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Biomedical subjects

P E Puddu

Publications and source records attributed to P E Puddu.

At least 19 recordsLinked to original sources
PubMed2006

Preconditioning effects of levosimendan in coronary artery bypass grafting--a pilot study.

BACKGROUND: The calcium sensitizer levosimendan protects against myocardial ischaemia and reperfusion injury in animal models. METHODS: The present pilot study investigated whether a short infusion before coronary artery bypass grafting (CABG) would protect the myocardium and improve postoperative haemodynamics. Twenty-four patients with stable angina undergoing elective CABG surgery were randomized to receive either placebo or levosimendan (24 microg kg(-1)) infused i.v. over a 10 min period just before placing the patient on cardiopulmonary bypass. RESULTS: Perioperative haemodynamic variables, concentrations of cardiac troponin I over the 48 h postoperative period, and clinical outcomes were assessed. There were no adverse effects related to levosimendan. Compared with control patients, levosimendan-treated patients had lower postoperative troponin I concentrations (P<0.05) and a higher cardiac index (P<0.05). CONCLUSION: Patients receiving a short infusion of levosimendan before CABG showed evidence of less myocardial damage, suggestive of a preconditioning effect. Larger outcome studies are thus indicated to confirm benefit.

Aged↗
PubMed2003

Twenty-five-year coronary mortality trends in the seven countries study using the accelerated failure time model.

The 'accelerated failure time model' (AFT) was tested in the 25-year experience of the Seven Countries Study, to describe the shape of hazard for coronary heart disease (CHD) mortality during long-term follow-up. Sixteen cohorts of men aged 40-59 at entry were enrolled in eight countries (USA, Finland, The Netherlands, Italy, Croatia, Serbia, Greece and Japan) for a total of 12,763 subjects. Risk factors were measured and CHD mortality data collected during 25 years. The AFT incorporating the Weibull survival distribution was applied to the pooled cohorts of each country, with CHD mortality as endpoint. Cumulative hazards and the annual hazard for CHD mortality were estimated during 25 years and compared among countries. The annual hazard for CHD in 25 years tended to reduce relatively or flatten out in the northern American and northern European countries, exponentially increased in Serbia and Japan, and increased moderately in the other countries of southern Europe. Positive correlations were found between the shape of the hazard curve and population mean risk factor changes (serum cholesterol and systolic blood pressure) observed during the first 10 years follow-up. The Japanese group was an outlier. The countries with the largest relative decline in the annual hazard function were the same where, during the same historical period, the largest decreases in official death rates from CHD were recorded and vice versa. The curve shape in the annual hazard for CHD mortality in different countries seems related to changes in mean levels of serum cholesterol and systolic blood pressure.

Adult↗
PubMed2001

Assessment of flow velocity reserve by transthoracic Doppler echocardiography and venous adenosine infusion before and after left anterior descending coronary artery stenting.

OBJECTIVES: We sought to evaluate whether coronary flow velocity reserve (CFR) (the ratio between hyperemic and baseline peak flow velocity), as measured by transthoracic Doppler echocardiography during adenosine infusion, allows detection of flow changes in the left anterior descending coronary artery (LAD) before and after stenting. BACKGROUND: The immediate post-stenting evaluation of CFR by intracoronary Doppler has shown mixed results, due to reactive hyperemia and microvascular stunning. Noninvasive coronary Doppler echocardiography may be a more reliable measure than intracoronary Doppler. METHODS: Transthoracic Doppler echocardiography during 90-s venous adenosine infusion (140 microg/kg body weight per min) was used to measure CFR of the LAD in 45 patients before and 3.7 +/- 2 days after successful stenting, as well as in 25 subjects with an angiographically normal LAD (control group). RESULTS: Adequate Doppler spectra were obtained in 96% of the patients. Pre-stent CFR was significantly lower in patients than in control subjects (diastolic CFR: 1.45 +/- 0.5 vs. 2.72 +/- 0.71, p < 0.01; systolic CFR: 1.61 +/- 1.02 vs. 2.41 +/- 0.68, p < 0.01) and increased toward the normal range after stenting (diastolic CFR: 2.58 +/- 0.7 vs. 2.72 +/- 0.75, p = NS; systolic CFR: 2.43 +/- 1.01 vs. 2.41 +/- 0.52, p = NS). Diastolic CFR was often damped, suggesting coronary steal in patients with > or =90% versus <90% LAD stenosis (0.86 +/- 0.23 vs. 1.69 +/- 0.43, p < 0.01). Coronary stenting normalized diastolic CFR in these two groups (2.45 +/- 0.77 and 2.64 +/- 0.69, respectively, p = NS), even though impaired diastolic CFR persisted in three of four patients with > or =90% stenosis. Stenosis of the LAD was better discriminated by diastolic (F = 49.30) than systolic (F = 12.20) CFR (both p < 0.01). CONCLUSIONS: Coronary flow reserve, as measured by transthoracic Doppler echocardiography, is impaired in LAD disease; it may identify patients with > or =90% stenosis; and it normalizes early after stenting, even in patients with > or =90% stenosis.

