Biomedical subjects

J V Jones

Publications and source records attributed to J V Jones.

At least 37 records · Page 2Linked to original sources

PubMed1997

Reduction in external K causes increased action potential shortening in ventricular myocytes from the spontaneously hypertensive rat.

OBJECTIVES: (1) To study the effect of low external K and combined low K plus low Mg on the action potential of hypertrophied left ventricular myocytes isolated from the spontaneously hypertensive rat (SHR) and cells from normotensive control rats (NCR). (2) To identify differences in the response of SHR and NCR ventricular myocytes to low K and low K plus low Mg that could contribute to the increased number of arrhythmias observed in hypertrophied hearts. METHODS: Cells were superfused with Tyrode's solution containing 6 mmol/l K and stimulated at 1 Hz. Action potentials were recorded using the patch clamp technique. The effect of low K (2.4 mmol/l) and combined low K plus low Mg (2.4 mmol/l K and nominally zero Mg) on the characteristics of the action potential was measured in nine SHR, eight Wistar-Kyoto rat and 5 Wistar rat cells. RESULTS: With 6 mmol/l K, the action potential was prolonged significantly in SHR cells at 50, 70, 90 and 95% repolarizations. Both low K and low K plus low Mg shortened the action potential significantly only at 70% repolarization in NCR cells. In contrast, both low K and low K plus Mg led to marked action potential shortening at 70 and 90% repolarizations in SHR cells (P < 0.01) and also at 50 and 95% repolarizations (P < 0.05). Combined low K plus low Mg produced no additional effect on the action potential shape either in SHR or in NCR cells compared with that produced by low K alone. Although in SHR cells low K and combined low K plus low Mg produced a greater shortening of the action potential, which extended across a longer period of repolarization, a significant prolongation of the action potential still remained with low K at 50 and 95% repolarizations in SHR cells compared with that in NCR cells. CONCLUSIONS: Low K shortened the action potential both in NCR and in SHR cells but had a much greater effect on the action potential shape in SHR cells. Low K attenuated the difference in action potential shape between SHR and NCR by reducing the longer plateau observed in SHR cells. Combined low K plus low Mg exerted an effect on the action potential shape similar to that of low K alone in all cells. This increased shortening of the action potential produced by low K in SHR cells might be relevant to the increased incidence of arrhythmias associated with left ventricular hypertrophy, perhaps by shortening the wavelength of excitation and encouraging re-entrant arrhythmias, or by increasing the heterogeneity of repolarization within the ventricle.

Action Potentials↗

PubMed1996

Low magnesium enhances the pro-arrhythmic effect of low potassium in the hypertrophied rat heart but not in the normal rat heart.

OBJECTIVES: To investigate the influence of external magnesium on wall stress-induced arrhythmias and to establish whether early cardiac hypertrophy affects the sensitivity of the heart to these arrhythmias. METHODS: We used a modified isolated working heart model to compare hypertrophied hearts from the spontaneously hypertensive rat (SHR) with hearts from normotensive control rats from the Wistar and Wistar-Kyoto strains. Young rats (aged 137.9 +/- 2.04 days mean +/- SEM) were used to ensure left ventricular hypertrophy uncomplicated by fibrosis and cardiac failure. Arrhythmias were induced by 20 s increases in ventricular afterload during which the electrocardiogram was recorded. RESULTS: In control experiments SHR hearts showed a significantly greater arrhythmic response than did normotensive control rat hearts during perfusion with low-potassium (2.4 mmol/l) solutions. Concomitant low magnesium (0.4 mmol/l) perfusion significantly increased the arrhythmic response to 2.4 mmol/l potassium in SHR hearts but had no effect on arrhythmias in normotensive control rat hearts. With low magnesium, the number of ventricular premature beats was increased in SHR hearts compared with that in normotensive control rat hearts during perfusion with 4.2 and 2.4 mmol/l potassium. In addition, perfusion with low magnesium and 2.4 mmol/l potassium led to an increase in the complexity of arrhythmias, ventricular tachycardia occurring in nine of 10 SHR hearts but in only two of six normotensive control rat hearts. CONCLUSIONS: There is a synergistic effect of low magnesium and low potassium on wall-stress-induced arrhythmia in the SHR heart. An analogous effect might be important in patients with hypertension and left ventricular hypertrophy, in whom systolic blood pressure is frequently labile, leading to wide fluctuations in ventricular wall stress; combined potassium and magnesium depletion is a common complication of antihypertensive treatment.

