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Biomedical subjects

S C Pang

Publications and source records attributed to S C Pang.

At least 19 recordsLinked to original sources
PubMed2005

A potential role for the endothelin ETA receptor in salt-sensitive hypertension of the proANP gene-disrupted mouse.

We have previously shown that the partial disruption of the gene for atrial natriuretic peptide (ANP) results in a salt-sensitive phenotype. The present study examined the possibility that alterations in either the ANP natriuretic pathway or endothelin (ET) system in the kidney of the salt-challenged ANP +/- mouse was responsible for its salt-sensitive phenotype. Plasma ANP levels and renal cGMP activity were increased in response to a salt load in both ANP +/+ and +/- mice. However, the mRNA expression of proANP was found to be increased only in the ANP +/- kidney along with its guanylyl cyclase-linked receptor, NPRA; the upregulation of NPRA mRNA was limited to the renal medulla. This suggests that the renal ANP pathway remains capable of responding to a salt load in the ANP +/- animal, but may be compensating for other dysfunctional pathways. We also report a significant increase in renal ET-1 mRNA and ETA receptor protein expression in medulla and cortex of the salt-treated, ANP +/- mouse, but not its wild-type counterpart. In fact, ETA expression decreased in the renal cortex of the ANP +/+ salt-treated animal. The ETB receptor expression was not affected by diet in either genotype. We hypothesize that the salt-sensitive hypertension in the ANP +/- mouse is exacerbated, and possibly driven by the vasoconstrictive effects resulting from an upregulated ET-1/ETA pathway.

Animals↗
PubMed2005

The additional risk of malignant mesothelioma in former workers and residents of Wittenoom with benign pleural disease or asbestosis.

AIMS: To examine the hypothesis that people with benign pleural disease or asbestosis have an increased risk of malignant mesothelioma beyond that attributable to their degree of asbestos exposure. METHODS: Former workers and residents of the crocidolite mining and milling town of Wittenoom are participating in a cancer prevention programme (n = 1988). The first plain chest radiograph taken at the time of recruitment into the cancer prevention programme was read for evidence of benign pleural disease and asbestosis, using the UICC classification. Crocidolite exposure of former workers was derived from employment records and records of dust measurements performed during the operation of the asbestos mine and mill between 1943 and 1966. Based on fibre counts, exposure for former residents was determined using duration of residence and period of residence (before and after a new mill was commissioned in 1957) and interpolation from periodic hygienic measures undertaken from personal monitors between 1966 and 1992. Cox proportional hazards modelling was used to relate benign pleural disease, asbestosis, asbestos exposure, and mesothelioma. RESULTS: Between 1990 and 2002, there were 76 cases of mesothelioma (56 of the pleura and 20 of the peritoneum). Cases had more radiographic evidence of (all) benign pleural disease, pleural thickening, blunt/obliterated costophrenic angle, and asbestosis than non-cases. Adjusting for time since first exposure (log years), cumulative exposure (log f/ml-years), and age at the start of the programme, pleural thickening (OR = 3.1, 95% CI 1.2 to 7.6) and asbestosis (OR = 3.3, 95% CI 1.3 to 8.6) were associated with an increased risk of peritoneal mesothelioma. There was no increased risk for pleural mesothelioma. CONCLUSION: The presence of benign pleural disease, in particular pleural thickening, and asbestosis appears to increase the risk of mesothelioma of the peritoneum, but not of the pleura beyond that attributable to indices of asbestos exposure in this cohort of subjects exposed to crocidolite.

Aged↗
PubMed2005

The effect of asbestosis on lung cancer risk beyond the dose related effect of asbestos alone.

AIMS: To determine if the presence of asbestosis is a prerequisite for lung cancer in subjects with known exposure to blue asbestos (crocidolite). METHODS: Former workers and residents of Wittenoom with known amounts of asbestos exposure (duration, intensity, and time since first exposure), current chest x ray and smoking information, participating in a cancer prevention programme (n = 1988) were studied. The first plain chest radiograph taken at the time of recruitment into the cancer prevention programme was examined for radiographic evidence of asbestosis according to the UICC (ILO) classification. Cox proportional hazards modelling was used to relate asbestosis, asbestos exposure, and lung cancer. RESULTS: Between 1990 and 2002 there were 58 cases of lung cancer. Thirty six per cent of cases had radiographic evidence of asbestosis compared to 12% of study participants. Smoking status was the strongest predictor of lung cancer, with current smokers (OR = 26.5, 95% CI 3.5 to 198) having the greatest risk. Radiographic asbestosis (OR = 1.94, 95% CI 1.09 to 3.46) and asbestos exposure (OR = 1.21 per f/ml-year, 95% CI 1.02 to 1.42) were significantly associated with an increased risk of lung cancer. There was an increased risk of lung cancer with increasing exposure in those without asbestosis. CONCLUSION: In this cohort of former workers and residents of Wittenoom, asbestosis is not a mandatory precursor for asbestos related lung cancer. These findings support the hypothesis that it is the asbestos fibres per se that cause lung cancer, which can develop with or without the presence of asbestosis.

