion, in decreasing order of potency, predominantly stimulated adrenaline (AD) release from the adrenal medulla. During insulin hypoglycaemia AD and CgA rose, but NPY was unchanged. Neither NPY nor CgA were altered by caffeine. The rise in CgA after intense adrenal medullary stimulation was greater than its rise after intense sympathetic neuronal stimulation (1.4-versus 1.2-fold, respectively). 4. Infusion of tyramine, which disrupts sympathetic neuronal vesicular NA storage, elevated systolic blood pressure and NA, while NPY and CgA were unchanged. After reserpine, another disruptor of neuronal NA storage, NA transiently rose and then fell; NPY and CgA were unaltered. After the non-exocytotic adrenal medullary secretory stimulus glucagon. AD rose while NA, CgA and NPY did not change. After amantadine, an inhibitor of protein endocytosis, both CgA and fibrinogen rose, while NA and NPY remained unaltered. Neither CgA, NPY, nor catecholamines were altered by the catecholamine uptake and catabolism inhibitors desipramine, cortisol, and pargyline. 5. Human sympathetic nerve contained a far higher ratio of NPY to catecholamines than human adrenal medulla, while adrenal medulla contained far more CgA than sympathetic nerve. 6. It is concluded that peptides are differentially co-stored with catecholamines, with greater abundance of CgA in the adrenal medulla and NPY in sympathetic nerve. Activation of catecholamine release from either the adrenal medulla or sympathetic nerves, therefore, results in quite different changes in plasma concentrations of the catecholamine storage vesicle peptides CgA and NPY. Only profound, intense stimulation of chromaffin cells or sympathetic axons measurably perturbs plasma CgA or NPY concentration; lesser degrees of stimulation perturb plasma catecholamines only. Neither CgA nor NPY are released during non-exocytotic catecholamine secretion.

Adrenal Medulla↗

PubMed1994

Renal hemodynamics in essential hypertension. Racial differences in response to changes in dietary sodium.

Previous studies have suggested striking racial differences in hypertension-related renal disease. To explore potential mechanisms responsible for these differences, we investigated changes in renal hemodynamics in white and black essential hypertensive patients in response to alterations in dietary sodium. Patients were untreated, age-matched, and blood pressure-matched white (n = 59) and black (n = 22) males with essential hypertension. Studies were conducted on an inpatient metabolic ward and included assessment of blood pressure, urinary sodium excretion, glomerular filtration rate, renal plasma flow, and renal blood flow after 5 days each of high and low salt diets. In response to high dietary salt intake, both white and black patients demonstrated significantly higher mean arterial pressure, renal plasma flow, and renal blood flow, and there were no racial differences in the changes in these parameters. However, whites and blacks differed significantly in glomerular filtration rate, with black hypertensive patients showing an increase in glomerular filtration rate (+17.3 +/- 5.3 mL/min per 1.73 m2, F = 7.586, P = .007) and white hypertensive patients showing no change (-0.2 +/- 3.3 mL/min per 1.73 m2) in response to high dietary sodium. These data demonstrate racial differences in the autoregulation of glomerular filtration rate in response to changes in dietary sodium. These differences suggest that glomerular hyperfiltration in response to a high salt diet may be a mechanism contributing to the racial disparity in hypertension-related renal disease.

Adult↗

PubMed1994

Glucocorticoid activation of chromogranin A gene expression. Identification and characterization of a novel glucocorticoid response element.

Glucocorticoids regulate catecholamine biosynthesis and storage at several sites. Chromogranin A, an abundant protein complexed with catecholamines in secretory vesicles of chromaffin cells and sympathetic axons, is also augmented by glucocorticoids. This study reports isolation of the rat chromogranin A promoter to elucidate transcriptional regulation of chromogranin A biosynthesis by glucocorticoids in neuroendocrine cells. Endogenous chromogranin A gene expression was activated up to 3.5-fold in chromaffin cells by glucocorticoid, in time-dependent fashion. Inhibition of new protein synthesis by cycloheximide did not alter the rise in chromogranin A mRNA, suggesting that glucocorticoids directly activate the chromogranin A promoter; nuclear runoff assays confirmed a 3.3-fold increased rate of initiation of new chromogranin A transcripts after glucocorticoid. Transfected rat chromogranin A promoter/luciferase reporter constructs were activated 2.6-3.1-fold by glucocorticoid, and selective agonist/antagonist studies determined that dexamethasone effects were mediated by glucocorticoid receptors. Both rat and mouse chromogranin A promoter/luciferase reporter constructs were activated by glucocorticoid. A series of promoter deletions narrowed the region of glucocorticoid action to a 93-bp section of the promoter, from position -526 to -619 bp upstream of the cap site. A 15-bp sequence ([-583 bp] 5'-ACATGAGTGTGTCCT-3' [-597 bp]) within this region showed partial homology to a glucocorticoid response element (GRE; half-site in italics) consensus sequence, and several lines of experimental evidence confirmed its function as a GRE: (a) site-directed mutation of this GRE prevented glucocorticoid activation of a chromogranin A promoter/reporter; (b) transfer of this GRE to a heterologous (thymidine kinase) promoter/reporter conferred activation by glucocorticoid, in copy number-dependent and orientation-independent fashion; and (c) electrophoretic gel mobility shifts demonstrated binding of this GRE by ligand-activated glucocorticoid receptor, though at 2.75-fold lower affinity than the glucocorticoid receptor interaction with a consensus GRE. The rat chromogranin A GRE showed functional and structural similarities to GREs in other genes proportionally regulated by glucocorticoids. We conclude that a discrete domain of the chromogranin A promoter is both necessary and sufficient to confer glucocorticoid regulation onto the gene, and that the activity of this region also explains the degree of activation of the endogenous gene by glucocorticoid.

