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1.
Allergy ; 57(1): 9-16, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11991303

ABSTRACT

BACKGROUND: The purpose of the present study was to evaluate mould-specific immunoglobulin G (IgG) antibodies in children exposed to moisture and mould problems in their school, and the association between IgG antibodies and mould allergy, active or passive smoking and respiratory symptoms. METHODS: IgG antibodies were studied to 24 moulds in 93 children from three moisture problem schools and in 33 children from a reference school. The antibodies were measured by enzyme-linked immunosorbent assay and compared to positive adult sera. RESULTS: There were no significant differences in mould-specific IgG concentrations between exposed and non-exposed school-children. Antibodies to moulds common in moisture damaged buildings were associated with allergic diseases, as well as with mould-specific immunoglobulin E (IgE) or skin prick test (SPT) findings. Aspergillus fumigatus and A. versicolor were the moulds with the most consistent findings. Active and passive smoking were associated with low levels of antibodies to many moulds. Though the association between asthma, wheezing or cough symptoms, and IgG to moulds was not significant, 7 (39%) of the 18 children with multiple (> 7) elevated IgG findings suffered from asthma or wheezing. CONCLUSIONS: Allergy was, but asthma was not, associated with IgG antibodies to the moulds that can be found in moisture damaged buildings. However, no association was found between IgG antibodies to moulds and exposure to moisture and moulds in school.


Subject(s)
Antibodies, Fungal/blood , Fungi/immunology , Humidity/adverse effects , Schools , Adolescent , Air Pollution, Indoor , Asthma/epidemiology , Asthma/immunology , Asthma/microbiology , Child , Environmental Exposure , Female , Humans , Male , Mycoses/epidemiology , Mycoses/immunology , Mycoses/microbiology , Respiratory Hypersensitivity/epidemiology , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/microbiology , Skin Tests
2.
Pediatr Allergy Immunol ; 12(2): 87-94, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11338292

ABSTRACT

Dampness and moisture problems in a building may cause growth of moulds, leading to sensitization and symptoms in the inhabitants. The mechanism by which sensitization to moulds takes place has remained obscure; in particular, the role of atopy is not clear. In 1996, 622 pupils (7-13 years of age) attending a school with a moisture problem (index school; 414 pupils) and a control school (208 pupils) were screened using a questionnaire. Two-hundred and twelve children had doctor-diagnosed asthma, parental-reported wheezing or prolonged cough, and they participated in a clinical study, which included skin prick tests (SPT) to 12 moulds. An identical, follow-up study was performed 3 years later in 1999. In the follow-up study, 144 of the original 212 students participated. They were now attending four different schools: the index primary school had been renovated and the control school remained unchanged, but the two secondary schools had moisture and mould problems. The purpose of the study was to evaluate the occurrence of mould allergy in children of school age and to compare sensitization to moulds in relation to age, exposure, asthma, and atopy. In 1999, SPT responses to moulds were demonstrated in 17 (12%) of the 144 children. Six children had SPT reactions > or = 3 mm and all but one were older than 14 years. During the 3-year follow-up period, mould allergy developed in five children and disappeared in two children. Five of the six children with reactions > or = 3 mm to moulds had positive responses to other allergens, five had clinical atopy but only two had asthma. Likewise, all six children had been exposed to moisture and dampness in the school buildings. In conclusion, mould allergy diagnosed by SPTs was rare in students. Most reactions to moulds were in students older than 14 years with multiple SPT reactions to common allergens, and there was no significant association with asthma.


