Biomedical subjects

B Silke

Publications and source records attributed to B Silke.

At least 37 records · Page 2Linked to original sources

PubMed2000

Beta-adrenoceptor modulation and heart rate variability--the value of scatterplot measures of compactness.

This article compares different methods of scatterplot analysis to assess the optimal methodology. The scatterplot (Poincaré plot) is a nonlinear heart rate variability method where a "return map" is constructed by plotting each current cycle against the previous beat (RR vs. RR(n-1)). Geometric analysis of the scatterplot allows short-term and long-term heart rate variability (HRV) to be assessed. A three-dimensional construct is also possible, where the third axis represents the density of values, at any given RR vs. RR(n-1) intersection. Topological methods of analysis can compute the density distribution function or compactness of a dataset. Scatterplots that otherwise appear very similar in the two-dimensional plot may be clearly differentiated using this approach. Correct characterization may improve the ability of scatterplot analysis to predict outcomes in cardiovascular disease. We have assessed two computational approaches that take account of scatterplot density, namely, the heart rate variability fraction and the compactness measure. Scatterplots were constructed from three double-blind and randomized placebo controlled studies conducted in a total of 49 healthy subjects. Single oral doses of antagonists (atenolol 50 mg [beta-1], propranolol 160 mg [beta-1 and beta-2], and ICI 118,551 25 mg [beta-2]) or agonists (xamoterol 200 mg [beta-1], salbutamol 8 mg [beta-2], prenalterol 50 mg [beta-1 and beta-2], and pindolol 10 mg [mainly beta-2] of the cardiac beta-adrenoceptor were studied. Salbutamol, pindolol, and xamoterol increased compactness and reduced HRV fraction significantly compared with placebo. However, when compared with the more conventional scatterplot parameters, these newer density methods were found to be less discriminating. An alternative approach to improve scatterplot discrimination, using the combination of several scatterplot features, is under investigation.

Adrenergic beta-Agonists↗

PubMed2000

Breath isoprene during acute respiratory exacerbation in cystic fibrosis.

Patients with cystic fibrosis (CF) experience a combination of chronic systemic oxidative stress, generation of free radicals in the lungs due to a hyperimmune response and a diminished ability to scavenge free radicals secondary to malabsorption and increased consumption. The authors asked the question, "Does breath isoprene content reflect systemic oxidative stress?" The study involved 12 CF patients and 12 matched healthy controls. The patients were sampled during acute respiratory exacerbation (increased respiratory symptoms, reduction in forced expiratory volume (FEV1) of >10%, and a decision to treat with intravenous antibiotics) and after two weeks of antibiotic treatment. Blood samples were examined for markers of oxidative stress. Breath samples were analysed for isoprene content. Malondialdehyde (MDA), erythrocyte membrane polyunsaturated fatty acids, protein sulphydryls and protein carbonyls all showed evidence of increased oxidative stress which was moderated by antibiotic treatment. Breath isoprene production rate was significantly lower in patients during exacerbation than in controls with a mean difference of-39 (95% confidence interval (CI) -11-57) pmol.min.kg(-1) and increased to normal values following treatment (mean change 63 (95% CI 42-84) pmol.min.kg(-1)). In conclusion, breath isoprene cannot be considered a reliable marker of oxidative stress.

Adult↗

PubMed2000

Inotropic response to endothelin-1, isoprenaline and calcium in cardiomyocytes isolated from endotoxin treated rats: effects of ethyl-isothiourea and dexamethasone.

1. The contractile effects of endothelin-1, isoprenaline and extracellular calcium were assessed on ventricular cardiomyocytes isolated from lipopolysaccharide-treated rats. The involvement of nitric oxide was investigated using dexamethasone (in vivo) and ethyl isothiourea (in vitro). 2. Male Wistar rats (n=70) were injected with either saline (1 ml kg(-1)) or lipopolysaccharide (LPS; 5 mg kg(-1)) alone, or following pre-treatment with dexamethasone (DEX+LPS; 5 mg kg(-1)). Ventricular cell shortening was recorded using a video edge detection system, and concentration-response relationships were established for endothelin-1, isoprenaline and calcium, in the absence or presence of ethyl isothiourea (ETU; 10 microM). iNOS expression was assessed using reverse transcription-polymerase chain reaction. 3. iNOS mRNA expression was greater (P<0.001) in the LPS (iNOS/GAPDH ratio: 0.90+/-0.09) treated group compared to saline (iNOS/GAPDH ratio: 0.36+/-0.02). Baseline contractile amplitude was reduced (P<0.05) in the LPS (7.3+/-0.2 microm) and DEX+LPS groups (6.7+/-0.3 microm) compared to saline (8. 0+/-0.2 microm). 4. The concentration-dependent contractile response to endothelin-1 was attenuated (P<0.05) in the LPS group compared to saline (maximum change: 0.45+/-0.2 vs 1.8+/-0.2 microm). Neither ETU nor dexamethasone improved contractile function in the LPS-treated animals. 5. The concentration-dependent increase in the contractile response to isoprenaline was attenuated in the LPS-treated group compared to saline (P<0.05; maximum change: 1.7+/-0.4 vs 3.1+/-0.4 microm). This effect was reversed by ETU (maximum change: 3.7+/-0.6 microm). Pre-treatment with dexamethasone prevented a significant fall in contraction amplitude (maximum change: 2.4+/-0.4 microm). 6. The contractile response to calcium was reduced (P<0.05) in the LPS group compared to saline (maximum change: 8.7+/-0.6 vs 10.7+/-0.8 microm). Neither ETU nor dexamethasone restored contractile function in the LPS-treated group. 7. In conclusion, a nitric oxide-mediated inhibitory pathway is not responsible for the diminished contractile response to either endothelin-1 or extracellular calcium, but contributes to the hyporesponsiveness to isoprenaline in lipopolysaccharide treated rats.