Animals↗

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

Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease.

BACKGROUND: Pheochromocytoma is a feature of two disorders with an autosomal dominant pattern of inheritance--multiple endocrine neoplasia type 2 (MEN-2) (with medullary thyroid carcinoma and hyperparathyroidism) and von Hippel-Lindau disease (with angioma of the retina, hemangioblastoma of the central nervous system, renal-cell carcinoma, pancreatic cysts, and epididymal cystadenoma). The frequency of these syndromes in patients with pheochromocytoma is not known. METHODS: In an unselected group of patients with pheochromocytoma, we performed pentagastrin tests, parathyroid hormone assays, computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, ophthalmoscopy, CT imaging of the abdomen, and ultrasonography of the testes. We also screened members of families with MEN-2 or von Hippel-Lindau disease for pheochromocytoma by measuring plasma and urine catecholamines and plasma chromogranin A and by performing abdominal ultrasonography, CT and MRI, and metaiodobenzylguanidine scintigraphy. RESULTS: Nineteen of 82 unselected patients with pheochromocytomas (23 percent) were carriers of familial disorders; 19 percent had von Hippel-Lindau disease and 4 percent had MEN-2. Prospectively, in 36 of 79 subjects at risk for pheochromocytoma (46 percent), 42 unsuspected pheochromocytomas were found. Overall, there were 130 patients with 185 pheochromocytomas; 43 had von Hippel-Lindau disease, 24 had MEN-2, and 63 had sporadic tumors. The patients with familial and those with sporadic pheochromocytomas differed in mean age at diagnosis (32 vs. 46 years, P < 0.001), multifocal localization (55 vs. 8 percent, P < 0.001), and cancer (0 vs. 11 percent, P = 0.005); but not in the frequency of extraadrenal tumors (24 vs. 16 percent). Thirty-eight percent of carriers of von Hippel-Lindau disease and 24 percent of carriers of MEN-2 had pheochromocytoma as the only manifestation of their syndrome. CONCLUSIONS: All patients with pheochromocytomas should be screened for MEN-2 and von Hippel-Lindau disease to avert further morbidity and mortality in the patients and their families. All patients in families with MEN-2 or von Hippel-Lindau disease should be screened for pheochromocytoma, even if they are asymptomatic.

Adolescent↗

PubMed1993

Assignment of the chromogranin A (Chga) locus to homologous regions on mouse chromosome 12 and rat chromosome 6.

Chromogranin A is an acidic protein, stored and released with catecholamines, and is overexpressed in genetic hypertension. In the human genome, its locus has previously been positioned on the long arm of Chromosome 14 in the 14q32 region. As a first step toward evaluating its potential linkage with hereditary hypertension, we determined its chromosomal position in mouse and rat. Chromogranin A was present as a single-copy gene in both mouse and rat. Analysis of the allele distribution in an interspecific mouse backcross by single-strand conformation polymorphism positioned the chromogranin A locus on Chromosome 12, between Igh-C and D12Pas1. Evaluation of a rat/mouse somatic cell hybrid panel indicated that chromogranin A is on rat Chromosome 6. In each case (mouse, rat, and human), chromogranin A is in a conserved region with nearby markers including the immunoglobulin heavy chain locus.

Animals↗

PubMed1993

Processing of chromaffin granule proteins: a profusion of proteases?

Evidence suggests that proenkephalin and members of the chromogranin/secretogranin family of proteins are prohormone precursors, giving rise to a variety of peptides with biologic activity. However, the specific proteases responsible for cleaving these proteins in vivo have not been fully established. Several candidate proteases have been described, some of which have been shown to cleave these proteins in vitro. Proteolytic processing of the chromogranins may be particularly complex, occurring in specific tissue-dependent patterns. To account for this level of complexity several protease systems may be operative, either alone or in concert, both within the neurosecretory granule and in the extracellular space. Specific proteases which are available within neurosecretory cells or in the local extracellular environment, and which may cleave these prohormones include PC1 and PC2 (recently described members of the Kex2/furin family of endoproteases), as well as kallikrein, acetylcholinesterase, and, more recently, the plasminogen/plasmin protease system. The potential role of these specific proteases in the processing of proenkephalin and the chromogranins is discussed, in particular, in the context of possible processing clues available from recent analysis of cDNA and genomic intron/exon structure.

Animals↗