Effects of prostaglandin F2 alpha on intracellular pH, intracellular calcium, cell shortening and L-type calcium currents in rat myocytes.
(9/11504)
OBJECTIVE: We have studied the mechanisms underlying the positive inotropic action of prostaglandin F2 alpha (PGF2 alpha) by monitoring intracellular calcium transients, intracellular pH, L-type calcium currents and cell shortening in isolated ventricular myocytes. METHODS: Rat myocytes were loaded with fura-2AM for intracellular calcium measurements, or BCECF-AM for pH measurements. Cell shortening was recorded using an edge detection system, and L-type calcium currents measured using whole cell patch clamping. RESULTS: PGF2 alpha (3 nmol l-1-3 mumol l-1 increased single myocyte shortening and reduced resting cell length in a concentration-dependent manner. While myocyte shortening was increased by PGF2 alpha, this was not associated with any change in the amplitude of intracellular calcium transients, diastolic calcium, or L-type calcium currents. However, the same myocytes were capable of responding to catecholamines with increases in calcium transient amplitude and L-type calcium currents. PGF2 alpha (3 mumol l-1 caused a reversible rise in intracellular pH of 0.08 +/- 0.01 pH units (n = 5, p < 0.05). The Na(+)-H+ exchanger inhibitor, HOE 694 (10 mumol l-1, abolished the PGF2 alpha-induced rise in pH and the increase in cell shortening. PGF2 alpha-induced increases in cell shortening and intracellular pH were also attenuated by the protein kinase C (PKC) inhibitor, chelerythrine (2 mumol l-1. CONCLUSION: The positive inotropic action of PGF2 alpha appears to be mediated via activation of the Na(+)-H+ exchanger with the possible involvement of PKC. This suggests that PGF2 alpha-produces intracellular alkalosis, which then sensitizes cardiac myofilaments to calcium. (+info)
Endothelial function is impaired in fit young adults of low birth weight.
(10/11504)
OBJECTIVE: Non-insulin-dependent diabetes, hypertension and ischaemic heart disease, with insulin resistance, are associated with low birth weight (the 'Small Baby Syndrome'). Common to these adult clinical conditions is endothelial dysfunction. We tested the hypothesis that endothelial dysfunction could precede their development in those of low birth weight. METHODS: Endothelial function was measured by ultrasonic 'wall-tracking' of flow-related brachial artery dilatation in fit 19-20 year old subjects randomly selected (blind to the investigators throughout the study) from low (< 2.5 kg) and normal (3.0-3.8 kg) birth weight subjects in the 1975-7 cohort of the Cardiff Births Survey and with no known cause for endothelial dysfunction. RESULTS: Flow-related dilatation was impaired in low birth weight relative to normal birth weight subjects (median 0.04 mm [1.5%] [n = 22] cf. 0.11 mm [4.1%] [n = 17], p < 0.05; 0.04 mm [1.5%] [n = 15] cf. 0.12 mm [4.4%] [n = 12], p < 0.05 after exclusion of inadvertently included ever-smokers). CONCLUSION: The findings suggest that endothelial dysfunction is a consequence of foetal malnutrition, consistent with contributing to the clinical features of the 'Small Baby Syndrome' in later adult life. (+info)
Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse.
(11/11504)
Idiopathic nephrotic syndrome of childhood is thought to be associated with T lymphocyte dysfunction often triggered by viral infections, with the production of circulating factor(s) resulting in proteinuria. In view of the conflicting evidence of T cell activation and Th1 or Th2 pattern of cytokine synthesis in this disease, this study examined the mRNA expression of interleukin-2 (IL-2), interferon-gamma, IL-4, and IL-13 from CD4+ and CD8+ T cells in steroid-responsive nephrotic patients in relapse and remission. Fifty-five children with steroid-responsive nephrotic syndrome were included in this study, together with 34 normal controls and 24 patient controls with viral infections. RNA was isolated from purified CD4+ or CD8+ cells from peripheral blood and subjected to reverse transcription-PCR. Cytokine mRNA expression was measured semiquantitatively, and a cytokine index was derived from densitometric readings, with cyclophilin as the housekeeping gene. Both cross-sectional and paired data showed an increased CD4+ and CD8+ IL-13 mRNA expression in patients with nephrotic relapse as compared to remission, normal, and patient controls (P < 0.008). This was also associated with increased cytoplasmic IL-13 expression in phorbol myristate acetate/ionomycin-activated CD3+ cells (6.66+/-3.39%) from patients with nephrotic relapse compared to remission (2.59+/-1.35%) (P < 0.0001). However, there was no significant difference in CD4+ or CD8+ IL-2, interferon-gamma and IL-4 mRNA expression. IL-13 is an important T cell cytokine with anti-inflammatory and immunomodulatory functions on B cells and monocytes. It is conceivable that IL-13 may act on monocytes to produce vascular permeability factor(s) involved in the pathogenesis of proteinuria in patients with relapse nephrotic syndrome. (+info)
Renal function in high-output heart failure in rats: role of endogenous natriuretic peptides.