Adenosine↗
PubMed2001

Impact of the Gubbio population study on community control of blood pressure and hypertension. Gubbio Study Research Group.

BACKGROUND: Awareness and treatment of hypertension have markedly increased in the last 30 years in most parts of the world, but a satisfactory control of blood pressure is still infrequent OBJECTIVES: To describe trends in community control of hypertension and blood pressure levels in the small town of Gubbio, Italy. METHODS: Large samples of the populations (aged 30-79 years) were examined 6 years apart for measurement of blood pressure, other cardiovascular risk factors and knowledge, attitude and practice towards control of hypertension. Data were available from a total of 1125 men and 1445 women with two examinations and 1566 men and 1658 women with at least one examination. Two different definitions of hypertension were used (old definition: systolic blood pressure (SBP) > or = 160 mmHg or diastolic blood pressure (DBP) > or = 95 mmHg or use of antihypertensive drugs; recent definition: SBP > or = 140 mmHg or DBP > or =90 mmHg or use of anti-hypertensive drugs). RESULTS: Awareness, treatment and control of hypertension increased from one survey to the other, whatever definition of hypertension was used. Control rose from 41 to 63% (old definition) and from 12 to 24% (recent definition). In a 6-year period, the average population SBP declined 2-8 mmHg and DBP declined 2-3 mmHg depending on type of analysis, against an expected rise of 9 mmHg for SBP and 2 mmHg for DBP. These trends are partly explained by a marked decline in alcohol consumption and by more common and intensive anti-hypertensive treatment, while change in body mass index, which showed a slight but systematic increase, cannot be considered as a contributor to this trend. CONCLUSIONS: An epidemiological study has motivated a population group and its medical profession towards a better control of hypertension.

Adult↗
PubMed2001

Serum uric acid for short-term prediction of cardiovascular disease incidence in the Gubbio population Study.

OBJECTIVE: The Gubbio Study is an Italian population study measuring risk factors for and incidence of major cardiovascular diseases. This analysis investigates the association of serum uric acid with the incidence of coronary and cardiovascular events. METHODS: A population sample of 2469 men and women aged 35-74 years, free from major cardiovascular diseases and in whom serum uric acid was measured in 1983 along with other standard risk factors, were followed up for 6 years and the incidence of coronary heart disease (CHD) and all cardiovascular atherosclerotic (CVD) events, both fatal and non-fatal, was computed. Proportional hazards models were used for the prediction of these events. RESULTS: In six years 61 CHD hard criteria, 109 CHD any criterion and 149 CVD events were recorded. Age-adjusted rates per 1000 of the 3 event categories were computed in sex-specific quintiles (Q) of serum uric acid with 428 +/- 76 (Q5) and 198 +/- 42 (Q1) micromol/l, respectively. Although higher rates were seen in Q5 as compared to Q1 for all three first event categories considered (relative risks 6.2, 3.6 and 3.7, respectively), a statistically significant trend was seen only for CVD all criteria (t = 3.63, p < 0.036). These trends were borderline significant for CHD any criterion (t = 2.92, p < 0.06) and not significant for CHD hard criteria (t = 2.23, p < 0.11). In multivariate models, adjusted for 8 other risk factors, serum uric acid showed a statistically significant contribution to predict CVD incidence [relative risk (RR) for 92 micromol/l difference of 1.24 with 95% confidence intervals (CI) 1.05-1.45], whereas the statistical contribution to predict CHD any criterion (RR = 1.19 with CI 0.98-1.45) and CHD hard criteria (RR = 1.20 with CI 0.93-1.55) was not significant. Diuretic treatment and blood urea, as further confounders, were positively and significantly related to event incidence (RR ranging from 1.21 to 2.00) but serum uric acid maintained its independent and statistically significant role in the prediction of CVD events (RR = 1.18 with CI 1.00-1.39). Presence of specific treatments to lower serum uric acid levels (in 1.13% of the population), tested as final confounders, was not statistically contributory. CONCLUSIONS: Increased serum uric acid levels are independently and significantly associated with risk of CVD events in the 6-year follow-up of the Gubbio Study. Longer follow-up is needed before the contributory role of serum uric acid can be properly assessed to explain CHD incidence.

