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Biomedical subjects

G Ruvolo

Publications and source records attributed to G Ruvolo.

At least 19 recordsLinked to original sources
PubMed2006

Cryopreservation of biopsied embryos at the blastocyst stage.

BACKGROUND: The availability of an efficient cryopreservation program is especially important in the case of embryos that have undergone blastomere biopsy for PGD. Unfortunately, the freezing/thawing of biopsied embryos has given disappointing results when performed at the cleavage stage. In this study, embryos diagnosed as normal after PGD were grown to the blastocyst stage, frozen and thawed for successive frozen embryo transfer. METHODS: A total of 34 patients performed a thawing cycle in which 47 blastocysts were thawed. The cryopreservation solutions were based on HEPES-buffered medium supplemented with human serum albumin (HSA), sucrose and 1,2-propanediol. The same protocol was applied to embryos from 88 IVF/ICSI patients, which underwent 92 thawing cycles with 150 thawed blastocysts. RESULTS: The survival rate was similar in the two groups (53% after PGD and 58% in IVF/ICSI cycles), as well as the cumulative pregnancy rate per patient (59% after PGD versus 47% in IVF/ICSI cycles), despite a higher maternal age and a lower proportion of embryos available for transfer or cryopreservation in the PGD group. CONCLUSIONS: Neither the survival rate nor the subsequent development and chances of implantation, differed between embryos frozen at the blastocyst stage following biopsy and those frozen intact.

Biopsy↗
PubMed2006

The inhibition of the human sperm phosphatidylinosytol 3-kinase by LY294002 does not interfere with sperm/oocyte interaction.

It has recently been reported that the selective inhibition of phosphatidylinosytol 3-kinase (PI3K) enhances human sperm motility. However, little information exists on a possible role of PI3K in other sperm functions involved in the fertilization process. In this study, we investigated whether LY294002 could affect human sperm ability to fuse with oocytes, by means of the hamster egg penetration test (HEPT). The effect on acrosome reactions (AR) and on sperm/zona pellucida (ZP) binding was also evaluated. The pre-incubation with scalar doses of LY294002 (0.1, 1 and 10 microm) did not interfere with sperm ability to fuse with oocytes either in the conventional version of the HEPT or in the version enhanced with progesterone (P). No interference with the stimulatory effect on AR exerted by P or mannose-bovine serum albumin (mannose-BSA) was revealed. Finally, LY294002 had no effect on sperm/ZP binding. These results indicate that the inhibition of PI3K by LY294002 does not interfere with sperm interaction with oocytes. This is noteworthy in the view of a possible clinical use of LY294002 as an in vitro stimulator of the sperm motility of asthenozoospermic patients for assisted reproduction techniques.

Acrosome Reaction↗
PubMed2002

Effect of human sperm exposure to progesterone on sperm-oocyte fusion and sperm-zona pellucida binding under various experimental conditions.

In this study, the effect of human sperm exposure to progesterone on sperm/oocyte fusion, using the hamster egg penetration test, and on sperm/zona pellucida (ZP) binding, using the hemizona assay, was investigated under various experimental conditions. A brief exposure of human spermatozoa to progesterone exerted a stimulatory effect on sperm/oocyte fusion which was dose-dependent, capacitation-dependent, influenced by the source of serum albumin in capacitating medium, and was higher than that produced by the exposure to progesterone from the onset of capacitation. The exposure of capacitated spermatozoa to progesterone during 20 min-spermatozoa/ZP-coincubation produced an enhancement of ZP-binding, which was not significantly influenced by the source of serum albumin in capacitating medium. A significantly lower ZP-binding was exhibited by spermatozoa exposed to progesterone from the beginning of capacitation. These results indicate that progesterone exerts a stimulatory effect on human sperm's fertilizing ability, which occurs mainly in post-capacitation events directly involved in sperm/oocyte fusion and in ZP-binding. Conditions optimizing these effects are provided. They should be taken into account in the standardization of experimental and clinical studies designed to evaluate the response of human spermatozoa to progesterone.

Animals↗
PubMed2002

Factors influencing immediate and long-term results after button's technique.