Animals↗

PubMed2000

Endothelin(A) receptor subtype mediates endothelin-induced contractility in left ventricular cardiomyocytes isolated from rabbit myocardium.

Endothelin (ET)-1 is a potent positive inotropic agent, the effects of which are mediated by increases in cytosolic Ca(2+) in the myocardium. The object of this study was to examine 1) the influence of ET(A) and ET(B) receptor subtypes, and 2) the role of the phospholipase C (PLC) pathway in mediating ET-1-induced contraction. Left ventricular cardiomyocytes were isolated from the hearts of New Zealand White rabbits (2-2.5 kg) by the use of Langendorff perfusion with collagenase. Cardiomyocyte function was examined during unloaded, electrically stimulated (0.5 Hz) contractions with a video-edge detection system. ET-1 increased cell shortening with greater potency than ET-3: mean EC(50) values were 1.1 x 10(-11) and 2.6 x 10(-10) M, respectively. With the same order of potency, ET-1 and ET-3 increased (P <.05) velocity of cell shortening. The ET(A) receptor-selective antagonist ABT-627 shifted the ET-1-induced cell shortening response curve to the right with a pA(2) value of 10.3. The ET(B) receptor-selective antagonist A-192621 (10(-8)-10(-7) M) did not alter the concentration-response of ET-1. Moreover, the ET(B) receptor-selective agonist sarafotoxin 6c did not have any effect on cell shortening over the concentration range of 10(-11) to 10(-7) M. ET-1 in the presence of the PLC inhibitor U-73122 did not alter the contractile amplitude. However, ET-1 in the presence of the protein kinase C inhibitor bisindolylmalemide increased cell shortening. These findings indicate that 1) the ET(A) receptor subtype, and not the ET(B) receptor subtype, mediates the positive inotropic effect of ET-1, and 2) the response of ET-1 is mediated by a PLC pathway, but not through protein kinase C, in ventricular cardiomyocytes isolated from rabbit myocardium.

Animals↗

PubMed1999

Forearm reactive hyperaemia is not mediated by nitric oxide in healthy volunteers.

AIMS: To determine the role of nitric oxide (NO) in forearm reactive hyperaemia in healthy human subjects. METHODS: Ten healthy subjects aged 19-34 years underwent brachial artery cannulation. Forearm circulatory arrest was achieved by means of an upper arm cuff inflated to 200 mmHg for 5 min. The blood flow responses during reactive hyperaemia were measured using venous occlusion plethysmography following a 10 min intra-arterial infusion of 8 micromol min-1 N-monomethyl L-arginine (L-NMMA) and following matching placebo administered in random order. Results were analysed by repeated measures anova and t-tests. RESULTS: L-NMMA resulted in a significant reduction of basal forearm blood flow indicating inhibition of basal NO release (P=0.005). There was no significant difference between the blood flow responses during reactive hyperaemia following L-NMMA and placebo (P=0.97). CONCLUSIONS: Nitric oxide production does not make a significant contribution to the vasodilatation associated with reactive hyperaemia in the human forearm.

Adult↗

PubMed1999

Evaluation of the effect on heart rate variability of a beta2-adrenoceptor agonist and antagonist using non-linear scatterplot and sequence methods.