Subject(s)
Allergens/immunology , Fungi/immunology , Hypersensitivity/etiology , Schools , Skin Tests , Students , Adolescent , Allergens/adverse effects , Asthma/epidemiology , Child , Cough/epidemiology , Environmental Microbiology , Finland/epidemiology , Follow-Up Studies , Fungi/isolation & purification , Humans , Hypersensitivity/epidemiology , Respiratory Sounds , Surveys and Questionnaires , Water
3.
Acta Paediatr ; 88(12): 1373-9, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10626525

ABSTRACT

AIM OF THE STUDY: Initially, we performed a questionnaire study on 622 school children aged 7 to 13 y. The study was supplemented with a clinical study including skin prick tests to 13 molds in 212 (34%) children with doctor-diagnosed asthma or parental-reported wheezing or prolonged cough. These children were attending one of two elementary schools, one with moisture problems (index) school, the other being the control school. The objective of the study was to evaluate whether exposure to moisture and sensitization to molds are associated with respiratory manifestations in school children. RESULTS: The prevalence of asthma was 4.8%, which was similar in the children from both schools. The children from the index school more often had wheezing (16% vs 6%; p <0.001) and cough (21% vs 9%: p < 0.001) symptoms than control children. Positive skin reactions to molds were rare (2.4%), being present in 7% of asthmatic and in 1-2% of non-asthmatic children (NS). Lower respiratory tract infections were more common in the spring than in the fall in children from the index school, but not in control children, and the difference between the schools was significant in emergency visits (OR =2.0, p <0.01) and antibiotic courses (OR = 2.1, p < 0.01). CONCLUSIONS: We found evidence of an association between moisture or mold problems in the school building and the occurrence of respiratory infections, repeated wheezing and prolonged cough in school children.


Subject(s)
Asthma/epidemiology , Respiratory Tract Infections/epidemiology , Schools , Adolescent , Child , Female , Finland/epidemiology , Fungi , Humans , Male , Seasons , Skin Tests , Water
4.
Acta Paediatr ; 86(11): 1181-7, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9401510

ABSTRACT

OBJECTIVE: We performed a clinical study in 99 children attending schools with moisture problems and compared the findings with those of 34 children from a reference school. The aim of the study was to evaluate the possible association between respiratory or allergic diseases in the pupils and moisture or mould problems in the school buildings. RESULTS: Asthma was diagnosed in nine (6.7%) children: eight of them came from the moisture-problem schools and all were over 10 y old. In addition, 17 non-asthmatic children had suffered from wheezing and 21 from long-term cough, both symptoms being suggestive of occult asthma. If moisture problems were observed both at home and in the school, the frequency of asthma was 21% and the combined frequency of asthma and wheezing was 43%. The presence of allergic rhinoconjuntivitis or atopic dermatitis had no association with moisture or mould problems. We performed skin-prick tests to 13 moulds in all the 133 children. A positive reaction (> 3 mm) was observed in only six (5%) of them. All six positive children reacted to at least one moisture-indicative mould, Fusarium roseum, Aspergillus fumigatus, Phoma herbarum or Rhodotorula rubra. None of these cases came from the reference school. There was a significant association between positive reactions to moisture-indicative moulds and asthma; four (44%) of the nine children with asthma had such reactions. In addition, all the 6 reactive children had either asthma or wheezing. CONCLUSIONS: We report preliminary evidence for an association between moisture or mould problems in the school building and the presence of manifest and occult asthma in the pupils. Our results show that skin-test positivity to moulds is rare in children. However, reactivity to moisture-indicative moulds seems to be associated with the occurrence of asthma or wheezing.


Subject(s)
Fungi , Humidity/adverse effects , Respiratory Hypersensitivity/epidemiology , Schools , Adolescent , Asthma/epidemiology , Asthma/etiology , Child , Environmental Exposure , Female , Finland/epidemiology , Humans , Male , Mycoses/epidemiology , Respiratory Hypersensitivity/etiology , Skin Tests
5.
Acta Physiol Scand ; 159(3): 257-60, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9079157