Adult↗
PubMed2000

Adenosine triphosphate-dependent potassium channel modulation and cardioplegia-induced protection of human atrial muscle in an in vitro model of myocardial stunning.

OBJECTIVES: Although adenosine triphosphate-dependent potassium channel openers have been shown to enhance cardioplegic protection in animal myocardium, there is a lack of data on human cardiac tissues. We aimed at determining, on human atrial muscle, whether adenosine triphosphate- dependent potassium channels are involved in protection caused by high-potassium cardioplegia and whether adenosine triphosphate-dependent potassium channel activation might improve cardioplegic protection in an in vitro model of myocardial stunning. METHODS: Human atrial trabeculae were obtained from adult patients undergoing cardiac operations. In an organ bath at 37 degrees C, the preparations were subjected to 60 minutes of hypoxia at a high stimulation rate either in Tyrode solution (control, n = 17) or in St Thomas' Hospital solution without additives (n = 6) or associated with 100 nmol/L bimakalim (n = 7) or 1 micromol/L glibenclamide (n = 7), followed by 60 minutes of reoxygenation and 15 minutes of positive inotropic stimulation with 1 micromol/L dobutamine. RESULTS: Atrial developed tension was reduced by hypoxia to 27% +/- 5% of baseline and incompletely recovered after reoxygenation to 38% +/- 7%, whereas dobutamine restored contractility to 74% +/- 7% of basal values. St Thomas' Hospital solution with or without bimakalim improved developed tension after reoxygenation and dobutamine (P <.0001 vs control), whereas glibenclamide inhibited these protective effects of cardioplegic arrest (P =.001 vs St Thomas' Hospital solution). After reoxygenation, the protective effect of bimakalim disappeared at a high pacing rate (400- and 300-ms cycle length) but recovered during dobutamine superfusion. CONCLUSIONS: Adenosine triphosphate-dependent potassium channels are likely involved in the cardioprotective effects of cardioplegia in human atrial trabeculae and adenosine triphosphate-dependent potassium channel activation with bimakalim used as an additive to cardioplegia enhanced protection.

Adenosine Triphosphate↗
PubMed2000

Comparison of the Framingham risk function-based coronary chart with risk function from an Italian population study.

AIMS: The aim is to compare the coronary risk chart published by the European Task Force for Prevention of Coronary Heart Disease and produced using a Framingham risk function, with a risk function derived from an Italian population study. METHODS AND RESULTS: Coronary risk function in this study was the result of longitudinal experience in an Italian middle-aged population of 1656 male subjects followed-up for 25 years. To comply with the Framingham equation the same risk factors (age, systolic blood pressure, total serum cholesterol and smoking habits), end-points (any possible coronary event including angina pectoris), and length of follow-up (10 years) were used, and the model (log-linear accelerated time failure model, accommodating the Weibull distribution) was similar. Comparisons were made computing the coronary risk for each cell of the coronary risk chart for men aged 40, 50 and 60 years. The Italian risk function produced highly significant coefficients for all four risk factors. Forty-four out of a total of 120 cells had a coronary risk of 20% or more in 10 years following the coronary risk chart, whereas this was reduced to four while using the Italian risk function (P<0.001). The Italian risk function largely underestimated the corresponding levels produced by the coronary risk chart and vice versa. CONCLUSION: The Framingham risk function-based coronary risk chart overestimates absolute coronary risk in countries characterized by a lower incidence of coronary events and should be used with caution.