AIMS: To examine the impact on heart rate variability (HRV), of agonism or antagonism at the cardiac beta2-adrenoceptor in healthy volunteers, using standard time-domain summary statistics and non-linear methods (scatterplot and quadrant analysis). METHODS: Under double-blind and randomised conditions (Latin square design), 17 normal volunteers received placebo, salbutamol (beta2-adrenoceptor partial agonist), ICI 118,551 (specific beta2-adrenoceptor antagonist), or salbutamol plus ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22.30 h, with HRV assessed from the sleeping heart rates. RESULTS: Salbutamol reduced the long-term (SDNN: 135 ms [120, 156], SDANN: 107 ms [89, 124]) time-domain indicators of HRV compared with placebo (SDNN: 39 [24, 55], SDANN 42 [29, 56], [mean difference [95% confidence intervals of difference]]). Alone, ICI 118,551 did not effect HRV, but in combination blocked the actions of salbutamol. Scatterplot length (944 ms [869, 1019]) and area (222*10(3) ms2 [191, 253]) were reduced by salbutamol compared with placebo; (length difference (164 [98, 230]) and area difference 59 [36, 83]). Scatterplot width (dispersion) was lower at both low (width RR-1 25% salbutamol 277 ms [261, 293]: salbutamol minus placebo 14 ms [0, 28]) and high (width 75% salbutamol 417 [391, 443]: salbutamol minus placebo 41 [20, 62]) heart rates. ICI 118,551 alone did not alter scatterplot parameters but in combination blocked the effect of salbutamol. Cardiac acceleration episodes (i.e. consecutive deltaRR and deltaRRn+1 shorten) were increased following salbutamol 7288 [6089, 8486] compared with placebo -1890 [-2600, -1179]; the beat-to beat difference (deltaRRn+1) was reduced after salbutamol compared with the other treatments. ICI 118,551 did not effect acceleration episodes but reduced the effect of salbutamol when used in combination. CONCLUSIONS: Agonism at the cardiac beta2-adrenoceptor in healthy volunteers with salbutamol altered autonomic balance towards sympathetic dominance; this re-balancing was blocked by ICI 118,551 given in combination with salbutamol. However antagonism at the beta2-adrenoceptor with ICI 118,551 alone did not significantly alter the HRV. The beta2-adrenoceptor modulates HRV in healthy volunteers; the implications of agonism and antagonism at the beta2-adrenoceptor in cardiovascular disease states warrants further investigation.

Adrenergic beta-Agonists↗

PubMed1999

Heart-rate variability effects of beta-adrenoceptor agonists (xamoterol, prenalterol, and salbutamol) assessed nonlinearly with scatterplots and sequence methods.

Full antagonists of the cardiac beta-adrenoceptor improve heart-rate variability (HRV) in humans; however, partial agonism at the beta2-adrenoceptor has been suggested to decrease HRV. We therefore studied the HRV effects of some partial agonists of the beta1- and beta2-adrenoceptors in normal volunteers. Under double-blind and randomised conditions (Latin square design), eight healthy volunteers received placebo; xamoterol, 200 mg (beta1-adrenoceptor partial agonist); prenalterol, 50 mg (beta1- and beta2-adrenoceptor partial agonist); salbutamol, 8 mg (beta2-adrenoceptor partial agonist); ICI 118,551, 25 mg (selective beta2-adrenoceptor antagonist); and combinations of each partial agonist with ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22:30 h with HRV assessed from the overnight sleeping heart rates. HRV was determined by using standard time-domain summary statistics and two nonlinear methods, the Poincaré plot (scatterplot) and cardiac sequence analysis. On placebo, the sleeping heart rate decreased significantly, between 2 and 8 h after dosing. The heart rate with ICI 118,551 was unaltered. Xamoterol, prenalterol, and salbutamol increased the sleeping heart rate. ICI 118,551 blocked the heart-rate effects of salbutamol, attenuated those of prenalterol, but did not influence the xamoterol heart rate. The scatterplot (Poincaré) area was reduced by beta1-adrenoceptor (xamoterol), beta2-adrenoceptor (salbutamol), and combined beta1- and beta2-adrenoceptor (prenalterol) agonism. A reduction in scatterplot length followed salbutamol, prenalterol alone, and prenalterol in combination with ICI 118,551. The geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR intervals. At higher heart rates (i.e., 25 and 50% of RR scatterplot length), dispersion was decreased after xamoterol, prenalterol, and prenalterol/ICI 118,551. Cardiac sequence analysis (differences between three adjacent beats; deltaRR vs. deltaRRn+1) assessed the short-term patterns of cardiac acceleration and deceleration; four patterns were identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). Cardiac acceleration or deceleration episodes (i.e., number of times deltaRR and deltaRRn+1 were altered in the same direction) were increased after salbutamol and prenalterol. In conclusion, partial agonism at either the cardiac beta1-adrenoceptor (xamoterol), beta2-adrenoceptor (salbutamol), and beta1- plus beta2-adrenoceptors (prenalterol) altered the autonomic balance toward sympathetic dominance in healthy volunteers; blockade of the beta2-adrenoceptor with the highly selective beta2-antagonist ICI 118,551 prevented the effects of salbutamol on HRV, attenuated the HRV effects of prenalterol, but had no effect on the actions of xamoterol. Agonism at both the beta1- and beta2-adrenoceptor reduced HRV in healthy subjects; the implications for the preventive use of the beta-adrenoceptor compounds in cardiovascular disease warrant further investigation.