ABSTRACT

Brain natriuretic peptide (BNP) messenger RNA was measured with a semiquantitative method from heart auricles and ventricles of vasopressin-deficient Brattleboro rats (DI) and from desmopressin treated Brattleboro rats (DI + DDAVP). Desmopressin had been injected peripherally and Long-Evans rats (LE) served as controls. The 3-day substitution treatment had shifted the fluid balance of DI almost to that of LE. In the present study, the amount of BNP mRNA, normalized to the glyceraldehyde-3-phosphate dehydrogenase mRNA content, was constant in all three groups in the right auricle. No changes were when the right auricular and left auricular mRNA levels were compared within each group. In the left auricle, desmopressin treatment increased significantly (P < 0.05) the amount of BNP mRNA compared with that of LE rats (from 1.09 +/- 0.21, n = 7 to 1.72 +/- 0.17, n = 8, arbitrary units). In all groups, the left ventricle had significantly (P < 0.05) higher mRNA content than the right ventricle (LE: 2.24 +/- 0.23 vs. 0.67 +/- 0.13, n = 6; DI: 2.30 +/- 0.60 vs. 0.33 +/- 0.05, n = 8; DI + DDAVP: 2.36 +/- 0.29 vs. 0.37 +/- 0.07, n = 10). In the right ventricle, both DI and DI + DDAVP rats had significantly (P < 0.05) lower mRNA content than LE rats (0.33 +/- 0.5 vs. 0.67 +/- 0.13 and 0.37 +/- 0.07 vs. 0.67 +/- 0.13, respectively). To conclude, these findings suggest that brain natriuretic peptide gene expression dissociates from, or rapidly adapts to, the chronic effects of peripheral desmopressin treatment which have shifted the fluid balance to almost normal in Brattleboro rats. The left ventricular pressure appears to regulate the brain natriuretic peptide gene expression.


Subject(s)
Myocardium/chemistry , Nerve Tissue Proteins/genetics , Rats, Brattleboro/physiology , Vasopressins/genetics , Animals , Deamino Arginine Vasopressin/pharmacology , Gene Expression/drug effects , Gene Expression/physiology , Immunoblotting , Male , Myocardium/metabolism , Natriuretic Peptide, Brain , RNA, Messenger/analysis , Rats , Renal Agents/pharmacology , Vasopressins/deficiency , Water-Electrolyte Balance/physiology
6.
Acta Physiol Scand ; 154(1): 35-42, 1995 May.
Article in English | MEDLINE | ID: mdl-7572200

ABSTRACT

To understand the secretion and synthesis of atrial natriuretic peptide we measured immunoreactive atrial natriuretic peptide from plasma, heart tissues and brain areas, and ANP mRNA was determined from heart auricles and ventricles of vasopressin-deficient Brattleboro rats (DI) and from desmopressin treated Brattleboro rats (DI+DDAVP). Long-Evans rats (LE) served as controls. DI+DDAVP rats were given for 3 days sc. injections of 0.5 micrograms 1-desamino-8-D-arginine vasopressin in 1 mL saline twice a day. The rats were housed in single metabolic cages and urinary output and water intake were measured daily. All the body and organ weight parameters were similar in the three groups when the rats were killed. No change was seen in the plasma ANP level between the groups. The right ventricle of DI+DDAVP rats had significantly (P < 0.05) higher concentration of ANP than LE rats (15.8 +/- 4.4 vs. 3.4 +/- 0.6 ng mg-1 tissue). The left ventricle of DI and DI+DDAVP had significantly (P < 0.05) lower amounts of ANP mRNA than LE rats (0.5 +/- 0.2 vs. 1.3 +/- 0.2 and 0.5 +/- 0.1 vs. 1.3 +/- 0.2 arbitrary units). In the hypothalamus, the ANP concentration was significantly (P < 0.05) lower both in DI and in DI+DDAVP rats than in LE rats (9.3 +/- 1.3 vs. 14.5 +/- 1.6 and 6.1 +/- 0.6 vs. 14.5 +/- 1.6 pg mg-1 tissue). To conclude, although the water intake and urinary output of DI rats were changed towards normal with desmopressin treatment, the heart ventricular and hypothalamic ANP did not parallel the change.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Atrial Natriuretic Factor/metabolism , Brain/metabolism , Myocardium/metabolism , RNA, Messenger/metabolism , Rats, Brattleboro/metabolism , Animals , Atrial Natriuretic Factor/genetics , Body Weight , Deamino Arginine Vasopressin/pharmacology , Diabetes Insipidus/physiopathology , Drinking , Heart Atria/metabolism , Heart Ventricles/metabolism , Hypoglycemic Agents/pharmacology , Male , Organ Size , Rats , Urination , Vasopressins/deficiency , Water-Electrolyte Balance/physiology
8.
Can J Physiol Pharmacol ; 69(10): 1514-24, 1991 Oct.
Article in English | MEDLINE | ID: mdl-1838021