Adult↗
PubMed2000

Coronary heart disease incidence in northern and southern European populations: a reanalysis of the seven countries study for a European coronary risk chart.

OBJECTIVE: A systematic reanalysis of 10 year coronary heart disease incidence data from the northern and the southern European cohorts of the seven countries study, to contribute indirectly to the production of a European coronary risk chart. DESIGN AND SETTING: Men aged 40-59 years at entry were studied in three northern European cohorts based in Finland and Netherlands (n = 2213); and in 10 southern European cohorts based in Italy, former Yugoslavia, and Greece (n = 5897). Multiple logistic models for the prediction of coronary deaths, coronary incidence (hard criteria), and coronary incidence (any criterion) were solved for the two geographical groups and their pool. Risk factors fed into the models were age, systolic blood pressure, serum total cholesterol, and cigarette smoking. RESULTS: 10 year coronary heart disease mortality and incidence were higher in northern than in southern Europe, with ratios around 2.65. Ratios among the three coronary heart disease manifestations were identical in the two cultural groupings. Coefficients of the multiple logistic models were similar and not significantly different between the two groupings. When applying the coefficients back to the same or the opposite population, the relative risk was large and similar in the different cultures. Relative risk was larger for more severe coronary heart disease manifestations. The absolute risk was overestimated when applying the northern European model to southern European populations and vice versa, with ratios of about 1.5 and 0.5, respectively. Coronary risk charts created to reproduce the shape of those incorporated in recent European guidelines confirmed the excess of absolute risk in the northern compared with the southern European cohorts, all else being equal. CONCLUSIONS: In theory, a more appropriate European coronary risk chart could be produced by adopting coefficients to correct for different background incidence rates in different cultures. Other coefficients could appropriately be used to transform mortality risk into incidence risk.

Adult↗
PubMed2000

Long-term time-related predictivity of coronary events as a function of a single measurement of serum cholesterol and systolic blood pressure.

OBJECTIVE: To study the time-related association of a single measurement of serum cholesterol and systolic blood pressure with the occurrence of a first coronary event in a population sample of middle-aged men. METHODS AND RESULTS: A single measurement of serum total cholesterol and systolic blood pressure (along with age, cigarette consumption, physical activity at work and body mass index as possible confounders) was made in 1,605 coronary disease-free men aged 40-59 belonging to the Italian rural cohorts of the Seven Countries Study. During 25 years of follow-up 353 men developed a first event, that is a coronary death (sudden or not), and definite or possible myocardial infarction. Twenty-five partitioned proportional hazards models were solved, one for each independent year of follow-up, to predict the risk of incident events. Single-year hazard functions, separately for serum cholesterol and systolic blood pressure, were cumulated and smoothed. The resulting curves showed a regularly increasing risk for coronary events. They fit straight lines, with large correlation coefficients for both serum total cholesterol (r = 0.99) and systolic blood pressure (r = 0.99). These slopes were similar to the coefficients estimated by a single proportional hazards model solved for all events during 25 years. CONCLUSION: A single measurement of serum total cholesterol and systolic blood pressure in middle aged-men maintains a regular and monotonic relationship with occurrence of a first coronary event during 25 years of follow-up.

Adult↗
PubMed2000

First risk functions for prediction of coronary and cardiovascular disease incidence in the Gubbio Population Study.

BACKGROUND: The Gubbio study is an Italian population study which measures the risk factors and incidence of major cardiovascular diseases. This analysis produces multivariate models for the prediction of cardiovascular end-points. METHODS: A population sample of 2,963 men and women aged 35-74, free from major cardiovascular diseases, was examined in 1983 with risk factor measurement, and a 6-year incidence was computed for coronary heart disease and all cardiovascular (atherosclerotic) events. Proportional hazards models were solved for the prediction of these events. RESULTS: Over a 6-year period, 74 hard criteria, and 126 any criterion coronary heart disease and 174 cardiovascular events were recorded. Multivariate models showed the predictive power of sex (relative risk ranging 1.63 to 2.60), age (relative risk for 5-year difference ranging 1.38 to 1.48), systolic blood pressure (relative risk for 20 mmHg difference ranging 1.17 to 1.27), HDL cholesterol (relative risk for a difference of 10 mg/dl ranging 0.73 to 0.81), non-HDL cholesterol (relative risk for 40 mg/dl difference ranging 1.15 to 1.27), cigarette smoking (relative risk for 10 cigarette difference ranging 1.21 to 1.28), and body mass index (relative risk for 3 units ranging 0.99 to 1.02). All coefficients were statistically significant except that for body mass index, they were larger for hard criteria coronary heart disease, and their magnitude was similar to that found in previous Italian population studies. CONCLUSIONS: Traditional cardiovascular risk factors predict coronary and cardiovascular events in another Italian population study confirming previous findings and similar predictive models.