Adrenergic beta-Agonists↗

PubMed1999

Epidemiology and treatment of left ventricular hypertrophy in the elderly.

Left ventricular hypertrophy (LVH) is an important independent risk factor for cardiovascular disease and is associated with an increased risk of ventricular dysrhythmia, coronary artery disease, myocardial infarction, stroke, heart failure and peripheral artery disease. The prevalence of LVH increases strongly with advancing age and, consequently, the prevention or reduction of LVH should be an important consideration in the older age-group. This review summarises current knowledge on LVH and discusses management issues with particular reference to the elderly. Evidence suggests that antihypertensive treatment can reverse or prevent LVH. There have been few studies of LVH in the elderly, but since age does not appear to be a factor in the regression of LVH, results of studies among younger hypertensive patients can be extrapolated to the elderly population. Meta-analyses of clinical studies have not established conclusively that angiotensin-converting enzyme inhibitors and calcium antagonists are necessarily more effective than diuretics and beta-adrenoceptor antagonists in reducing LVH.

Aged↗

PubMed1999

Oxidative stress during acute respiratory exacerbations in cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis experience chronic systemic oxidative stress. This is coupled with chronic inflammation of the lung involving bronchial polymorphonuclear neutrophil accumulation and activation. We hypothesised that, during periods of acute respiratory exacerbation, free radical activity and consequent damage would be most marked and that intensive treatment of the infection would result in improvement towards values found during stable periods. METHODS: Plasma and red blood cells were collected from 12 healthy normal volunteers and from 12 patients with cystic fibrosis with an acute respiratory exacerbation (increased respiratory symptoms, reduction in forced expiratory volume in one second (FEV1) of more than 10%, and a decision to treat with intravenous antibiotics). Further samples were collected from patients following two weeks of treatment. Samples were analysed for inflammatory markers, markers of free radical damage, and aqueous and lipid phase scavengers. RESULTS: During respiratory exacerbations FEV1 and forced vital capacity (FVC) were lower than in controls (mean differences -2.82 (95% CI -2.12 to -3.52) and -3. 79 (-3.03 to -4.55) l, respectively) but improved following treatment (mean change 0.29 (95% CI 0.18 to 0.40) and 0.33 (0.23 to 0.43) l, respectively). Inflammatory markers during exacerbations were significantly higher in patients than in controls with the following mean (95% CI) differences: C reactive protein (CRP), 46 (17 to 75) g/l; neutrophil elastase alpha1-antiprotease complexes (NEAPC), 4.4 (1.77 to 7.07) mg/l; white cell count (WCC), 5.3 (4.7 to 5.9) x 10(9)/l. These markers decreased significantly following treatment with the following mean (95% CI) changes: CRP -26 (-10 to -42) g/l; NEAPC -3.1 (-1.3 to -4.9) mg/l; WCC -1.5 (-1.3 to -1.7) x 10(9)/l. Malondialdehyde (MDA) as a marker of free radical activity was significantly higher in patients during exacerbations than in controls with a mean (95% CI) difference of 193 (107 to 279) which improved with treatment (mean change -56 (95% CI -28 to -84) nmol/mmol cholesterol). Red blood cell polyunsaturated fatty acids were significantly lower in patients than in controls with a mean difference of -4.4(95% CI -2.6 to -6.2) moles percent, but did not improve significantly after treatment. Protein carbonyls during exacerbations were not different from controls but did increase with treatment compared with levels during the exacerbation (mean change 0.39 (95% CI 0.11 to 0.67) micromol/g protein). Aqueous and lipid phase scavengers in patients during exacerbations were significantly lower than in controls with the following mean (95% CI) differences: ascorbate, -19.0 (-2.7 to -35.3) micromol/l; sulphydryls, -122 (-77 to -167) micromol/l; retinol, -237 (-47 to -427) nmol/mmol cholesterol; beta-carotene, -52.8 (-11.8 to -93.8) nmol/mmol cholesterol; luteine, -50.4 (-10.4 to -90.4) nmol/mmol cholesterol; lycopene, -90.1 (-30.1 to -150.1) nmol/mmol cholesterol. Treatment resulted in improvement with the following mean (95% CI) changes: sulphydryls, 50 (32 to 68) micromol/l; retinol, 152 (47 to 257) nmol/mmol cholesterol; alpha- and beta-carotene, 0.6 (0.0 to 1.2) and 7.6 (0.0 to 15.2) nmol/mmol cholesterol, respectively; alpha-tocopherol, 839 (283 to 1405) nmol/mmol cholesterol; and lycopene, 8.2 (0.0 to 16.2) nmol/mmol cholesterol. CONCLUSIONS: Abnormalities of markers of inflammation, free radical activity, and radical scavengers were significantly more extreme during acute respiratory exacerbations and showed improvement with treatment. The need to provide protection from inflammation and free radical damage should therefore be dynamic and related to the inflammatory and oxidative processes.