ABSTRACT

Atrial natriuretic factor (ANF), a peptide hormone that regulates salt and water balance and blood pressure, is synthesized, stored, and secreted from mammalian myocytes. Stretching of atrial myocytes stimulates ANF secretion, but the cellular processes involved in linking mechanical distension to ANF release are unknown. We reported that phorbol esters, which mimic the action of diacylglycerol by acting directly on protein kinase C and the Ca2+ ionophore A23187, which introduces free Ca2+ into the cell, both increase basal ANF secretion in the isolated perfused rat heart. Phorbol ester also increased responsiveness to Ca2+ channel agonists, such as Bay k8644, and to agents that increase cAMP, such as forskolin and membrane-permeable cAMP analogs. In neonatal cultured rat atrial myocytes, protein kinase C activation by 12-O-tetradecanoylphorbol 13-acetate stimulated ANF secretion, whereas the release was unresponsive to changes in intracellular Ca2+. Endothelin, which stimulates phospholipase C mediated hydrolysis of phosphoinositides and activates protein kinase C, increased both basal and atrial stretch-induced ANF secretion from isolated perfused rat hearts. Similarly, phorbol ester enhanced atrial stretch-stimulated ANF secretion, while the increase in intracellular Ca2+ appeared to be negatively coupled to the stretch-induced ANF release. Finally, phorbol ester stimulated ANF release from the severely hypertrophied ventricles of hypertensive animals but not from normal rat myocardium. These results suggest that the protein kinase C activity may play an important role in the regulation of basal ANF secretion both from atria and ventricular cells, and that stretch of atrial myocytes appears to be positively modulated by phorbol esters.


Subject(s)
Atrial Natriuretic Factor/metabolism , Heart/physiology , Myocardium/metabolism , Animals , Humans , Myocardium/enzymology
10.
Br J Pharmacol ; 102(2): 453-61, 1991 Feb.
Article in English | MEDLINE | ID: mdl-1826618

ABSTRACT

1. To determine the cellular mechanisms of atrial natriuretic peptide (ANP) release from ventricular cardiomyocytes, the secretory and the cardiac effects of a phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), known to stimulate protein kinase C activity in heart cells, were studied in isolated, perfused heart preparations from 2- and 21-month-old Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. TPA was added to the perfusion fluid for 30 min at a concentration of 46 nM after removal of atrial tissue. Additionally, atrial and ventricular levels of immunoreactive ANP (IR-ANP) and ANP mRNA, the distribution of ANP within ventricles as well as the relative contribution of atria and ventricles in the release of ANP were studied. 2. Ventricular hypertrophy that gradually developed in hypertensive rats resulted in remarkable augmentation of ANP gene expression, as reflected by elevated levels of immunoreactive ANP and ANP mRNA. The total amount of IR-ANP in the ventricles of the SHR rats increased 41 fold and ANP mRNA levels 12.9 fold from the age of 2 to 21 months. At the age of 21 months, levels of IR-ANP and ANP mRNA in the ventricles of SHR rats were 5.4 fold and 3.7 fold higher, respectively, than in the normotensive WKY rats. Immunohistochemical studies demonstrated ANP granules within the hypertrophic ventricles of the old SHR rats, but not within normal ventricular tissue. 3. In isolated perfused heart preparations, the severely hypertrophied ventricular tissue of SHR rats after atrialectomy secreted more ANP into the perfusate than did the control hearts. Interestingly, the ANP release from the hypertrophied ventricles of the old SHR rats increased considerably (from 413 + 30 to the maximum of 623 + 75 pgml-1, F = 10.8, P < 0.001, two-way analysis of variance), whereas only a small increase was seen in old WKY rats and no effect was observed in young animals of either strain. When intact rat hearts (without atrialectomy) were used, infusion of phorbol ester also increased the ANP secretion into the perfusate in young animals. 4. Our present results indicate that the phorbol ester TPA increases the release of ANP from the hypertrophied, but not from normal rat myocardium. Thus, hypertrophied rat ventricular myocytes appear to possess the cellular mechanisms necessary to secrete ANP by a regulated pathway. The results further suggest that protein kinase C activity may be involved in the the regulation of ANP secretion from ventricular cells, as has been shown earlier for atrial myocytes.