Adult↗
PubMed2000

Twenty-five-year cardiovascular disease incidence among middle-aged men. Disease burden, time shape, predictors, risk probabilities.

BACKGROUND: This analysis aims at describing the 25-year experience in cardiovascular incidence in a sample of middle-aged men in rural Italy. METHODS: A total of 1712 men aged 40-59 years were examined in 1960 in two rural Italian cohorts belonging to the Seven Countries Study. Major risk factors were measured and a monitoring system for incidence of cardiovascular events was in operation for the next 25 years centered on the first event occurring within each subgroup of cardiovascular diseases. Data were modeled by the Weibull distribution incorporated in the accelerated failure time model. RESULTS: Among 1695 cardiovascular disease-free men at entry, 51.3% experienced at least one cardiovascular event, the first being a coronary heart disease (35.6%), a cerebrovascular disease (17.8%) or a peripheral artery disease (13.0%). Among all first events the most common was intermittent claudication (17.6%), followed by angina pectoris (16.6%). A proportion of 13% of all initial episodes was rapidly fatal, whereas 38 % of subjects developing a cardiovascular event died within the 25-year deadline. Age, cigarette smoking, diabetes, corneal arcus, serum cholesterol, systolic blood pressure, and vital capacity fed into the accelerated failure time model showed a statistically significant association with cardiovascular disease incidence (inverse for vital capacity). The same model provided the shape of hazard during the 25 years with major events continuing to appear in an increasing exponential fashion, while soft criteria events were less likely to appear as a first event in the late phase of follow-up. CONCLUSIONS: In middle-aged men 25-year incidence of cardiovascular diseases is high and more relevant compared to that of traditional hard criteria coronary heart disease that in the past has attracted almost exclusive interest.

Adult↗
PubMed1999

Cicletanine prevents the excitation-conduction blocks induced by terfenadine in ischemic myocardium.

Terfenadine, a histamine H(1) receptor antagonist, has been associated with clinical ventricular arrhythmias and in vitro excitation-conduction blocks, whereas anti-ischemic and antiarrhythmic effects have been shown with cicletanine, a prostacyclin generation stimulator. We aimed at determining in vitro if cicletanine can protect the ischemic myocardium from excitation-conduction blocks and specifically those induced by terfenadine. In a double-chamber bath, isolated guinea pig ventricular strips were partly exposed to normoxia and partly to ischemic, then reperfused, conditions, in the presence of 10 microM terfenadine, 10 microM indomethacin (prostacyclin generation blocker) or the solvent (dimethylsulfoxide 1:100, control) randomly allocated, and thus either in the absence (n=20) or presence (n=21) of 10 microM cicletanine during the total protocol duration. The multivariate Cox's model was used to predict the excitation-conduction block events and to assess the estimated survival of preparations (excitation-conduction block-free rate). Cicletanine protected the preparations (relative risk=0.08, t=-3.28) from the ischemia-induced excitation-conduction blocks (estimated survival=0.83 versus 0.30 in control), and this effect was abolished by indomethacin (estimated survival=0.35). Terfenadine enhanced 3. 58-fold the risk of occurrence of excitation-conduction blocks during ischemia (t=2.10) and this effect was inhibited by cicletanine pretreatment (estimated survival=0.40 versus 0.10 in untreated preparations). In conclusion, these in vitro findings have provided evidence for (1) protective effects of cicletanine against ischemia-induced excitation-conduction blocks, possibly related to its stimulating activity on local prostacyclin generation, and (2) efficacy of cicletanine to prevent excitation-conduction blocks induced by terfenadine in ischemic cardiac tissue.

Animals↗
PubMed1999

Enoximone coupled to very low dose dobutamine echocardiography detects myocardial viability in akinetic and dyskinetic post-myocardial infarcted areas.