Acute Disease↗

PubMed1998

Stimulation of L-type Ca2+ current by the endothelin receptor A-selective antagonist, BQ-123 in ventricular cardiomyocytes isolated from the rabbit myocardium.

BQ-123 is extensively used as an antagonist at endothelin (ET) receptors, having selectivity at the ET(A) receptor subtype. In this study, the effects of BQ-123 per se on action potentials, L-type calcium currents, and potassium currents, were examined in ventricular cardiomyocytes isolated from adult, male, New Zealand White rabbits, using the patch-clamp technique. BQ-123 (1 microM) increased (P < 0.02) the duration of the action potential to 267 +/- 36 ms from a control duration of 228 +/- 30 ms. BQ-123 did not have any effect on the inward rectifier or transient outward potassium currents, but increased (P < 0.02) the L-type Ca2+ current to -2.76 +/- 0.3 nA from a control value of -2.45 +/- 0.28 nA. The increases in both duration of the action potential and L-type Ca2+ current were reversed upon washout (233 +/- 28 ms and -2.32 +/- 0.31 nA, respectively) and were not different from the control values in the absence of BQ-123. In contrast, the endothelin receptor antagonists, BQ-788, PD155080 and PD145065 (1-10 microM) did not affect the L-type Ca2+ current. These results indicate that, unlike PD155080, BQ-788 and PD145065, the conventional ET(A) receptor-selective antagonist, BQ-123, exerts a unique positive effect on the L-type Ca2+ current in ventricular cardiomyocytes isolated from rabbit myocardium. The mechanism of action of BQ-123, therefore, is not confined to ET receptor antagonism.

Action Potentials↗

PubMed1998

The use of angiotensin converting enzyme inhibitors in general practice--appropriate or inappropriate?

AIMS: To evaluate the pattern of prescribing of angiotensin-converting enzyme (ACE) inhibitors in general practice, related to the primary clinical diagnosis and concomitant medication. DESIGN: A descriptive survey of general practitioners' prescribing habits, presumptive diagnosis and patient demography over a period of 2 weeks in April 1994. SETTING: A stratified quota sample of 22 practices in Northern Ireland. RESULTS: The major clinical indication for the use of ACE inhibitors was essential hypertension (61.5%) with only a minority usage (19.9%) in congestive heart failure. Co-prescription of drugs with potential for interaction with angiotensin-converting enzyme inhibitors was not uncommon (16.7%). Of the 353 patients with a diagnosis of congestive heart failure, only 64 (18.1%) were receiving ACE inhibitors. The dosages used were lower than recommended for this indication. A significantly higher proportion of elderly patients with heart failure were prescribed hypnotic drugs (14.7% versus 8.3%; p<0.001) and had the co-existence of insomnia (11.8% versus 6.9%; p<0.001) compared to patients without heart failure. CONCLUSIONS: ACE inhibitors were underused in the treatment of congestive heart failure, and were often prescribed in suboptimal dosages. The frequent concurrent prescription of hypnotics and the co-existence of insomnia in heart failure may reflect this therapeutic strategy.

Journal Article↗

PubMed1998

Heart rate variability effects of an agonist or antagonists of the beta-adrenoceptor assessed with scatterplot and sequence analysis.