Subject(s)
Atrial Natriuretic Factor/metabolism , Cardiomegaly/physiopathology , Heart/drug effects , Tetradecanoylphorbol Acetate/pharmacology , Animals , Atrial Natriuretic Factor/genetics , Cardiomegaly/genetics , Gene Expression , Heart/physiology , Hemodynamics/drug effects , In Vitro Techniques , Male , Perfusion , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY
11.
Acta Physiol Scand ; 139(2): 355-60, 1990 Jun.
Article in English | MEDLINE | ID: mdl-2142374

ABSTRACT

The present study documents the effects of hypophysectomy and the effects of dexamethasone substitution on the NaCl-stimulated release and on the basal secretion rates of ANP from the rat atria in vitro. We also measured the concentration of mRNA in the atria after hypophysectomy. Rats (n = 12) were subjected to hypophysectomy by a parapharyngeal approach. One group of rats (n = 6) received dexamethasone 0.2 mg s.c. daily for 4 weeks, while the other group was left unsubstituted. After 4 weeks, the atrial block (n = 10) was excised, placed in an organ bath (field stimulation 4 s-1, 20 V, 1 ms; resting tension = 5 mN) and superfused (7 ml min-1) either with a physiological buffer solution (295 mosmol kg-1) or with a hyperosmotic NaCl solution (330 mosmol kg-1). The atria from the hypophysectomized rats did not respond to the stimulus: the concentration of ANP in the 1-min samples of the perfusate was under 100 pg ml-1. Dexamethasone treatment significantly (P less than 0.05) increased the ANP concentration to a maximum of 165 +/- 17 (mean +/- SEM) pg ml-1 during the superfusion while the control concentration was 110 +/- 19 pg ml-1. The ANP mRNA/18 S RNA ratios did not differ between the atria of hypophysectomized and control rats. In conclusion, glucocorticoids are required in the stimulus-induced release of ANP and the impaired release of ANP after hypophysectomy does not depend on an impaired synthesis of ANP.


Subject(s)
Adrenal Cortex/physiology , Atrial Natriuretic Factor/metabolism , Sodium Chloride/pharmacology , Animals , Atrial Natriuretic Factor/genetics , Densitometry , Dexamethasone/pharmacology , Heart Atria , Hypophysectomy , Male , Myocardium/metabolism , Osmolar Concentration , RNA, Messenger/metabolism , Rats , Rats, Inbred Strains
12.
Br J Pharmacol ; 99(4): 701-8, 1990 Apr.
Article in English | MEDLINE | ID: mdl-2141796

ABSTRACT

1. Ventricular hypertrophy is characterized by stimulation of ventricular synthesis of atrial natriuretic peptide (ANP). To examine the role of ventricular ANP levels in the secretion of ANP into the circulation, atrial and ventricular levels of immunoreactive-ANP (IR-ANP) as well as ANP messenger RNA (mRNA), and the release of IR-ANP from isolated perfused hearts, both before and after atrialectomy, were measured simultaneously in control and minoxidil-treated Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. 2. IR-ANP levels in the ventricles of untreated, 12 month-old SHR with severe ventricular hypertrophy were increased when compared to age-matched WKY rats. Minoxidil treatment for 8 weeks in both strains resulted in a decrease in mean arterial pressure and increases in ventricular weight to body weight ratios, plasma IR-ANP concentrations (in WKY from 133 +/- 20 to 281 +/- 34 pg ml-1, P less than 0.01; in SHR from 184 +/- 38 to 339 +/- 61 pg ml-1, P less than 0.05), and in ventricular IR-ANP contents (in WKY: 53%; in SHR: 41%). A highly significant correlation was found between ventricular IR-ANP content and ventricular weight to body weight ratio (r = 0.59, P less than 0.001, n = 26). 3. When studied in vitro, in isolated perfused heart preparations, the hypertrophied ventricular tissue after atrialectomy secreted more ANP into the perfusate than ventricles of the control hearts; ventricles contributed 28%, 22%, 18% and 15% of the total ANP release to perfusate in the minoxidil-treated SHR, control SHR, minoxidil-treated WKY and control WKY, respectively. A significant correlation was found between the IR-ANP release from ventricles and ventricular weight to body weight ratio (r = 0.56, P < 0.01, n = 24). 4. These studies demonstrate that the ventricles contribute substantially to the circulating level of ANP, and that the amount released depends on the degree of ventricular hypertrophy.