BACKGROUND: Aim of this study was to evaluate the factors influencing immediate and long-term results in patients undergoing aortic root replacement with a composite graft. METHODS: Between January 1989 and February 1999, 105 patients (83 males, 22 females) who underwent Bentall technique were studied. Preoperative diagnosis was annulo-aortic ectasia in 54, aortic dissection in 27, atherosclerotic aneurysm in 21, and aortitis in 3 cases. Seventeen patients were affected by Marfan's syndrome. All cases, elective, urgent, and emergency were included. Button technique was performed and the associated surgical procedures were coronary artery bypass grafting in 21, total aortic arch replacement in 15, proximal hemi arch in 5, and mitral valve replacement in 5 cases. RESULTS: The overall hospital mortality rate was 7.6% (n=8). Univariate analysis using chi(2) and/or two-sample "t"-test showed that dissection, aortitis, aneurysm rupture into-pleura or pericardium, emergency status, redo, prolonged pump times and circulatory arrest, were predictors influencing in-hospital mortality. Coagulopathy, low cardiac output, stroke, perioperative myocardial infarction, surgical bleeding leading to reoperation, were significantly related to in-hospital mortality (by correlation analysis). A multivariate analysis showed that, emergency status (p=0.027), aortic dissection (p=0.029), perioperative myocardial infarction (p=0.0021), reoperation for bleeding (p=0.0023), and pump time >180 min (p=0.011), were significant. The actuarial survival rate at 10 years follow-up was 84.7%. There were 8 late deaths. The Kaplan-Meier showed significant differences when considering dissection vs non-dissection (p=0.018), but did not reach significance in Marfan vs non-Marfan groups (p=0.83). NYHA class IV (p=0.052), previous cardiac surgery procedure (p=0.041), concomitant CABG (p=0.021), total aortic arch reconstruction (p=0.001), and mitral valve replacement (p=0.016), were identified as significant by Log Rank test. CONCLUSIONS: The Bentall procedure for aortic root replacement is safe and durable; in hospital mortality in elective status it was 1.28%; early and long-term mortality higher in patients with acute dissection. Six late deaths were procedures related. Sixty-six patients (76.4%) were in NYHA I class at follow-up. The incidence of late outcomes, thromboembolism (1.03%), graft infection (2.06%), pseudoaneurysm (0%), reoperation in ascending aorta or aortic valve (3.1%), operations on the remaining aorta (6.7%), and hemorrhage due to anticoagulant therapy (1.03%), are very low.

Actuarial Analysis↗
PubMed2001

Emergency operation for acute type A aortic dissection: neurologic complications and early mortality.

BACKGROUND: Acute type A aortic dissection is a surgical emergency still associated with high postoperative complications. The aim of this study was to investigate factors for hospital mortality and neurologic deficit in patients undergoing emergency operation for acute type A aortic dissection. METHODS: Eighty-five consecutive patients (age range, 20 to 82 years) operated on for acute type A aortic dissection over a 6-year period were evaluated. Univariate and stepwise multiple logistic regression analyses were conducted among 32 perioperative variables. RESULTS: All patients underwent surgical procedures under deep hypothermic circulatory arrest. Antegrade or retrograde cerebral perfusion was used in 23 patients (27.1%) and 18 patients (21.2%), respectively. Forty-three patients underwent arch/hemiarch replacement and the ascending aorta was replaced in 42 patients. Overall mortality rate was 25.9% (22 of 85 patients). Multiple logistic regression analysis showed that lack of cerebral perfusion (p = 0.021) and postoperative renal failure (p = 0.006) were the best predictors for hospital death. Twenty-one patients (24.7%) experienced neurologic accidents. The risk factor for postoperative neurologic complication was lack of cerebral perfusion (p = 0.013). Hospital mortality was 13% (3 of 23 patients) and 16.7% (3 of 18 patients) in the antegrade and retrograde cerebral perfusion groups (p > 0.05) and neurologic deficit was 13% (3 of 23 patients) and 11.1% (2 of 18 patients), respectively (p > 0.05). CONCLUSIONS: Hospital mortality and neurologic complications in patients undergoing emergent operation for acute type A aortic dissection were reduced when cerebral perfusion was used with deep hypothermic circulatory arrest.

Adult↗
PubMed2001

Genetic, andrological and clinical characteristics of patients with congenital bilateral absence of the vas deferens.