There is evidence that the processes regulating heart rate variations reflect non-linear complexity and show 'chaotic' determinism. Data analyses using non-linear methods may therefore reveal patterns not apparent with conventional statistical approaches. We have consequently investigated two non-linear methods, the Poincaré plot (scatterplot) and cardiac sequence (quadrant) analysis, and compared these with standard time-domain summary statistics, during a normal volunteer investigation of an agonist and antagonists of the cardiac beta-adrenoceptor. Under double-blind and randomized conditions (Latin square design), 12 normal volunteers received placebo, celiprolol (beta 1- and beta 2-adrenoceptor partial agonist), propranolol (beta 1- and beta 2-adrenoceptor antagonist), atenolol (beta 1-adrenoceptor antagonist) and combinations of these agents. Single oral doses of medication (at weekly intervals) were administered at 22:30 hours with sleeping heart rates recorded overnight. The long (SDNN, SDANN) and short-term (rmsSD) time-domain summary statistics were reduced by celiprolol--effects different from the unchanged or small increases after atenolol and propranolol alone. The Poincaré plot was constructed by plotting each RR interval against the preceding RR interval, but unlike previous descriptions of the method, an automated computer method, with a high level of reproducibility, was employed. Scatterplot length and area were reduced following celiprolol and different from the small increases after propranolol and atenolol. The geometric analysis of the scatterplots allowed width assessment (i.e. dispersion) at fixed RR intervals. Differences between the drugs were confined to the higher percentiles (i.e. 75% and 90% of scatterplot length: low heart rate). The long-term time-domain statistics (SDNN, SDANN) correlated best with scatterplot length and area whereas the short-term heart rate variability (HRV) indices (rmsSD), pNN50) correlated strongly with scatterplot width. Cardiac sequence analysis (differences between three adjacent beats; delta RR vs delta RRn+1) assessed the short-term patterns of cardiac acceleration and deceleration, four patterns are identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). A running count of events by quadrant, together with the average magnitude of the differences was computed. The beta-adrenoceptor partial agonist celiprolol increased acceleration sequences. The duration of beat-to-beat difference shortened after celiprolol; this contrasted with increased duration of beat-to-beat difference after propranolol and atenolol. These results demonstrated a shift towards sympathetic dominance after the beta-adrenoceptor partial agonist celiprolol contrasting in parasympathetic dominance after the beta-adrenoceptor antagonists propranolol and atenolol. These non-linear methods appear to be valuable tools to investigate HRV in health and in cardiovascular disease and to study the implications of alterations in autonomic control during therapeutic intervention.

Adrenergic beta-Agonists↗

PubMed1998

Evaluation of the effect on heart rate variability of some agents acting at the beta-adrenoceptor using nonlinear scatterplot and sequence methods.

There is evidence that the processes regulating heart rate variability (HRV) reflect nonlinear complexity and show "chaotic" determinism. Data analyses using nonlinear methods may therefore reveal patterns not apparent with the standard methods for HRV analysis. We have consequently used two nonlinear methods, the Poincaré plot (scatterplot) and cardiac sequence (quadrant) analysis, in addition to the standard time-domain summary statistics, during a normal volunteer investigation of the effects on HRV of some agents acting at the cardiac beta-adrenoceptor. Under double-blind and randomized conditions (Latin square design), 25 normal volunteers received placebo, salbutamol 8 mg (beta 2-adrenoceptor partial agonist), pindolol 10 mg (beta 2-adrenoceptor partial agonist), or atenolol 50 mg (beta 1-adrenoceptor antagonist). Single oral doses of medication (at weekly intervals) were administered at 22:30 hours, with sleeping heart rates recorded overnight. The long-term (SDNN, SDANN) and short-term (rMSSD) time-domain summary statistics were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo. The reductions in both SDNN and SDANN were greater after salbutamol 8 mg compared with pindolol 10 mg. The reduced HRV after pindolol 10 mg differed from the increased HRV following atenolol 50 mg. The Poincaré plot, constructed by plotting each RR interval against the preceding RR interval, was measured using a reproducible computerized method. Scatterplot length and area were reduced by salbutamol 8 mg and increased by atenolol 50 mg compared with placebo; scatterplot length and area were lower after pindolol 10 mg compared with atenolol 50 mg. Geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR intervals. At the higher percentiles (i.e., 90% of scatterplot length: low HR), salbutamol 8 mg reduced and atenolol 50 mg increased dispersion; at lower percentiles (i.e., 10%, 25%, and 50% length), atenolol 50 mg and pindolol 10 mg increased dispersion compared with placebo and salbutamol 8 mg. Cardiac sequence analysis (differences between three adjacent beats; delta RR vs. delta RRn + 1) was used to assess the short-term patterns of cardiac acceleration and deceleration. Four patterns were identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). Cardiac acceleration episodes (i.e., number of times delta RR and delta RRn + 1 were both changed) were increased in quadrants -/- and +/+ following pindolol 10 mg and salbutamol 8 mg; the beat-to-beat difference (delta RRn + 1) was reduced after salbutamol 8 mg compared with the three other groups. These results demonstrated a shift towards sympathetic dominance (beta-adrenoceptor partial agonist salbutamol 8 mg) or parasympathetic dominance (beta 1-adrenoceptor antagonist atenolol 50 mg); pindolol 10 mg exhibited HR-dependent effects, reducing HRV at low but increasing variability at high prevailing heart rates. These nonlinear methods appear to be valuable tools to investigate HRV in health and to study the implications of perturbation of HRV with drug therapy in disease states.