(12/11504)
The physiologic and pathophysiologic importance of natriuretic peptides (NP) has been imperfectly defined. The diminished renal responses to exogenous atrial NP in heart failure have led to the perception that the endogenous NP system might be less effective and thus contribute to renal sodium retention in heart failure. This study tests the hypothesis that in experimental heart failure, the renal responses to an acute volume load are still dependent on the NP system. The specific antagonist HS-142-1 was used to block the effects of NP in a model of high-output heart failure induced by an aortocaval shunt. Plasma cGMP levels and renal cGMP excretion were significantly lower in shunted and sham-operated rats receiving HS-142-1, compared with vehicle-treated controls, indicating effective blockade of guanylate cyclase-coupled receptors. Baseline sodium excretion and urine flow rate were lower in HS-142-1-treated sham-operated rats (15.2+/-1.1 microl/min versus 27.5+/-3.1 microl/min with vehicle, P < 0.001) and in HS-142-1-treated shunted rats (8.1+/-1.3 microl/min versus 19.9+/-2.3 microl/min with vehicle, P < 0.001). After an acute volume load, the diuretic and natriuretic responses were attenuated by HS-142-1 in control and shunted rats. The renal responses were reduced by HS-142-1 to a significantly greater extent in shunted rats than in control rats. HS-142-1 did not induce any significant systemic hemodynamic changes in either group, nor did it alter renal blood flow. However, the GFR in HS-142-1-treated shunted rats was lower than that in vehicle-treated shunted rats, both at baseline (0.6+/-0.3 ml/min versus 2.1+/-0.4 ml/min with vehicle, P < 0.05) and after an acute volume load (1.2+/-0.4 ml/min versus 2.6+/-0.4 ml/min with vehicle, P = 0.01), whereas no such effect was observed in control rats. These data indicate that the maintenance of basal renal function and the responses to acute volume loading are dependent on the NP system. The NP seem to be of particular importance for the maintenance of GFR in this model of experimental heart failure. These observations provide new insights into the importance of the renal NP system in heart failure. (+info)
Atrioventricular nodal ablation and implantation of mode switching dual chamber pacemakers: effective treatment for drug refractory paroxysmal atrial fibrillation.
(13/11504)
OBJECTIVE: To assess the effect of atrioventricular node ablation and implantation of a dual chamber, mode switching pacemaker on quality of life, exercise capacity, and left ventricular systolic function in patients with drug refractory paroxysmal atrial fibrillation. PATIENTS: 18 consecutive patients with drug refractory paroxysmal atrial fibrillation. METHODS: Quality of life was assessed before and after the procedure using the psychological general wellbeing index (PGWB), the McMaster health index (MHI), and a visual analogue scale for cardiac symptoms. Nine of the patients also underwent symptom limited exercise tests and echocardiography to assess left ventricular systolic function. RESULTS: The procedure allowed a reduction in antiarrhythmic drug treatment (p < 0.01). PGWB and symptom scores improved (p < 0.01) but the MHI score did not change. Left ventricular systolic function and exercise capacity were unchanged. CONCLUSIONS: Atrioventricular node ablation and implantation of a DDDR/MS pacemaker is effective treatment for refractory paroxysmal atrial fibrillation, producing improved quality of life while allowing a reduction in drug burden. The popularity of the treatment is justified, but further studies are needed to determine optimum timing of intervention. (+info)
Fetal tachycardias: management and outcome of 127 consecutive cases.
(14/11504)
OBJECTIVE: To review the management and outcome of fetal tachycardia, and to determine the problems encountered with various treatment protocols. STUDY DESIGN: Retrospective analysis. SUBJECTS: 127 consecutive fetuses with a tachycardia presenting between 1980 and 1996 to a single tertiary centre for fetal cardiology. The median gestational age at presentation was 32 weeks (range 18 to 42). RESULTS: 105 fetuses had a supraventricular tachycardia and 22 had atrial flutter. Overall, 52 fetuses were hydropic and 75 non-hydropic. Prenatal control of the tachycardia was achieved in 83% of treated non-hydropic fetuses compared with 66% of the treated hydropic fetuses. Digoxin monotherapy converted most (62%) of the treated non-hydropic fetuses, and 96% survived through the neonatal period. First line drug treatment for hydropic fetuses was more diverse, including digoxin (n = 5), digoxin plus verapamil (n = 14), and flecainide (n = 27). The response rates to these drugs were 20%, 57%, and 59%, respectively, confirming that digoxin monotherapy is a poor choice for the hydropic fetus. Response to flecainide was faster than to the other drugs. Direct fetal treatment was used in four fetuses, of whom two survived. Overall, 73% (n = 38) of the hydropic fetuses survived. Postnatally, 4% of the non-hydropic group had ECG evidence of pre-excitation, compared with 16% of the hydropic group; 57% of non-hydropic fetuses were treated with long term anti-arrhythmics compared with 79% of hydropic fetuses. CONCLUSIONS: Non-hydropic fetuses with tachycardias have a very good prognosis with transplacental treatment. Most arrhythmias associated with fetal hydrops can be controlled with transplacental treatment, but the mortality in this group is 27%. At present, there is no ideal treatment protocol for these fetuses and a large prospective multicentre trial is required to optimise treatment of both hydropic and non-hydropic fetuses. (+info)
Cardiac autoimmunity in HIV related heart muscle disease.