Subject(s)
Atrial Natriuretic Factor/metabolism , Cardiomegaly/metabolism , Minoxidil , Myocardium/metabolism , Animals , Atrial Natriuretic Factor/blood , Atrial Natriuretic Factor/genetics , Body Weight/drug effects , Cardiomegaly/chemically induced , Hemodynamics/drug effects , In Vitro Techniques , Kidney/drug effects , Male , Norepinephrine/blood , Organ Size/drug effects , Osmolar Concentration , RNA, Messenger/analysis , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Sodium/blood
13.
Circulation ; 80(2): 390-400, 1989 Aug.
Article in English | MEDLINE | ID: mdl-2526698

ABSTRACT

Left ventricular hypertrophy is characterized by stimulation of ventricular synthesis of atrial natriuretic peptide (ANP). This study was designed to test the hypothesis that the increased ventricular ANP levels participate in the release of ANP into the circulation. Swimming was used as a physiologic model to induce ANP release from the heart, and atrial and ventricular levels of immunoreactive ANP (IR-ANP) and ANP messenger RNA (mRNA) were measured simultaneously in the spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats at rest and after swimming. IR-ANP concentration in the left ventricle of 1-year-old SHR with severe left ventricular hypertrophy was increased in association with the augmentation of ANP mRNA levels, whereas right ventricular levels of ANP were reduced in SHR compared with normotensive controls. A 30-minute exercise in hypertensive and in normotensive rats resulted in marked increases in mean arterial pressure, heart rate, plasma catecholamine levels, blood lactate levels, and plasma IR-ANP concentration. The increased ANP secretion was associated with a decrease in left (34-39%) and right (24%) ventricular concentration of IR-ANP; transmurally, this depletion of ventricular IR-ANP was greatest (28%) in the endocardial layer of the left ventricle of SHR. No significant differences were noted in total atrial and left or right auricular IR-ANP concentration between SHR and WKY rats or between the resting and swimming rats. When studied in vitro with an isolated, perfused heart preparation, the hypertrophic ventricular tissue after atrialectomy secreted more ANP into the perfusate than did control hearts; in SHR, ventricles contributed 28% of the total ANP release to perfusate, and in normotensive control rats, ventricles contributed 8%. These studies show that stimulated release of ANP is associated with depletion of endocardial left ventricular stores. The amount of ANP released in vitro and in vivo correlated with the degree of hypertrophy of the ventricle. Finally, the phorbol ester, known to increase ANP secretion from intact perfused hearts, had only a limited effect on ANP release after atrialectomy, suggesting that the secretion of ANP from ventricular cells may be mainly of the constitutive type.


Subject(s)
Atrial Natriuretic Factor/metabolism , Cardiomegaly/metabolism , Physical Exertion , Animals , Catecholamines/blood , Heart Ventricles , Hypertension/metabolism , Lactates/blood , Lactic Acid , Male , Myocardium/metabolism , RNA, Messenger/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Swimming
14.
Endocrinology ; 124(5): 2595-603, 1989 May.
Article in English | MEDLINE | ID: mdl-2523304