Animals↗

PubMed1996

Testicular adrenal rest tissue in congenital adrenal hyperplasia: findings at Gray-scale and color Doppler US.

PURPOSE: To study the ultrasound (US) features of scrotal adrenal rest tissue in congenital adrenal hyperplasia (CAH). MATERIALS AND METHODS: Gray-scale and color Doppler US examinations were performed of scrotal masses in eight patients. The masses were evaluated for size, location, echogenicity, sound attenuation, and vascularity. RESULTS: Seventeen intratesticular masses and one extratesticular mass were examined. All were hypoechoic except for one intratesticular mass that contained hyperechoic areas. Six masses demonstrated sound attenuation. The mediastinum testis was found in the center of 11 of the 17 intratesticular masses. At color Doppler US, six masses were hypervascular, seven were isovascular, and five were hypovascular relative to the normal testicle. All intratesticular masses contained vascular structures that entered them from the normal testis without change in course or caliber. Eleven masses showed a spoke-like pattern of converging vessels. CONCLUSION: The US features of scrotal adrenal rests assist diagnosis of CAH.

Adolescent↗

PubMed1996

A preliminary study of flutamide, testolactone, and reduced hydrocortisone dose in the treatment of congenital adrenal hyperplasia.

Treatment outcome in congenital adrenal hyperplasia is often suboptimal due to hyperandrogenism, treatment-induced hypercortisolism, or both. As a new approach, we hypothesized that the effects of androgen could be blocked by an antiandrogen (flutamide) and an inhibitor androgen to estrogen conversion (testolactone), thus allowing the hydrocortisone dose to be reduced. We conducted a short term pilot study in 12 children with congenital adrenal hyperplasia in a randomised cross-over open design to determine whether flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone are more effective than hydrocortisone and fludrocortisone treatment in normalizing linear growth, weight gain, and bone maturation. Each regimen was administered for 6 months, with a 3-month washout period, consisting of hydrocortisone and fludrocortisone treatment, between regimens. Compared to hydrocortisone and fludrocortisone treatment, the regimen of flutamide, testolactone, reduced hydrocortisone dose (from 12.9 to 7.9 mg/m2 day), and fludrocortisone produced an increase in plasma 17-hydroxyprogesterone levels (P < 0.05) and a decline in urinary cortisol (P < 0.01), linear growth rate (-0.9 +/- 0.5 vs. 1.4 +/- 0.6 SD U; P = 0.003), weight velocity (-0.80 +/- 4.0 vs 0.6 +/- 0.4 SD U; P = 0.01), and bone maturation (0.6 +/- 0.6 vs. 1.4 +/- 0.9 yr bone age/yr chronological age; P = 0.02). Although no important adverse effects were observed, the known potential for flutamide-induced hepatotoxicity made frequent monitoring essential. We conclude that the regimen of flutamide, testolactone, reduced hydrocortisone does, and fludrocortisone improve the short term control of growth and bone maturation in children with congenital adrenal hyperplasia. Long term studies are required to determine whether this approach can improve these children's growth and development.

17-alpha-Hydroxyprogesterone↗

PubMed1995

Is ventricular wall stress rather than left ventricular hypertrophy an important contributory factor to sudden cardiac death?