Aged↗
PubMed2003

Radiographic (ILO) readings predict arterial oxygen desaturation during exercise in subjects with asbestosis.

BACKGROUND: Exercise impairment is common in subjects with asbestosis. Arterial oxygen desaturation during exercise is an important contributor to exercise limitation. The International Labour Office (ILO) classification of plain chest radiographs correlates with resting pulmonary function, but its value in predicting abnormal ventilatory responses to exercise, including desaturation, has not been explored. AIMS: To determine in subjects with asbestosis (1) if radiographic profusion scores and the extent of small irregular shadows on plain chest radiographs correlate with resting lung function and abnormal ventilatory responses to exercise; and (2) if radiographic scores add value to resting lung function tests in predicting abnormal ventilatory responses to exercise. METHODS: Thirty eight male subjects with asbestosis were included. Plain chest radiographs were read according to the ILO classification independently by three observers. All subjects underwent assessment of lung function and an incremental exercise test. RESULTS: Profusion scores and number of affected zones correlated significantly with the percentage predicted values of single breath diffusing capacity (DLCO), forced vital capacity (FVC), and total lung capacity (TLC). Arterial oxygen desaturation occurred in 29% of the subjects. The severity of desaturation correlated significantly with profusion and the number of affected zones. The combined use of number of affected zones, FEV(1)/FVC ratio and DLCO predicted desaturation during exercise with an explained variance of 41%. VO(2)max was significantly related only to DLCO but was not predicted by the ILO score. CONCLUSION: Arterial oxygen desaturation correlated with the profusion and extent of parenchymal abnormality on chest radiographs. The addition of morphological indices to physiological measurements is valuable for predicting oxygen desaturation during exercise but not for VO(2)max. Refinement of the radiographic scoring system and the addition of more sophisticated imaging techniques may further improve the predictive power.

Aged↗
PubMed2002

Investigation of a cyclopic, human, term fetus by use of magnetic resonance imaging (MRI).

Using magnetic resonance imaging (MRI), the internal neural and craniofacial malformations of a cyclopic fetus are described. External facial features were characterized by a tubular proboscis situated above a single eye slit. The brain was recognized as 'pancake' type alobar holoprosencephaly (a condition where the undifferentiated telencephalon partially surrounds a monoventricle). Displacement of some bones that normally contribute to the orbit could be clearly discerned. Absence of neural structures (e.g. falx cerebri, corpus callosum) and missing components of the ethmoid bone indicated a midline deficit. This correlates with proposed theories of cyclopic embryopathy, which suggest that the prechordal plate and the neural crest cells are affected during the third week of gestation in cyclopia.

Abnormalities, Multiple↗
PubMed2002

Silicosis compensation in Western Australian gold miners since the introduction of an occupational exposure standard for crystalline silica.

UNLABELLED: Occupational exposure limits for crystalline silica are under review worldwide because of the large numbers of exposed people and, especially, because of the recent International Agency for Research on Cancer classification of silica as a human carcinogen. OBJECTIVES: The aims of this study were to (i) re-examine the incidence of silicosis in Western Australian gold miners and, using estimates of the total population at risk, (ii) estimate the upper confidence limit for the risk of silicosis in Western Australian gold miners since 1974, when the current exposure standard for crystalline silica was implemented. METHODS: Work histories of cases compensated for pneumoconiosis after 1974 were examined. Numbers of workers in the total workforce likely to be exposed to crystalline silica in Western Australia were estimated as the population at risk. RESULTS: There were no cases of compensated silicosis in Western Australian miners whose first dust exposure began during or after 1974. The upper 95% confidence interval for this zero rate was estimated to be 4.8 per 100,000 person-yr. CONCLUSIONS: There have been no compensated cases of silicosis in Western Australia among miners first exposed to crystalline silica after introduction of the current exposure standard. A rate of compensated silicosis higher than five cases per 100,000 person-yr is unlikely.