ABSTRACT

To evaluate the role of vasopressin in the regulation of atrial natriuretic peptide (ANP) secretion, the plasma, atrial, ventricular, and hypothalamic levels of ANP were measured in Long-Evans (LE) and vasopressin-deficient Brattleboro (DI) rats. Total atrial immunoreactive ANP (IR-ANP) as well as right auricular IR-ANP concentration were higher in the DI than in the LE rats, whereas no significant difference was noted in left auricular IR-ANP concentration. In the left ventricle of DI rats, the IR-ANP concentration was 82% greater than that in the LE rats, while no substantial difference was found in the right ventricular IR-ANP concentration between the strains. Normal LE rats had low levels of left ventricular ANP mRNA and barely detectable ANP mRNA in the right ventricle, DI rats showed a 3-fold greater ANP mRNA concentration in the left ventricle than age-matched LE controls, and ANP mRNA levels were also increased in the left auricle of DI rats. The hypothalamic IR-ANP content, but not the concentration, was significantly increased in the DI compared to the LE rats. Despite increased cardiac IR-ANP and ANP mRNA levels, plasma IR-ANP concentrations were similar in the conscious DI rats (97 +/- 9 pg/ml; n = 13) and the LE rats (95 +/- 8 pg/ml; n = 15). Volume expansion (1.1 ml/100 g BW of 0.9% saline, iv) increased right atrial pressure and caused a significant rise in plasma IR-ANP in both strains (P less than 0.01). Elevations of plasma IR-ANP concentrations caused by volume loading were comparable in LE and DI rats in either the absence or presence of exogenous vasopressin (5 ng/kg.min, iv), which, when infused alone, did not significantly influence the plasma IR-ANP concentration. However, the relation between the change in IR-ANP concentration and the change in right atrial pressure shifted to the left, and thus, for a given increase in right atrial pressure, a greater amount of IR-ANP was released in the vasopressin-treated rats than in the control animals. These results demonstrate that although acute volume expansion does not necessarily require endogenous vasopressin for the ANP secretory response, vasopressin increased the ability of volume expansion to induce ANP release, thus modulating the direct mechanical stimulus-induced ANP secretion. The increased left ventricular levels of immunoreactive ANP and augmentation of ANP mRNA levels in Brattleboro rats despite normal left ventricular weight to body weight ratio show that increased ANP gene expression may occur in the ventricles independently of hypertrophy.


Subject(s)
Atrial Natriuretic Factor/metabolism , Hypothalamus/metabolism , Myocardium/metabolism , Rats, Brattleboro/metabolism , Rats, Mutant Strains/metabolism , Vasopressins/deficiency , Animals , Atrial Natriuretic Factor/blood , Body Weight , Heart Atria , Heart Ventricles/anatomy & histology , Hemodynamics/drug effects , Male , Organ Size , Plasma Substitutes/pharmacology , RNA, Messenger/metabolism , Radioimmunoassay , Rats , Rats, Inbred Strains
15.
Biochem Pharmacol ; 37(20): 3861-6, 1988 Oct 15.
Article in English | MEDLINE | ID: mdl-3263862

ABSTRACT

Three imidazole antimycotic drugs, ketoconazole, clotrimazole and miconazole, were studied to characterize the inhibition of aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECDE) and 7-ethoxyresorufin O-deethylase (ERDE) activities in human liver and placenta in vitro in comparison with liver enzymes from control, phenobarbital (PB) and 3-methylcholanthrene (MC) pretreated rats. All three compounds inhibited rat liver enzymes, although MC pretreatment seemed to lead to a resistance of inhibition relative to PB-treated and control animals. There were large differences in the extent of inhibition of human hepatic and placental activities. Furthermore, while the type of inhibition of the hepatic ERDE was competitive or mixed, that of the placental enzyme cannot be described in ordinary terms of inhibition kinetics. Ketoconazole and clotrimazole were relatively potent inhibitors of maternal cigarette smoking-induced placental ECDE activities (IC50 values from 0.5 microM to 5 microM), whereas much less inhibition of the placental AHH activity was obtained with ketoconazole and miconazole (IC50 values from 50 microM to 500 microM). In most cases, hepatic enzymes were less sensitive to antimycotics than placental activities. This was in contrast with results from rat enzyme studies, in which MC pretreatment seemed to decrease the inhibitory response.