Sudden cardiac death comprises a significant proportion of cardiac mortality in Western society. Left ventricular hypertrophy has been identified by many authors as a possible risk factor for sudden cardiac death, however, left ventricular hypertrophy develops in response to external stimuli on the heart as a means of normalizing wall stress. It is possible that the fundamental abnormalities in wall stress, rather than the left ventricular hypertrophy itself, pose the increased risk of sudden death. Left ventricular hypertrophy, the consequence of raised wall stress, is easy to measure and easy to study and it is understandable why this parameter should have received more attention. Wall stress by contrast is difficult to measure, and worse, is variable throughout the ventricle so that it cannot be measured in a single quantifiable figure. As a consequence, only a limited amount of attention has been paid to wall stress as a possible trigger mechanism for cardiac arrhythmia. However, there is evidence from both basic and clinical research to suggest that raised wall stress may be a risk factor for sudden cardiac death and cardiac arrhythmia. This review discusses the evidence for and against left ventricular hypertrophy and wall stress as risk factors for sudden cardiac death, and also presents recent evidence that left ventricular hypertrophy in isolation can protect the heart against the arrhythmogenic effects of raised wall stress.

Death, Sudden, Cardiac↗

PubMed1995

EMD 57033 enhances arrhythmias associated with increased wall-stress in the working rat heart.

1. EMD 57033 produces a positive inotropic effect by increasing the sensitivity of cardiac muscle myofilaments to calcium. Since the elevation in intracellular calcium produced by conventional inotropic compounds is thought to be arrhythmogenic, it is hoped that compounds such as EMD 57033 may increase cardiac output without exacerbating arrhythmias in patients with cardiac failure. This is the first study to examine whether EMD 57033 influences the susceptibility of the heart to ventricular arrhythmias. 2. We used the isolated working rat heart to investigate the effect of EMD 57033 on wall-stress-induced ventricular arrhythmia. Arrhythmias were induced by increases in ventricular afterload, and the effect of 2 mumol/l EMD 57033 on ventricular arrhythmias was investigated. The effect of 2 mumol/l EMD 57033 on contractility and arrhythmias was also assessed in the presence of different levels of perfusate calcium. 3. EMD 57033 was positively inotropic in the working rat heart, but it also produced a reversible increase in wall-stress-induced ventricular arrhythmia. The incidence of both ventricular ectopics and complex arrhythmias such as ventricular tachycardia were significantly increased by EMD 57033. Arrhythmias increased progressively as the level of perfusate calcium was raised within the physiological range. 4. The mechanism by which EMD 57033 increases wall-stress-induced arrhythmia is unclear, but it seems unlikely to be directly due to elevation of intracellular calcium. Further studies of the arrhythmogenic profile of this novel compound are required in a variety of models to assess its suitability and safety as a potentially therapeutic compound in heart failure.

Animals↗

PubMed1995

Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients.

We identify and describe clinical findings in hypocomplementemic urticarial vasculitis syndrome (HUVS), an uncommon to rare illness related to systemic lupus erythematosus (SLE). A patient with recurrent, idiopathic urticaria-like lesions was diagnosed as having HUVS if a lesional biopsy showed leukocytoclastic vasculitis, the serum C1q was markedly decreased, and antibody to C1q was detected in the patient's serum. The clinical characteristics, serologic findings, and outcome of patients who met these criteria were determined from prospective and retrospective data, including hospital and office records, patient interviews, previously banked serum samples, and freshly drawn sera. Eighteen patients with HUVS were identified, and high incidences of angioedema, ocular inflammation, glomerulonephritis, and obstructive pulmonary disease were found. Renal and lung biopsies showed mesangial or membranoproliferative glomerulonephritis and severe pulmonary emphysema without vasculitis. Pulmonary function was measured in 17 patients, 11 of whom had dyspnea. All dyspneic patients had moderate to severe airflow obstruction, which progressed in all 11 and subsequently improved in only 1. Six of these 11 patients died of respiratory failure, 1 underwent lung transplantation, and 3 of the remaining 4 have moderately severe to life-threatening respiratory insufficiency. Treatment did not appear to alter the progression of obstructive lung disease. In contrast, renal insufficiency improved with treatment in 2 of 2 patients. Angioedema, ocular inflammation, obstructive lung disease, and glomerulonephritis appear to be common in HUVS, and lung disease causes substantial morbidity and mortality. The pathogenesis of HUVS may involve humoral autoimmunity, although it is not clear how autoimmunity would participate in development of obstructive lung disease. Cigarette smoking appears to be a risk factor for fatal lung disease in HUVS. All patients with HUVS should be made aware of this possibility and should be advised, encouraged, and helped to avoid tobacco smoke.