Adult↗
PubMed2001

Cardiac troponin I is modified in the myocardium of bypass patients.

BACKGROUND: Selective proteolysis of cardiac troponin I (cTnI) is a proposed mechanism of contractile dysfunction in stunned myocardium, and the presence of cTnI degradation products in serum may reflect the functional state of the remaining viable myocardium. However, recent swine and canine studies have not demonstrated stunning-dependent cTnI degradation. METHODS AND RESULTS: To address the universality of cTnI modification, myocardial biopsy samples were obtained from coronary artery bypass patients (n=37) before and 10 minutes after removal of cross-clamp. Analysis of biopsy samples for cTnI by Western blotting revealed a spectrum of modified cTnI products in myocardium both before and after cross-clamp, including degradation products (7 products resulting from differential N- and C-terminal processing) and covalent complexes (3 products). In particular, a 22-kDa cTnI degradation product with C-terminal proteolysis was identified, which may represent an initial ischemia-dependent cTnI modification, similar to cTnI(1-193) observed in stunned rat myocardium. Although no systematic change in amount of modified cTnI was observed, subgroups of patients displayed an increase (n=10, 85+/-5% of cTnI remaining intact before cross-clamp versus 75+/-5% after) or a decrease (n=12, 67+/-5% before versus 78+/-5% after). Electron microscopy demonstrated normal ultrastructure in biopsy samples, which suggests no necrosis was present. In addition, cTnI modification products were observed in serum through a modified SDS-PAGE methodology. CONCLUSIONS: cTnI modification, in particular proteolysis, occurs in myocardium of bypass patients and may play a key role in stunning in some bypass patients.

Biopsy↗
PubMed2001

Increased body mass index is related to apparent circumscribed pleural thickening on plain chest radiographs.

BACKGROUND: Diffuse pleural thickening and pleural plaques are the commonest radiological manifestations of asbestos exposure. Differentiation between subpleural fat and non-calcified pleural plaques is important clinically and medico-legally. This study aims to determine if apparent circumscribed pleural thickening on chest radiographs is related with obesity. METHODS: Surveillance chest x-rays of 693 former asbestos workers were read with the ILO classification. Subjects with costophrenic angle obliteration (n = 57) were analyzed separately. The remaining subjects were subdivided according to their body mass index (BMI): Group 1 < 26 kg/m(2); Group 2 26-30 kg/m(2); Group 3 > 30 kg/m(2). RESULTS: Baseline characteristics, asbestos exposure, and profusion scores were evenly distributed. BMI of > 30 kg/m(2) was associated with a higher prevalence of pleural thickening on CXR (Gp1 = 8.5%; Gp2 = 9.3%; Gp3 = 18.3%). This relationship was strongest in the subgroups with 25-50% of the lateral chest wall involved and pleural thickness of < 10 mm. CONCLUSIONS: Obesity (BMI > 30 kg/m(2)) is related to apparent circumscribed pleural thickening on CXR, especially thin (< 1 cm) shadows covering 25-50% of the lateral chest wall.

Adipose Tissue↗
PubMed2001

Expression of B-type natriuretic peptide in atrial natriuretic peptide gene disrupted mice.

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are two hormones produced and secreted by the heart to control blood pressure, body fluid homeostasis and electrolyte balance. Each peptide binds to a common family of 3 receptors (GC-A, GC-B and C-receptor) with varying degrees of affinity. The proANP gene disrupted mouse model provides an excellent opportunity to examine the regulation and expression of BNP in the absence ofANP. A new radioimmunoassay (RIA) was developed in order to measure mouse BNP peptide levels in the plasma, atrium and ventricle of the mouse. A detection limit of 3-6 pg/tube was achieved by this assay. Results show that plasma and ventricular level of BNP were unchanged among the three genotypes of mice. However, a significant decrease in the BNP level was noted in the atrium. The homozygous mutant (ANP-/-) had undetectable levels of BNP in the atrium, while the heterozygous (ANP+/-) and wild-type (ANP+/+) mice had 430 and 910 pg/mg in the atrium, respectively. Northern Blot analysis shows the ANP-/- mice has a 40% reduction of BNP mRNA level in the atrium and a 5-fold increase in the ventricle as compared with that of the ANP+/+ mouse. Our data suggest that there is a compensatory response of BNP expression to proANP gene disruption. Despite the changes in the atrial and ventricular tissue mRNA and peptide levels, the plasma BNP level remains unaltered in the ANP-/- mice. We conclude that the inability of BNP to completely compensate for the lack of ANP eventually leads to chronic hypertension in the proANP gene disrupted mice.