Dobutamine and enoximone stimulate independently inotropic reserve by increasing intracellular cyclic adenosine monophosphate. The potential of enoximone (0.75 mg/kg body weight over 10 minutes) followed by very low dose (2.5 microg/kg/min) dobutamine echocardiography to predict recovery of ventricular function in akinetic and dyskinetic postinfarcted areas was studied. We enrolled 22 patients with previous Q-wave myocardial infarction and regional wall motion abnormalities related to left anterior descending arterial disease, left ventricular ejection fraction <40%, and all scheduled for myocardial revascularization. A 10 microg/kg/min dobutamine test was performed 48 hours before the study protocol. Test images obtained at peak of pharmacodynamic effects were compared with those obtained at 4 months after myocardial revascularization. We used a 16-segment ventricular model and a 5-grade scoring system. Resting regional myocardial dysfunction graded > or =2 was present in 267 of 352 segments evaluated. Contractile reserve (decrease in resting wall motion score > or =2 grades) at peak effect of enoximone infusion was present in 34 of 112 severely hypokinetic, 42 of 117 akinetic, and 14 of 38 dyskinetic segments. The inotropic reserve evaluated after very low dose dobutamine was observed in 34 of 112 severely hypokinetic, 49 of 117 akinetic, and 20 of 38 dyskinetic segments. After revascularization, recovery of function was observed in 31 of 112 severely hypokinetic, 49 of 117 akinetic, and 21 of 38 dyskinetic segments. Overall, there was a significant correlation between absolute score changes of segments which were abnormal at baseline (n = 267) to enoximone peak effects (r = 0.49, p <0.001) to predict absolute changes after revascularization; after dobutamine there was progress toward identity (r = 0.62, p <0.001) and the difference was significant among correlation slopes of dobutamine alone, enoximone alone, and enoximone plus very low dose dobutamine echocardiograophy (0.45+/-0.04, 0.51+/-0.04, and 0.63+/-0.04, respectively, F = 5.25, p = 0.005). Therefore, enoximone followed by very low dose dobutamine may assess myocardial viability of postinfarcted akinetic and dyskinetic areas. This test may be useful when evaluating patients with more severe cardiac failure and/or life-threatening arrhythmias.

Adult↗
PubMed1999

KATP channels and 'border zone' arrhythmias: role of the repolarization dispersion between normal and ischaemic ventricular regions.

1. In order to investigate the role of KATP channel activation and repolarization dispersion on the 'border zone' arrhythmias induced by ischaemia-reperfusion, the effects of glibenclamide and bimakalim, agents modifying action potential (AP) duration, were studied in an in vitro model of myocardial 'border zone'. 2. The electrophysiological effects of 10 microM glibenclamide and 1 microM bimakalim (n=8 each), respectively KATP channel blocker and activator, were investigated on guinea-pig ventricular strips submitted partly to normal conditions (normal zone, NZ) and partly to simulated ischaemic then reperfused conditions (altered zone, AZ). 3. By preventing the ischaemia-induced AP shortening (P<0.0001), glibenclamide reduced the dispersion of AP duration 90% (APD90) between NZ and AZ (P<0.0001), and concomitantly inhibited the 'border zone' arrhythmias induced by an extrastimulus (ES), their absence being significantly related to the lessened APD90 dispersion (chi2=8.28, P<0.01). 4. Bimakalim, which also reduced the APD90 dispersion (P<0.005) due to differential AP shortening in normal and ischaemic tissues, decreased the incidence of myocardial conduction blocks (25% of preparations versus 83% in control, n=12, P<0.05) and favoured 'border zone' spontaneous arrhythmias (75% of preparations versus 25% in control, P<0.05). 5. During reperfusion, unlike bimakalim, glibenclamide inhibited the ES-induced arrhythmias and reduced the incidence of the spontaneous ones (12% of preparations versus 92% in control, P<0.05), this latter effect being significantly related (chi2=6.13, P<0.02) to the lessened ischaemia-induced AP shortening in the presence of glibenclamide (P<0.0001). 6. These results suggest that KATP blockade may protect the ischaemic-reperfused myocardium from 'border zone' arrhythmias concomitantly with a reduction of APD90 dispersion between normal and ischaemic regions. Conversely, KATP channel activation may modify the incidence of conduction blocks and exacerbate the ischaemia-induced 'border zone' arrhythmias.