Adult↗

PubMed1995

Immunomodulating effects of synchronised plasmapheresis and intravenous bolus cyclophosphamide in systemic lupus erythematosus.

Recent studies have suggested that synchronised plasmapheresis and intravenous pulse cyclophosphamide therapy reduce disease activity in SLE patients. The aim of the present study was to examine the immunomodulating effects of this therapy and compare it with changes seen with cyclophosphamide alone. Four patients with active SLE were studied. Two were treated with synchronised therapy and two received cyclophosphamide only for up to 26 weeks. Disease activity was measured by the SLE disease activity index (SLEDAI). Immunological studies were performed immediately prior to each treatment. Patients in both treatment groups improved as reflected by a fall in mean SLEDAI scores: synchronised therapy 33.5 to 11; cyclophosphamide only 13.5 to 4.5. Following synchonised therapy only there was a prompt and sustained increase in the mean percentage of CD8+ cells (20.8 to 54.8) which resulted in a fall in the CD4:CD8 ratio (1.95 to 0.62). With both treatment modalities there was a fall in the proportion of CD20+ cells (B lymphocytes) (synchronised therapy 10.5 to 3.2; cyclophosphamide only 5.6 to 2.2). However, only synchronised therapy resulted in a fall in the in vitro production of immunoglobulins which was unchanged or increased following cyclophosphamide alone. These results suggest that although both treatment modalities are efficacious in the treatment of active SLE they produce different immunomodulatory effects. Thus, both therapies reduce the number of circulating B lymphocytes whereas synchronised therapy also modifies cellular immunity by promoting the emergence of a phenotypic suppressor T lymphocyte population.

Adjuvants, Immunologic↗

PubMed1995

Requirement of beta 2 glycoprotein I as cofactor in the binding for IgM and IgA anticardiolipin antibodies.

OBJECTIVE: To determine if IgM and IgA anticardiolipin (aCL) antibodies require beta 2 glycoprotein I (beta 2-GPI) as a cofactor for antibody binding. METHODS: Sera were selected from 7 patients with systemic lupus erythematosus (SLE), 6 of whom had high IgM and 6 high IgA aCL antibody binding. Control sera were obtained from 2 healthy individuals with no aCL antibodies. Serum proteins were initially separated by sepharose CL6B get filtration chromatography, and IgM was further purified by affinity chromatography with mannan binding protein. IgA was isolated from CL6B filtrate by jacalin lectin affinity chromatography. Levels of beta 2-GPI in the immunoglobulin preparations were determined by antigen capture ELISA: Anticardiolipin antibody binding IgM and IgA was examined by ELISA with and without the addition of beta 2-GPI (10 micrograms/ml) or 4% normal human serum and expressed in optical density units (OD). RESULTS: beta 2-GPI was required as a cofactor for IgM aCL antibody binding in 4 to 6 patients with SLE. In these, antibody binding to cardiolipin increased from (mean +/- SEM) 0.10 +/- 0.01 TO 1.06 +/- 0.22 (p = 0.005) with the addition of beta 2-GPI. For IgA, 5 of 6 patients with SLE demonstrated a requirement of beta 2-GPI as a cofactor. Antibody binding increased from 0.27 +/- 0.05 to 1.77 +/- 0.35 (p = 0.003) with the addition of beta 2-GPI. CONCLUSION: beta 2-GPI is required as a cofactor for IgM and IgA aCL antibody binding.

Antibodies, Anticardiolipin↗

PubMed1995

Antiphospholipid antibodies in a healthy population: methods for estimating the distribution.