Adrenergic beta-Agonists↗

PubMed1998

Accuracy and precision of blood pressure determination with the Finapres: an overview using re-sampling statistics.

The Finapres non-invasive blood pressure (BP) monitor uses the method of Penaz to indirectly record the arterial waveform; studies on its accuracy have suggested little systematic bias vs intra-arterial pressure (IAP) but substantial variability. Inconsistency between studies, in respect of the magnitude, direction and variance of bias, was described in the validation studies against the direct IAP. We have employed a novel re-sampling statistical method to combine the data from 20 published studies; a robust overall estimate of the accuracy and precision of the Finapres was thereby obtained. Based on 449 patients and 4490 re-samples, the average Finapres systolic bias (IAP- Finapres) was 2.2 mm Hg (s.d.+/-12.4) with limits of agreement (bias+/-2 s.d.) of -22.6 and 26.9 mm Hg. The average precision was 12.1 mm Hg (s.d.+/-8.4). The Finapres diastolic bias was -0.3 mm Hg (s.d.+/-7.9) with the limits of agreement of -16.1 and 15.5 mm Hg. The average precision was 7.6 mm Hg (s.d.+/-5.3). The average Finapres mean arterial pressure bias was 2.1 mm Hg (s.d.+/-8.6) with precision of 7.6 mm Hg (s.d.+/-5.3). The calculated percentage of Finapres systolic values expected to fall within +/-5 or +/-10 of the direct intra-arterial pressure was 35.9% and 73.1%, respectively. The calculated precision of the Finapres systolic pressure between 0-5 mm Hg was 1.6% and between 0-10 mm Hg 36.4%. The comparable values for Finapres diastolic BP for accuracy were 63.5% and 92.8% and for precision 23.1% and 79.2%. The Finapres device can provide an accurate estimate of diastolic and mean arterial pressure compared with the intra-arterial record; the apparent inaccuracy of the Finapres systolic pressure may have a physiological explanation. When the Finapres device is used in experimental or in clinical situations, then calibration against a reliable reference arterial pressure is desirable to obviate the possibility of an 'offset' error.

Blood Pressure Determination↗

PubMed1998

Receptor-mediated effects of endothelin on the L-type Ca++ current in ventricular cardiomyocytes.

The purpose of this study was to establish whether specific receptor subtypes are responsible for mediating the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on the L-type calcium current (ICa) using a number of receptor-selective antagonists, including PD155080 (ETA), BQ-788, RES-701 and IRL-1038 (ETB) and the ETA/ETB receptor-non-selective antagonist PD145065. Ventricular cardiomyocytes were isolated from adult New Zealand White rabbits using Langendorff perfusion with collagenase. ICa was recorded using a whole-cell patch-clamp technique. ET-1 decreased, whereas ET-3 increased, ICa at equimolar concentrations of 10 nM. The decrease in ICa produced by ET-1 was completely blocked by PD155080 and PD145065 (1 and 10 microM); however, ICa was increased upon washout of PD155080. Although the decrease in ICa produced by ET-1 was partially blocked by BQ-788 (1 and 10 microM), ET-1 in combination with either RES-701 (1 and 10 microM) or IRL-1038 (1 microM) produced a decrease in ICa similar to that produced by ET-1 alone. The increase in ICa by ET-3 was completely abolished by either BQ-788 or IRL-1038 (1 microM). These data indicate that the decrease in ICa produced by ET-1 in rabbit ventricular cardiomyocytes is mediated by the ETA receptor subtype, because PD155080 completely inhibited this response. The ETB receptor-selective antagonists RES-701 and IRL-1038 did not alter the decrease in current produced by ET-1, although the response was partially sensitive to BQ-788, which may lack receptor-subtype selectivity in these cells. In contrast, the increase in ICa produced by ET-3 was mediated by the ETB receptor subtype, because BQ-788 and IRL-1038 abolished this response.

Animals↗

PubMed1997

Characterisation of a cellular model of cardiomyopathy, in the rabbit, produced by chronic administration of the anthracycline, epirubicin.