(15/11504)
OBJECTIVE: To assess the frequency of circulating cardiac specific autoantibodies in HIV positive patients with and without echocardiographic evidence of left ventricular dysfunction. SUBJECTS: 74 HIV positive patients including 28 with echocardiographic evidence of heart muscle disease, 52 HIV negative people at low risk of HIV infection, and 14 HIV negative drug users who had all undergone non-invasive cardiac assessment were studied along with a group of 200 healthy blood donors. RESULTS: Cardiac autoantibodies detected by indirect immunofluorescence (serum dilution 1/10) were more common in the HIV positive patients (15%), particularly the HIV heart muscle disease group (21%), than in HIV negative controls (3.5%) (both p < 0.001). By ELISA (dilution 1/320), abnormal anti-alpha myosin autoantibody concentrations were found more often in HIV patients with heart muscle disease (43%) than in HIV positive patients with normal hearts (19%) or in HIV negative controls (3%) (p < 0.05 and p < 0.001, respectively). Anti-alpha myosin autoantibody concentrations were greater in HIV positive patients than in HIV negative controls, regardless of cardiac status ((mean SD) 0.253 (0.155) v 0.170 (0.076); p = 0.003). In particular the mean antibody concentration was higher in the HIV heart muscle disease patients (0.291 (0.160) v 0.170 (0.076); p = 0.001) than in HIV negative controls. On follow up, six subjects with normal echocardiograms but raised autoantibody concentrations had died after a median of 298 days, three with left ventricular abnormalities at necropsy. This compared with a median survival of 536 days for 21 HIV positive patients with normal cardiological and immunological results. CONCLUSIONS: There is an increased frequency of circulating cardiac specific autoantibodies in HIV positive individuals, particularly those with heart muscle disease. The data support a role for cardiac autoimmunity in the pathogenesis of HIV related heart muscle disease, and suggest that cardiac autoantibodies may be markers of the development of left ventricular dysfunction in HIV positive patients with normal hearts. (+info)
Relationship between mucosal levels of Helicobacter pylori-specific IgA, interleukin-8 and gastric inflammation.
(16/11504)
Mucosal IgA is important in local immune defence. Helicobacter pylori induces a specific IgA response in antral mucosa, but its immunopathology is unknown. Interleukin-8 (IL-8) has been suggested to be important in H. pylori-induced inflammation. Current information on the relationship between H. pylori-induced IgA and mucosal inflammation is limited. To investigate possible associations between mucosal-specific IgA, the toxinogenicity of H. pylori, mucosal levels of IL-8 and gastric inflammation, 52 endoscoped patients were studied. These comprised 28 patients with peptic ulcer and 24 with non-ulcer dyspepsia. Of these patients, 38 had H. pylori infection: 28 with peptic ulcer and 10 with non-ulcer dyspepsia. Antral biopsies were taken for histology, H. pylori culture and measurement of mucosal levels of IL-8 (pg/mg) and specific IgA (A450x1000) by ELISA. Mucosal H. pylori IgA was detectable in 35 out of 38 patients with H. pylori infection, with a median (interquartile) level of 220 (147, 531) units. There was no significant difference in mucosal levels of the IgA antibodies between patients infected with cytotoxin-positive or cagA-positive strains of H. pylori and those with toxin-negative or cagA-negative strains. The IgA levels in those patients with severe neutrophil infiltration were lower than in those with mild or moderate infiltration (P<0.05). There was a weak inverse correlation between antral mucosal IgA and IL-8 in infected patients (r=-0.36; P=0.04). H. pylori infection induced a significant local mucosal IgA response in most infected patients. The level of IgA antibodies does not appear to be correlated with the toxinogenicity of H. pylori. However, patients with severe active inflammation appear to have decreased levels of IgA. An inverse correlation between mucosal IL-8 and IgA may suggest that IL-8-induced inflammation compromises the mucosal IgA defence and renders the mucosa susceptible to further damage. (+info)