OBJECTIVE: To determine the distribution of antibodies to cardiolipin (IgG, IgM and IgA) in a healthy population. To classify subjects according to a cutpoint in order to determine what level of antibody measurement would yield 95% specificity. METHODS: Antiphospholipid (aPL) antibodies were measured using a conventional ELISA technique, with isotype specific antibody, to determine levels of IgG, IgM and IgA binding to cardiolipin. The subjects were 282 Red Cross blood donors, 82 undergraduate medical and nursing students, and 13 laboratory volunteers. RESULTS: The distribution of aPL antibodies measured in units of optical density is significantly skewed, while the distribution of aPL antibodies measured on the log scale is nearly symmetric. Neither distribution is normally distributed. There was no evidence that aPL antibodies differed significantly by age (up to age 50) or sex. We estimate the 90th, 95th, and 99th percentiles for IgG, IgM and IgA antibodies for the optical densities and binding indices. CONCLUSION: For 95% specificity we conclude that an adjusted IgG optical density above 0.386, an adjusted IgM optical density above 0.301, or an adjusted IgA optical density above 0.085 be considered positive.

Adult↗

PubMed1995

Wall stress induced arrhythmia is enhanced by low potassium and early left ventricular hypertrophy in the working rat heart.

OBJECTIVE: The aim was to investigate the effect of lowering external potassium on the sensitivity of the normal and hypertrophied rat heart to arrhythmias induced by increases in ventricular wall stress. METHODS: The isolated working heart model was used to compare hypertrophied hearts from the spontaneously hypertensive rat (SHR) with hearts from normotensive control rats (NCR) from the Wistar and Wistar-Kyoto strains. Young animals [131.5(SEM 0.64) days] were used to ensure uncomplicated left ventricular hypertrophy. Arrhythmias were induced by 20 s increases in ventricular wall stress. The ECG was recorded and the arrhythmic response of each heart was compared during perfusion with Tyrode solutions containing [K] 6, 4.8, 3.6, and 2.4 mM. RESULTS: Hypertrophied SHR hearts showed a significantly greater arrhythmic response than control hearts at all levels of afterload increase when perfused with [K] 3.6 and 2.4 mM (t test P < 0.05 and P < 0.01). Both the number and complexity of arrhythmias were increased in the SHR hearts; ventricular tachycardia occurred in 10/12 compared with 4/12 control hearts whereas ventricular fibrillation occurred in 5/12 hearts but in none of the control hearts. CONCLUSIONS: At higher levels of [K] the sensitivity of SHR and normal hearts to wall stress induced arrhythmias is similar. However, as [K] is lowered to 3.6 mM or below, hypertrophied hearts show a greatly enhanced response to increases in ventricular wall stress. They develop a larger number of ventricular ectopics and more complex ventricular arrhythmias when compared to normal hearts. This may be of relevance to arrhythmic sudden death in hypertensive patients in whom left ventricular hypertrophy, potassium depletion, and blood pressure lability is common. Excessive fluctuations in systolic pressure and therefore ventricular wall stress could provide a powerful arrhythmic stimulus in hypertensive patients with left ventricular hypertrophy, even before ischaemia, cardiac failure, or extensive extracellular fibrosis have developed.

Animals↗

PubMed1994

A faster twitch contraction of soleus in the spontaneously hypertensive rat is partly due to changed fibre type composition.

Contractile properties and fibre type composition of slow-twitch soleus muscles from spontaneously hypertensive rats (SHR) were compared with those from a control normotensive strain (Wistar-Kyoto, WKY). Male rats aged around 100 days were used, and muscle tension was recorded isometrically in vitro. Tetanic tension was reduced by about 15% in SHR; this decrease was highly significant when tension was expressed relative to muscle cross-sectional area. Twitch contraction and relaxation were 12-15% faster in SHR. There were no differences in the rate of rise of tension of either tetani or twitches, but the relaxation of tetanic tension was 17% faster in SHR. Twitch:tetanus ratios were 20% smaller in SHR. Histochemistry showed that SHR muscles had a threefold higher proportion of fast type II fibres compared to WKY. There were no significant changes in the contractile properties of the fast-twitch extensor digitorum longus (EDL) muscles of SHR compared with WKY. Whilst the higher proportion of type II fibres could account for some of the contractile changes in SHR soleus muscles, the lack of any difference in the rate of rise of twitch and tetanic tension is not consistent. The faster rate of relaxation of both twitch and tetanus in SHR suggests that a higher rate of removal of calcium, either from the myofilaments or from the cytoplasm, may be an important factor in causing the changes in SHR soleus. The faster relaxation may be compared with a similar change reported in SHR cardiac myocytes.