Animals↗
PubMed2000

Hypoxia induces the expression of a 43-kDa protein (PROXY-1) in normal and malignant cells.

This study was designed to determine the expression of cellular factors that may participate in phenotypic changes that occur under conditions of hypoxia. Using the RT-PCR differential display method, we isolated a cDNA fragment corresponding to a gene whose expression was induced in trophoblast and breast carcinoma cells cultured under 1 or 2% oxygen vs 4% oxygen or higher. This gene encodes a 43-kDa protein initially identified in homocysteine-treated endothelial cells and later shown to be upregulated in various human and mouse cell types (termed RTP, Drg1, Cap43, rit42, Ndr1). Herein we refer to this gene product as PROXY-1, for Protein Regulated by OXYgen-1. Elevated mRNA and protein levels were first observed in cells cultured in 1% oxygen for 8 h. Although PROXY-1 mRNA levels returned to near-control values within 2 h of reexposure to 20% oxygen, protein levels remained high 72 h after reexposure to 20% oxygen. Treatment of cells with hypoxia mimics such as cobalt or iron chelators also increased PROXY-1 expression. Moreover, presence of 30% carbon monoxide in the hypoxic atmosphere abrogated the upregulation of PROXY-1 expression. These findings suggest that hypoxia upregulates PROXY-1 levels through a heme protein-dependent pathway and that assessment of PROXY-1 expression may be of potential use in evaluating tissue hypoxia.

Animals↗
PubMed2000

Expression of phosphodiesterase 4D (PDE4D) is regulated by both the cyclic AMP-dependent protein kinase and mitogen-activated protein kinase signaling pathways. A potential mechanism allowing for the coordinated regulation of PDE4D activity and expression in cells.

Multiple families of cyclic nucleotide phosphodiesterases (PDE) have been described, and the regulated expression of these genes in cells is complex. Although cAMP is known to control the expression of certain PDE in cells, presumably reflecting a system of feedback on cAMP signaling, relatively little is known about the influence of non-cAMP signaling systems on PDE expression. In this study, we describe a novel mechanism by which activators of the protein kinase C (PKC)-Raf-MEK-ERK cascade regulate phosphodiesterase 4D (PDE4D) expression in vascular smooth muscle cells (VSMC) and assess the functional consequences of this effect. Whereas a prolonged elevation of cAMP in VSMC resulted in a protein kinase A (PKA)-dependent induction of expression of two PDE4D variants (PDE4D1 and PDE4D2), simultaneous activation of both the cAMP-PKA and PKC-Raf-MEK-ERK signaling cascades blunted this cAMP-mediated increase in PDE4D expression. By using biochemical, molecular biological, and pharmacological approaches, we demonstrate that this PDE4D-selective effect of activators of the PKC-Raf-MEK-ERK cascade was mediated through a mechanism involving altered PDE4D mRNA stability and markedly attenuated the cAMP-mediated desensitization that results from prolonged activation of the cAMP signaling system in cells. The data are presented in the context of activators of the PKC-Raf-MEK-ERK cascade having both short and long term effects on PDE4D activity and expression in cells that may influence cAMP signaling.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2000

ANP in regulation of arterial pressure and fluid-electrolyte balance: lessons from genetic mouse models.

The recent development of genetic mouse models presenting life-long alterations in expression of the genes for atrial natriuretic peptide (ANP) or its receptors (NPR-A, NPR-C) has uncovered a physiological role of this hormone in chronic blood pressure homeostasis. Transgenic mice overexpressing a transthyretin-ANP fusion gene are hypotensive relative to the nontransgenic littermates, whereas mice harboring functional disruptions of the ANP or NPR-A genes are hypertensive compared with their respective wild-type counterparts. The chronic hypotensive action of ANP is determined by vasodilation of the resistance vasculature, which is probably mediated by attenuation of vascular sympathetic tone at one or several prejunctional sites. Under conditions of normal dietary salt consumption, the hypotensive action of ANP is dissociated from the natriuretic activity of the hormone. However, during elevated dietary salt intake, ANP-mediated antagonism of the renin-angiotensin system is essential for maintenance of blood pressure constancy, inasmuch as the ANP gene "knockout" mice (ANP -/-) develop a salt-sensitive component of hypertension in association with failure to adequately downregulate plasma renin activity. These findings imply that genetic deficiencies in ANP or natriuretic receptor activity may be underlying causative factors in the etiology of salt-sensitive variants of hypertensive disease and other sodium-retaining disorders, such as congestive heart failure and cirrhosis.