The possibility of retrieving spermatozoa from the epididymis allows patients with congenital bilateral absence of the vas deferens (CBAVD) to father a child by means of assisted reproduction techniques. This has, however, increased the chance of transmitting a mutated allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene which increases the risk of generating offspring with cystic fibrosis (CF). Because of the increased heterogeneity of the CFTR locus, the study of a discrete number of mutations, as usually carried out in a diagnostic work-up, is unable to ascertain the presence of a mutation in a relatively high proportion of the patients screened. In an attempt to increase the chance of detecting the presence of CFTR gene abnormalities, 37 patients with CBAVD and one patient with congenital unilateral agenesis of the vas deferens (CUAVD) underwent an enlarged diagnostic protocol, which included screening for the most expected mutations of the CFTR gene in our population, evaluation of the five thymidine (5T) allelic variant, sweat test, respiratory function tests, evaluation of steatocrit, and an accurate evaluation of the history of the patient to search for symptoms commonly found in patients with CF. A single CFTR gene mutation was found in 18 patients (48.6%) with CBAVD and in the patient with CUAVD. The most frequent mutation observed was the Delta F508. Eleven patients (45.8%) had the 5T variant and in five of them it was not associated with any detectable mutation of the CFTR gene. Two female partners were found to be carriers of a mutation, whereas 5 (18.5%) had the 5T variant. As many as 71% of CBVAD patients had the simultaneous presence of at least two signs and/or symptoms suggestive of CF, albeit they were of mild intensity and the patients felt fit and healthy. In conclusion, these results suggested that some patients with CBAVD without CFTR gene mutation or 5T variant, even when their sweat test is negative, may show clinical suspicion of carrying a CFTR gene mutation and therefore are at risk of generating children affected by CF if the partner carries a mutation as well. The screening for mutations and a careful clinical examination may contribute to better identification of patients with CFTR-related CBAVD.

Adult↗
PubMed2001

Left ventricular thrombosis after blunt chest trauma.

A 22-year-old man was admitted to our observation with left ventricular thrombus arising after blunt chest trauma occurring during a ski accident one year before. None was obtained from a review of instrumental and laboratory data at trauma time. Transesophageal echocardiography showed an intraventricular thrombus and severe hypokinesia at the apex. Standard cardiac surgery procedure was performed and postoperative period was uneventful. Echocardiography controls at 6/12 months showed a normal apex kinesia. This case shows the importance of hospitalization, hemodynamics monitorization and late serial echocardiographic controls for timely diagnosis and management of myocardial contusion and consecutive ventricular thrombus formation to prevent life-threatening complications.

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

Intraoperative flow measurement in composite Y arterial grafts.

OBJECTIVE: Total arterial myocardial revascularization may be achieved by using the 'Y-graft' techniques with different free arterial conduits anastomosed off the side of an in situ internal thoracic artery to reach distal coronary segments. This study was assessed to measure intraoperative graft flow, resistance and clinical outcomes. METHODS: Seventy-six patients who underwent coronary artery bypass grafting during a time period of 27 months were enrolled in this prospective study. All patients received sequential grafting by using both internal thoracic arteries, inferior epigastric and right gastroepiploic artery joined as a composite Y graft. Intraoperative graft flow, resistance and derived variables were measured. RESULTS: All patients except one showed good flow (ml/min and waveform) in either branch of composite graft. In one case, a low-flow situation through the graft was registered requiring surgical correction. Temporary occlusion of either branch did not significantly affect flow in the other side of the arterial Y. Mid-term follow-up (3 and 15 months) and angiographic studies showed a high graft patency rate. CONCLUSION: Composite arterial grafts provide excellent early and mid-term clinical results. Flow reserve of the left internal thoracic artery did not affect blood flow and resistance on either branch of the Y graft when temporary occlusion on the other side of the arterial Y was performed.

Adult↗
PubMed2000

Arrhythmia prophylaxis after coronary artery bypass grafting: regimens of magnesium sulfate administration.

BACKGROUND: Arrhythmias are common after open heart surgery and may be related to hypomagnesaemia due to cardiopulmonary bypass. Although perioperative prophylactic Mg2+ administration may prevent arrhythmias after coronary artery bypass grafting (CABG), clear indications as well as the timing of Mg2+ substitution and dose regimen need to be clarified. Aim of this study was to evaluate the antiarrhythmic effects of Mg2+ infusion in patients who underwent elective CABG. METHOD: Ninety-seven patients who underwent elective CABG were divided in four Groups. In Group A 1 g of magnesium sulfate was added to the pump prime, Group B received 1 g in the pump prime plus 5 mmol/L in the cardioplegic solution, Group C received 5 mmol/L in the cardioplegic solution, and Group D was a placebo control Group. Groups A, B, and C also received 24 h continuous infusion of magnesium sulfate at 10 mmol/L. Three-channel electrocardiogram (II-V5-V6) continuous monitoring was performed 12 hours preoperatively and 48 hours postoperatively. Blood samples were taken for subsequent Serum magnesium measurements, at five different time points before, during and after CBP. RESULTS: In all Groups serum Mg2+ levels were reduced during CPB (Time 2) and statistically significant differences from pre-anaesthesia levels (Time 1) were noted (p <0.05). In Groups A, B, and C Serum Mg2+ levels increased progressively from Time 3 to Time 5; in Group D serum Mg2+ levels were still much lower at Time 5. Significant differences (p<0.05) were noted for Groups B and C vs Groups A and D in atrial ectopics, atrial fibrillation, and ventricular arrhythmic events. CONCLUSION: Our results demonstrate that Mg2+ sulfate administration regimens used in Group B and C reduce postoperative arrhythmic events in patients undergoing CABG.