Subject(s)
Clotrimazole/pharmacology , Imidazoles/pharmacology , Ketoconazole/pharmacology , Miconazole/pharmacology , Microsomes, Liver/enzymology , Placenta/enzymology , 7-Alkoxycoumarin O-Dealkylase , Animals , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Cytochrome P-450 CYP1A1 , Cytochrome P-450 Enzyme Inhibitors , Humans , Kinetics , Male , Oxidoreductases/antagonists & inhibitors , Oxygenases/antagonists & inhibitors , Rats , Rats, Inbred Strains
16.
Pharmacol Toxicol ; 62(5): 311-7, 1988 May.
Article in English | MEDLINE | ID: mdl-3413034

ABSTRACT

1. A panel of nine inhibitors displaying some P-450 isozyme specificity was used to characterize aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin 0-deethylase (ERDE) activities in human liver and placenta in vitro in comparison with liver enzymes from control, phenobarbital (PB) and 3-methylcholanthrene (MC) treated rats. 2. SKF 525A and cimetidine inhibited more potently hepatic AHH than the placental enzyme. 7,8-Benzoflavone inhibited more efficiently placental AHH than the hepatic enzyme, whereas ERDE was inhibited at the same level in both tissues. Quinine, quinidine, SKF 525A and metyrapone inhibited ERDE almost to the same extent in both tissues, but the variability was larger with the liver enzyme. Aminoglutethimide, debrisoquine or tetrahydrofuran did not inhibit AHH or ERDE significantly in either tissue. 3. When compared with inhibition profiles obtained with rat liver microsomes, the human hepatic and placental ERDE resembled most that of MC-treated rat liver enzyme. Inhibition profile of placental AHH activity was also similar, but the inhibition characteristics of hepatic AHH activity resembled more closely control or PB-induced rat liver. It also seems that isozymes for alcohol induction or debrisoquine hydroxylation do not contribute significantly to hepatic or placental AHH or ERDE. 4. The inhibitor panel selected on the basis of known pretreatment and isozyme specificity might be useful in the characterization of enzymes and metabolic biotransformations participating in the metabolism of new substrates.


Subject(s)
Cytochrome P-450 Enzyme Inhibitors , Isoenzymes/antagonists & inhibitors , Liver/enzymology , Placenta/enzymology , Aminoglutethimide/pharmacology , Animals , Benzoflavones/pharmacology , Cimetidine/pharmacology , Cytochrome P-450 CYP1A1 , Debrisoquin/pharmacology , Enzyme Inhibitors/pharmacology , Female , Furans/pharmacology , Humans , Male , Metyrapone/pharmacology , Oxidoreductases/antagonists & inhibitors , Pregnancy , Rats , Rats, Inbred Strains
17.
Biochem Int ; 11(6): 845-51, 1985 Dec.
Article in English | MEDLINE | ID: mdl-4091857

ABSTRACT

The degradation of ornithine decarboxylase was studied by an immunoblotting technique. The immunoblots of mouse kidney and brain cytosol preparations revealed degradation fragments of unequal size. The immunoreactive fragments found in kidney cytosol corresponded to molecular weights of 46 kDa and 32 kDa, whereas 36 kDa fragment was dominant in brain cytosol. When kidney cytosol was exposed to microsomal fraction of mouse brain before analysis, the kidney enzyme was degraded to 36 kDa-fragment. The microsomal fraction of mouse kidney, in turn, when incubated with brain cytosol brought about the appearance of immunoreactive protein corresponding to molecular weight of 35 kDa that was also found in kidney preparation, which was incubated as homogenate before electrophoretic run and immunoblotting. These results show that microsomal fractions effectively degrade enzyme protein, and suggest that the regulation mechanisms by the in vivo degradation of the enzyme are dissimilar in these tissues.


Subject(s)
Ornithine Decarboxylase/isolation & purification , Animals , Electrophoresis, Polyacrylamide Gel , Immunoassay , Kidney/enzymology , Male , Mice , Mice, Inbred Strains , Molecular Weight
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