Animals↗
PubMed2000

Altered expression of natriuretic peptide receptors in proANP gene disrupted mice.

BACKGROUND: The atrial natriuretic peptide (ANP) family is a complex system consisting of at least three polypeptides and at least three types of receptor. Each peptide interacts with different types of receptor at varying degrees of affinity. To determine if natriuretic peptide levels influence natriuretic peptide receptor expression and regulation, we examined the expression of guanylyl cyclase linked GC-A, GC-B and C-receptor in the lungs of mice with a mutation that inactivates the ANP gene (Nppa). METHODS: The mRNA level of GC-A, GC-B and C-receptor in the lung were studied by ribonuclease protection assays (RPA). RESULTS: Results of RPA showed that although the mRNA level of GC-A and GC-B of heterozygous ANP+/- was not different from wild type ANP+/+ mice, they were significantly higher in the homozygous mutant ANP-/- mice. In addition, C-receptor mRNA level in ANP+/- and ANP-/- was significantly lower than ANP+/+ mice. The C-receptor results were confirmed by receptor binding assays and affinity cross-linking studies. CONCLUSIONS: Taken together these data suggest that permanent removal of ANP from the natriuretic peptide system results in an up-regulation of GC-A and GC-B, and a corresponding down-regulation of C-receptor in the lung of proANP gene disrupted mice. We postulated that changes in the natriuretic peptide receptor population may result in chronic hypertension and cardiac hypertrophy in the ANP-/- mice.

Analysis of Variance↗
PubMed2000

Chest pain in asbestos-exposed individuals with benign pleural and parenchymal disease.

Many asbestos-exposed individuals complain of chest pain for which there is no clear explanation. To determine whether chest pain is associated with the presence of benign pleural or parenchymal disease on chest radiograph, we studied 1,280 subjects undergoing surveillance because of prior asbestos exposure at Wittenoom, Western Australia. All subjects completed the Rose questionnaire on chest pain and this revealed 556 subjects (43%) who experienced some chest pain. A posterior-anterior chest radiograph was performed at the same clinic visit and was subsequently graded independently by two experienced readers for diffuse parenchymal disease and pleural disease. Logistic regression models adjusted for sex, age, and cumulative asbestos exposure indicated that the presence of chest pain was significantly associated with the presence of both benign pleural disease and diffuse parenchymal disease. Further analysis after stratification of chest pain into nonanginal and anginal pain showed that there was a significant association between anginal pain and the presence of pleural and parenchymal asbestos-induced radiologic abnormalities and an association of nonanginal pain with parenchymal disease. We conclude that radiographic evidence of either parenchymal or pleural disease in subjects exposed to asbestos is significantly related to the presence of chest pain, particularly anginal pain.

Adolescent↗
PubMed2000

Tuberculosis surveillance in immigrants through health undertakings in Western Australia.

SETTING: Tuberculosis Control Program, Western Australia. OBJECTIVE: To assess the effectiveness and efficiency of tuberculosis (TB) surveillance in immigrants. DESIGN: Retrospective descriptive analysis of records of immigrants who first registered with the Tuberculosis Program from January 1994 to December 1995, having entered Western Australia on health undertakings (nonlegal contracts signed by those determined during premigration screening to require post-arrival evaluation). RESULTS: Of 1,344 immigrants on health undertakings for TB in the period, 587 (44%) had findings directly related to TB through pre-migration screening, 69 of whom required treatment for active disease. Another 443 (33%) had chest X-ray changes for which TB could not be excluded. Of the remaining 314 (23%), 172 had poor quality X-rays. Post-arrival assessment and follow-up of the whole group detected four of seven additional cases of active TB, 373 persons (28%) requiring on-going surveillance, 667 (50%) with non-TB conditions and 280 (21%) with normal chest X-rays. CONCLUSIONS: Migrant surveillance for TB in Australia is effective in detecting active disease and identifying a high-risk subgroup requiring further evaluation. Efficiency can be improved and high compliance achieved with simple administrative changes. Routine pre-migration Mantoux testing is inappropriate, and its inclusion in post-arrival assessments should be a national policy decision.

Adolescent↗
PubMed1999

Chronic regulation of arterial blood pressure in ANP transgenic and knockout mice: role of cardiovascular sympathetic tone.