Animals↗

PubMed1994

Factors affecting length of hospitalization in a rheumatic disease unit.

OBJECTIVE: To assess factors influencing length of stay in a 12-bed rheumatic disease unit of a university associated teaching hospital with secondary and tertiary care responsibilities for a geographically broad referral base. METHODS: Patient discharges over a 12-month period were studied and divided into 3 categories. RESULTS: In Category 1, 167 patients with a mean age of 47.12 had a hospital stay of 1-14 days. Within this group was a subgroup of 30 patients with systemic lupus erythematosus, mean age of 30.13 receiving iv pulse cyclophosphamide who had multiple admissions. Their omission elevated the mean age to 50.87. In Category 2, 81 patients with a mean age of 59, had a hospital stay of 15-28 days and in Category 3, 24 patients with a mean age of 50.9 were hospital stay of 15-28 days and in Category 3, 24 patients with a mean age of 50.9 were hospitalized more than 29 days. Principal diagnosis, major complications of disease, complications of procedure and treatment and concurrent nonrheumatologic pathologies were analyzed for each group. The presence of a large number of comorbid pathologies in Groups 1 and 2 relate to the tertiary referral nature of the practice. Category 2, the group with the higher mean age had more treatment related complications in the form of adverse reactions to 2nd line agents and nonsteroidal antiinflammatory drugs. The 24 patients in Category 3 showed an equal sex distribution and are noted for the presence of infectious agent arthritis, requiring longterm iv antibiotics, both as a principal diagnosis, and as a complication of other pathologies. Vasculitis as a complication of preexisting disease and as a principal diagnosis was also a feature of this group. CONCLUSION: Length of stay above the 14 day mean relates to disease severity and serious complications such as vasculitis or joint sepsis requiring prolonged treatment.

Adolescent↗

PubMed1993

Investigation of the mechanisms underlying the increased contraction of hypertrophied ventricular myocytes isolated from the spontaneously hypertensive rat.

OBJECTIVE: The aim was to investigate the cellular mechanisms responsible for the increased contraction of left ventricular myocytes isolated from the spontaneously hypertensive rat (SHR). METHODS: Single myocytes were isolated enzymatically from the left ventricles of SHR, Wistar-Kyoto (WKY), and Wistar rats. WKY and Wistar myocytes were used as normotensive controls. Cytoplasmic calcium was measured with Fura-2 and contraction was measured optically. Membrane potential was measured with microelectrodes and cells were voltage clamped to measure the amplitude of L-type calcium current (iCa). RESULTS: Under action potential conditions, SHR myocytes had a larger calcium transient and an increased sarcoplasmic reticular calcium content compared to normotensive myocytes. There was no detectable difference in the resting cytoplasmic calcium concentration between SHR and control myocytes. SHR myocytes also had a prolonged action potential compared to normotensive cells. However, when cells were voltage clamped and short pulses of 120 ms duration were applied (a similar duration of depolarisation to the action potential), the difference in the calcium transient or contraction between SHR and normotensive myocytes was abolished. SHR myocytes had an unchanged amplitude of ICa in comparison to control myocytes, and there was no detectable difference in the myofilament response to calcium between SHR and control myocytes. CONCLUSIONS: (1) Hypertrophied SHR myocytes stimulated with action potentials had an increased calcium transient compared to normotensive cells. The greater calcium transient in the SHR cells is likely to be a major factor responsible for their increased contraction. (2) SHR myocytes had a prolonged action potential in comparison to normotensive cells. (3) The amplitude of ICa and myofilament response to calcium were unchanged in SHR myocytes, suggesting that these factors do not play a role in the increased contraction of these cells. (4) Since the difference between SHR and control cells was abolished by voltage clamping the cells to prevent the difference of action potential, it is unlikely that an alteration of intrinsic mechanisms in SHR myocytes is responsible for their increased contraction. Rather, it suggests that the prolonged action potential of SHR myocytes plays a important role in causing their increased calcium transient and contraction. Our results indicate that the prolonged action potential in SHR cells results in an increased calcium content of the sarcoplasmic reticulum, which leads to a greater sarcoplasmic reticular calcium release upon stimulation and an increased contraction.