ATP-Binding Cassette Transporters↗
PubMed1999

Effects of bimakalim on human cardiac action potentials: comparison with guinea pig and nicorandil and use-dependent study.

Electrophysiologic effects of K(ATP) channel openers (KCOs) are rarely studied for tissue and species specificity, and use-dependent investigations in human tissues are lacking. We therefore investigated in vitro the concentration-dependent effects of the KCO bimakalim [from 10 nM to 10 microM, at 1,000 ms of cycle length (CL) and 37 degrees C] on human (atrium, n = 4, and ventricle, n = 6) and guinea pig (atrium, n = 7, and ventricle, n = 6) transmembrane action potential (AP). The frequency relation (from CL 1,600 to 300 ms, 31 degrees C) of human atrial AP duration 90% (APD90) shortening (10 microM vs. baseline, n = 7) also was determined. A parallel study was performed with the KCO nicorandil (from 10 nM to 1 mM, n = 3) in human atrial APs, at 31 degrees C. Resting membrane potential and maximal upstroke velocity of AP were not modified by bimakalim at maximal concentration, whereas AP amplitude was decreased in both guinea pig preparations (p < 0.05); APD90 was shortened in all tissues (p < 0.01). Median effective concentration (EC50) for APD90 shortening at 37 degrees C was 0.54 and 2.74 microM in atrial and ventricular human tissue, respectively, and 8.55 and 0.89 microM in atrial and ventricular guinea pig tissue, respectively. In human atrial tissue at 31 degrees C, EC50 with bimakalim was 0.39 microM; a much higher value was seen with nicorandil (210 microM). Bimakalim (10 microM)-induced APD90 shortening as a function of stimulation rate was greatest at longest CL. Evidence is provided for (a) species (human vs. guinea pig) and tissue (atrium vs. ventricle) differential AP sensitivity to bimakalim; (b) an approximately 500-fold higher efficacy of bimakalim versus nicorandil to shorten human atrial APD90; and (c) normal use-dependence of human atrial APD90 shortening with bimakalim at 10 microM.

Action Potentials↗
PubMed1999

Protection of human myocardium in vitro by K(ATP) activation with low concentrations of bimakalim.

We investigated whether the adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channel activation by bimakalim, at concentrations devoid of both negative inotropic and action-potential duration (APD) shortening effects, might exhibit myocardial protection after hypoxia and reoxygenation in human atrial myocardium by using 112 preparations. The recovery of contractility of human atrial trabeculae, subjected either to short-duration (5 min) or to long-duration (60 min) and severe (high pacing rate) hypoxia followed by reoxygenation, was assessed by challenging with dobutamine. Treated preparations were exposed to 10 or 100 nM bimakalim, 1 microM glibenclamide, or both before hypoxia. Variations of isometric developed tension (%DT) or APD90 were studied. At concentrations <100 nM, bimakalim showed no negative inotropic effects and did not modify significantly APD90 either in normoxia or in hypoxic conditions. In the short-duration hypoxia protocol, preparations treated with bimakalim showed a dobutamine-induced %DT increase significantly higher (p < 0.001) than in controls and similar to that observed in the absence of hypoxia. This bimakalim effect was blocked by glibenclamide. In the long-duration hypoxia protocol, %DT after dobutamine was 50% of that observed in normoxic preparations. Preparations treated with bimakalim showed after dobutamine %DT more than twofold above controls (p < 0.001), whereas in the glibenclamide group, recovery of DT with dobutamine remained 50% of what observed in normoxia (p < 0.001). In conclusion, exposure to hypoxia (either short- or long-lasting) and reoxygenation affects contractility of human atrial myocardium with pronounced reduction of the positive inotropic action of dobutamine. Pretreatment with bimakalim restores the response expected in the absence of hypoxia, and glibenclamide blocks the effect of bimakalim or further impairs the response to dobutamine when used alone before long-duration hypoxia. Evidence is provided for protective effects of the K(ATP) opener bimakalim on the human myocardial contractile function in conditions of hypoxia/reoxygenation, at concentrations at which negative inotropism and APD90 shortening are not contributory.

Adenosine Triphosphate↗