OBJECTIVE: Atrial natriuretic peptide (ANP) lowers arterial blood pressure (ABP) chronically, in association with vasodilation of the resistance vasculature. The mechanism mediating the chronic relaxant effect of ANP is likely indirectly mediated by interactions with tonic vasoeffector mechanisms, inasmuch as the resistance vasculature is relatively insensitive to direct cGMP-mediated relaxation by ANP. On the basis of evidence that ANP has widespread sympatholytic activity, the current study investigated whether the chronic hypotensive effect of ANP is mediated by attenuation of tonic cardiovascular sympathetic tone. METHODS: Total plasma catecholamine concentration and changes in basal ABP and heart rate (HR) following autonomic ganglionic blockade were measured as indices of underlying sympathetic nerve activity in hypotensive ANP-overexpressing transgenic mice (TTR-ANP), hypertensive ANP knockout mice (-/-) and the genetically-matched wild type (NT and +/+, respectively) control mice. Pressor and chronotropic responses to norepinephrine infusion were measured in ganglion-blocked mice of all genotypes, and norepinephrine receptor binding was assessed in representative tissues of -/- and +/+ mice, in order to determine whether peripheral adrenergic receptor responsiveness is altered by ANP-genotype. RESULTS: Basal ABP was significantly lower in TTR-ANP and higher in -/- compared to their wild-type controls. Basal HR did not differ significantly between mutant and control mice. Autonomic ganglionic blockade reduced ABP and HR in all genotypes, however, the relative decrease in ABP was significantly smaller in TTR-ANP and greater in -/- mice than in their respective controls. Total plasma catecholamine was significantly higher in -/- than in +/+ mice but did not differ significantly between TTR-ANP and NT mice. Norepinephrine infusion during ganglionic blockade elicited quantitatively similar pressor and chronotropic responses in mutant and control mice. Tissue norepinephrine binding did not differ significantly between -/- and +/+ mice. CONCLUSIONS: The present study shows that differences in endogenous ANP activity in mice, resulting in chronic alterations in ABP are accompanied by directional changes in underlying cardiovascular sympathetic tone, and suggests that the chronic vasodilator effect of ANP is, at least partially, dependent on attenuation of vascular sympathetic tone, possibly at a prejunctional site(s).

Analysis of Variance↗
PubMed1999

Chronic hypertension in ANP knockout mice: contribution of peripheral resistance.

Atrial Natriuretic Peptide (ANP) exerts a chronic hypotensive effect which is mediated by a reduction in total peripheral resistance (TPR). Mice with a homozygous disruption of the pro-ANP gene (-/-) fail to synthesize ANP and develop chronic hypertension in comparison to their normotensive wild-type (+/+) siblings. In order to determine whether alterations in basal hemodynamics underlie the hypertension associated with lack of endogenous ANP activity, we used anesthetized mice to measure arterial blood pressure (ABP) and heart rate (HR), as well as cardiac output (CO) by thermodilution technique. -/- (n = 7) and +/+ (n = 10) mice of comparable weight and age were used. Stroke volume (SV) and TPR were derived from CO, HR, and ABP by a standard formula. ABP (mm Hg) was significantly higher in -/- (132+/-4) (P < 0.0001) than in +/+ mice (95+/-2). CO (ml min(-1)), HR(beats min(-1))and SV (microl beat(-1)) did not differ significantly between -/- and +/+ mice (CO -/- = 7.3+/-0.5, +/+ = 8.3+/-0.6; HR -/- = 407+/-22, +/+ = 462+/-21; SV -/- = 17.6+/-1.1, +/+ = 17.6+/-1.7). However, TPR (mm Hg ml(-1) min(-1)) was significantly elevated in -/- mice (18.4+/-0.7) compared to +/+ mice (12.3+/-1) (P = 0.0003). Autonomic ganglion blockade with a mixture of hexamethonium and pentolinium was followed by comparable percent reductions in CO (-/- = 28+/-4, +/+ = 29+/-3), HR (-/- = 9+/-4, +/+ = 16+/-4) and SV(-/- = 21+/-4, +/+ = 15+/-6) in both genotypes. However, the concomitant decrease in ABP (%) in -/- (41+/-2) was significantly greater than in +/+ (23+/-4) mice (P = 0.0009) and was accompanied by a significant reduction in TPR. We conclude that the hypertension associated with lack of endogenous ANP is due to elevated TPR, which is determined by an increase in cardiovascular autonomic tone.

Animals↗