Action Potentials↗

PubMed1993

Cognitive impairment and autoantibodies in systemic lupus erythematosus.

Nervous system involvement in systemic lupus erythematosus (SLE) includes a wide array of manifestations some of which have been associated with specific autoantibodies. These include reactivity to surface neuronal and lymphocyte antigens, ribosomal P and cardiolipin. The aim of the present study was to examine the association between cognitive abnormalities and these autoantibodies in an unselected female population of SLE patients. Using a battery of standardized neuropsychological tests, cognitive impairment was identified in 15/70 (21%) SLE patients compared to 1/25 (4%) patients with rheumatoid arthritis and 1/23 (4%) healthy subjects (P = 0.04). Circulating antineuronal antibodies were measured by indirect immunofluorescence using human neuroblastoma cell lines IMR-6 and SK-N-SH. Lymphocytotoxic antibodies were measured by microcytotoxicity. Antibodies to ribosomal P and cardiolipin were measured by ELISA. Antineuronal antibodies were detected in 34%, lymphocytotoxic antibodies in 47%, anti-P antibodies in 17% and anticardiolipin antibodies in 24% of patients. In the cognitively impaired and unimpaired SLE patients there was no significant difference in the prevalence of antineuronal antibodies (33 vs 35%), lymphocytotoxic antibodies (40 vs 50%), anti-P antibodies (20 vs 17%) or anticardiolipin antibodies (7 vs 29%). The titre and isotype of autoantibodies were also similar in both groups. These results suggest that autoantibodies which have previously been associated with nervous system manifestations of SLE are not likely to be directly involved in the pathogenesis of cognitive dysfunction.

Antibodies, Anticardiolipin↗

PubMed1993

The electrophysiological characteristics of hypertrophied ventricular myocytes from the spontaneously hypertensive rat.

OBJECTIVE: Previous studies on multicellular preparations have shown that hypertrophied cardiac muscle from the spontaneously hypertensive rat (SHR) has a prolonged action potential. The first aim of the present study was to determine whether the action potential of isolated left ventricular myocytes was similarly prolonged and to study the underlying membrane currents that might be responsible. The second aim was to evaluate the L-type calcium current amplitude of SHR myocytes, as we have recently shown that they have an increased contraction and an increase in the calcium trigger entering via the L-type calcium channel might be one possible mechanism for this. METHODS: The electrophysiological characteristics of left ventricular myocytes isolated from the SHR were compared with those from normotensive control rats. Action potentials were recorded with microelectrodes. Cells were voltage-clamped and the membrane currents elicited by steps to different potentials were analysed. Blockers of potassium and calcium currents were used to reveal the contribution made by these currents to net membrane currents. RESULTS: SHR myocytes had prolonged action potentials. The action potential duration of SHR myocytes at 90% repolarization was found to be longer, although at 20% and 50% repolarization no difference was found. There was no difference in the resting membrane potential between SHR and control myocytes. Using a voltage clamp we studied the L-type calcium current and potassium currents. The major change in SHR myocytes was a decrease in the magnitude (normalized to the membrane capacitance) of the inward rectifier potassium current elicited by negative potentials. There was no detectable difference in either the transient outward or delayed rectifier potassium currents. We also found no difference in the magnitude, time course or voltage dependence of L-type calcium current in hypertrophied SHR myocytes. CONCLUSIONS: First, the action potential of SHR myocytes was prolonged compared with control myocytes. Secondly, the main change in SHR myocytes was that pulses to negative potentials elicited a lower inward rectifier potassium current. A reduction in the density of inward rectifier channels might play a role in prolonging the SHR action potential, since a lower outward repolarizing current will flow through inward rectifier potassium channels during the SHR action potential repolarization. Thirdly, there was no difference in L-type calcium current density or time course between SHR and control myocytes. Thus, a change in L-type calcium current probably plays no role in causing the prolonged SHR action potential or the increased contraction of hypertrophied SHR ventricular myocytes. Finally, the prolonged action potential in SHR myocytes may itself be one factor responsible for the increased contraction of these cells.