The objective of this study was to assess the structural, mechanical and electrophysiological changes associated with chronic administration of epirubicin (Pharmorubicin), which is a cardiotoxic anthracycline antibiotic used in conventional cancer chemotherapy. New Zealand white rabbits (8 weeks) were treated with twice-weekly infusions of epirubicin (2 mg/kg) or saline for a period of 6 weeks, followed by a wash-out period of 2 weeks. Myocardial damage consistent with cardiomyopathy was observed in the epirubicin-treated animals; electron micrographs indicated myofibril loss together with separation of the intercalated disc and dilation of the sarcotubular system. Contractile function, as measured by mechanical shortening, action potentials and L-type Ca2+ currents were examined in ventricular cardiomyocytes, which were isolated by means of enzymatic dissociation using collagenase. There was an attenuation in the contractile response to isoprenaline in cardiomyocytes isolated from the hearts of epirubicin-treated rabbits compared to control rabbits. Cardiomyocytes isolated from epirubicin-treated rabbits had greater basal contractile amplitude (11.0+/-0.3 %dL, n=8) than control myocytes (8.2+/-0.3 %dL, n=9), but had similar maximum responses of 19.1+/-0.6 %dL, and 17.3+/-0.5 %dL, respectively, when stimulated with 1 microM isoprenaline. No differences were noted in the peak L-type Ca2+ current of myocytes isolated from the hearts of control and epirubicin-treated rabbits; however, in the latter, there was a prolongation of the action potential duration (396+/-25 ms) compared to that in controls (321+/-26 ms). These results demonstrate structural and mechanical alterations in ventricular cardiomyocytes which are compatable with a mild cardiomyopathy following chronic treatment with the anthracycline, epirubicin. The increase in basal contraction is likely to be due to more efficient coupling of electrical stimulation, and the depressed inotropic responsiveness following stimulation with isoprenaline indicates that there may be changes in cell membrane properties. Compared to control cardiomyocytes, cells isolated from the hearts of epirubicin-treated rabbits were more heterogeneous, with respect to cell dimensions, and had significantly different electromechanical properties.

Animals↗

PubMed1997

Reliability of blood pressure determination with the Finapres with altered physiological states or pharmacodynamic conditions.

The blood pressure waveform is modified on distal propagation by phenomena such as dispersion, reflection and the state of the arterial compliance. The consequent effects are amplification and narrowing of the wave, with an increased systolic, reduced diastolic and essentially unaltered mean blood pressure. The Finapres measures the peripheral pressure using the volume clamp principle; it has not been validated under altered physiological conditions and during pharmacodynamic interventions. We studied simultaneous Finapres and brachial blood pressures (using a conventional oscillometric sphygmomanometer-Vitalmap) in ten normal volunteers at rest, and during dynamic exercise and a cold pressor test. The effects of pharmacodynamic intervention were examined following beta-adrenoceptor blockade with propranolol (160 mg) or beta-adrenoceptor modulation with the beta-adrenoceptor partial agonist celiprolol (400 mg). The Finapres systolic pressure was significantly higher than the brachial value during all three test states. The difference between the systolic pressures measured by the two devices was shown to increase significantly during the cold pressor test, but not during dynamic (supine bicycle) exercise. The Finapres diastolic pressure was significantly higher than the Vitalmap value during exercise and the cold pressor test. The differences between the two methods increased significantly over time. Beta-adrenergic blockade with propranolol or modulation with celiprolol had no significant interaction with the pressure differences between the Finapres and Vitalmap techniques. The results would support the view that the Finapres can provide blood pressure information which is robust under most circumstances. Although this pharmacodynamic intervention did not alter the relationship between the peripheral and central blood pressure, it is important to note that this dynamic relationship is sensitive to circulatory loading conditions and wave transmission characteristics; it is possible that the Finapres could be less reliable in clinical settings where potent vasoactive agents were being administered.

Adrenergic beta-Antagonists↗

PubMed1997

Contrasting actions of celiprolol and metoprolol on cardiac performance in normal volunteers.

A double-blind, randomized, placebo-controlled comparison of metoprolol (50 mg) and celiprolol (200 mg) was undertaken in nine normal volunteers. Rest and exercise (supine bicycle) hemodynamics were assessed at 0, 2, 4, 6, and 8 hours following single oral doses of medication administered at weekly intervals. The influence of the ancillary pharmacological properties of metoprolol and celiprolol on cardiac pumping indices was assessed from heart rate and peak aortic acceleration (pkA-Exerdop). Following placebo, the heart rate and pkA increased progressively with exercise duration and workload. Following metoprolol 50 mg, the heart rate (-9.7 beat/min at 75 watts exercise) and pkA decreased. The blunting of acceleration was greater at higher exercise workloads (-6.7 m/sec2 at 75 watts exercise). Celiprolol reduced heart rate (-6.9 beat/min at 75 watts exercise) without a change in pkA. The heart rate/pkA relationship showed significant parallel displacement, downwards after metoprolol but upwards after celiprolol. Thus, for a given heart rate increment there was a greater decrease in pkA after metoprolol compared with celiprolol. The different ancillary pharmacological profiles of metoprolol and celiprolol resulted in contrasting hemodynamic profiles. The observed differences in the heart rate/pkA relationships may be attributable to the peripheral actions of these agents. The therapeutic relevance of the better maintained cardiac pumping indices on celiprolol for ischemic patients with impaired cardiac function warrants further investigation.

Adrenergic beta-Antagonists↗