Action Potentials↗

PubMed1992

The paradoxical role of left ventricular hypertrophy in wall stress-related arrhythmia.

OBJECTIVE: To investigate the interrelationship between arrhythmias provoked by acute pressure changes, and the presence of left ventricular hypertrophy and electrolyte imbalances. DESIGN: An isolated working rat heart model was used in a prospective comparison of the effects of acute pressure changes in hypertensive and normotensive hearts during perfusion with perfusate containing differing electrolyte compositions. SETTING: An experimental laboratory study. STUDY MATERIALS: Forty-four rat hearts (20 hypertensive, 24 normotensive). INTERVENTIONS: Hearts were subjected to sudden pressure changes of varying sizes during perfusion with two different electrolyte solutions and the arrhythmias provoked were recorded. MAIN OUTCOME MEASURES: The size of the pressure change necessary to provoke arrhythmias, and the amount and severity of arrhythmias provoked by equivalent-sized pressure changes. RESULTS: During perfusion with normal electrolyte concentrations, no hypertrophied hearts developed arrhythmia compared with more than half of the normal hearts during equivalent-sized pressure changes, and a much larger pressure increase was necessary to produce any arrhythmia in the hypertrophied hearts. During perfusion with cation-depleted perfusate, arrhythmias significantly increased in both groups of hearts, but the pattern was reversed; more than half of the hypertrophied hearts compared with none of the normal hearts developed ventricular tachycardia during equivalent-sized pressure increases, whilst the minimum pressure change necessary to provoke arrhythmia became significantly smaller in the hypertrophied hearts compared with the normal hearts. CONCLUSIONS: Left ventricular hypertrophy plays a paradoxical role in the development of arrhythmias in this model. It appears to protect the heart from developing arrhythmias in response to sudden pressure changes when electrolyte concentrations are normal. However, it also seems to lead to a marked increase in the sensitivity of the myocardium to pressure changes during perfusion with low levels of potassium and magnesium. Under these conditions, potentially fatal arrhythmias can be readily provoked by relatively small pressure changes. These results may be of importance for the management of hypertension and may provide insight into some of the mechanisms underlying sudden death in hypertension. The findings may also be of relevance to other cardiac diseases associated with ventricular hypertrophy or abnormal wall stress.

Animals↗

PubMed1992

Contractile properties of ventricular myocytes isolated from spontaneously hypertensive rat.

OBJECTIVE: To determine whether there are any differences in contractile properties of individual cardiac myocytes isolated from the spontaneously hypertensive rat (SHR) in comparison with its normotensive control--the Wistar-Kyoto (WKY) rat. DESIGN: The effects of cardiac hypertrophy upon individual myocytes from SHR have not been studied previously. Isolated cardiac myocytes do not suffer from a number of problems inherent in experiments on multicellular preparations. METHODS: Seven SHR and eight WKY animals were studied. Age-matched animals were compared at 60 and 100 days old. Ventricular myocytes were isolated enzymatically. Myocyte length and width was measured. The cells were stimulated with extracellular electrodes and contraction was measured optically. The effects of altering stimulus rate and extracellular calcium concentration upon contraction were studied. RESULTS: SHR myocytes were found to be significantly wider than WKY myocytes. The contraction (i.e. unloaded cell shortening) of SHR myocytes at stimulation rate of 0.3, 1, 2 and 3 Hz was significantly increased. The time-course of contraction was altered, with SHR myocytes having an increased maximal velocity of shortening and relaxation. The response to changes in bathing calcium was similar in both strains. CONCLUSIONS: Individual cardiac myocytes isolated from SHR have an increased contraction. This indicates that cardiac hypertrophy, at least in the early stages, is a protective adaptation allowing the heart to overcome the increased afterload resulting from hypertension.

Animals↗