Arrhythmias, Cardiac↗
PubMed2000

Nitric oxide synthase inhibition in human sperm affects sperm-oocyte fusion but not zona pellucida binding.

There is recent evidence that mouse and human spermatozoa contain constitutive nitric oxide synthase (cNOS) and can synthesize nitric oxide. The aim of this study was to investigate whether the inhibition of human sperm cNOS could affect sperm-oocyte fusion and sperm binding to the zona pellucida (ZP). N(G)-nitro-L-arginine methyl ester (L-NAME) was used as cNOS inhibitor. Sperm-oocyte fusion was evaluated using the hamster egg penetration test (HEPT). The ZP binding was evaluated using the hemizona assay. L-NAME added from the onset of capacitation strongly inhibited sperm-oocyte fusion. This inhibitory effect was dose dependent, stereospecific, and suppressed by L-arginine in a dose-dependent manner. L-NAME also inhibited sperm-oocyte fusion in the HEPT enhanced with progesterone (P), where P (5 microM) was added for 15 min to capacitated sperm. A lesser but significant inhibition was also observed when sperm suspensions were exposed to L-NAME following capacitation in both versions of HEPT. On the contrary, L-NAME did not affect ZP binding. In conclusion, the present study provides the evidence that cNOS plays a role in the human sperm's capacity to fuse with oocyte but not in the ZP binding.

Animals↗
PubMed2000

Effect of normothermic versus hypothermic cardiopulmonary bypass on cytokine production and platelet function.

BACKGROUND: Proinflammatory cytokines and platelets play a key role in the systemic inflammatory response associated with cardiopulmonary bypass (CPB). The aim of this study was to evaluate the effects of both hypothermic and normothermic CPB on platelet activation, cytokine production, as well as their possible correlations. METHODS: Twenty patients who underwent CABG were randomly assigned into two groups receiving hypothermic and normothermic CPB. Blood samples were obtained through a venous catheter at 6 time points. The following parameters were measured: in vitro platelet aggregation, in vivo platelet activation, complete and differential blood cell counts, plasma soluble P-selectin levels, plasma IL-6, IL-1beta and TNFalpha levels. RESULTS: The results demonstrated that platelet abnormalities could be observed to a greater extent during hypothermic rather than normothermic CPB. The occurrence of in vivo platelet activation was suggested by the presence of a significantly increased percentage of platelets expressing CD62P on their surface, as well as by a decreased in vitro platelet aggregation induced by different agonists. Complete and differential blood cell counts showed no substantial decrease in platelet number without differences between groups. The results obtained also showed the presence of a significant release of sP-selectin during CPB, as well as a more pronounced increase of plasma sP-selectin levels in patients undergoing hypothermic compared to normothermic CPB. A comparison of cytokine levels demonstrated a significant elevation of plasma IL-6 levels during either hypothermic or normothenmic CPB, paralleling the neutrophil rise, while no differences were observed for TNF-alpha levels. Conversely, plasma IL-1beta levels were significantly elevated during hypothermic, but not during normothermic CPB. CONCLUSIONS: Hypothermic CPB is responsible for a greater platelet activation and endothelial dysfunction than normothermic CPB, leading to more profound changes in the hemostatic and inflammatory systems, which, in turn, might be responsible for the higher incidence of postoperative complications reported during hypothermic CPB.

Biomarkers↗
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

Sleeve resection and prosthetic reconstruction of the pulmonary artery for lung cancer.

BACKGROUND: Lobectomy associated with reconstruction of the pulmonary artery (PA) is a technically feasible alternative to pneumonectomy in patients with lung cancer. However, concern about postoperative complications and long-term survival limited its acceptance so far. METHODS: Between 1989 and 1996, we performed a PA reconstruction in 52 patients (41 men, 11 women; age range 35 to 75 years, mean 60 years) with lung cancer. Eleven patients had induction chemotherapy. We performed 15 PA sleeve resections, 34 PA reconstructions by a pericardial patch, and three PA reconstructions by a pericardial conduit, associated with a bronchial sleeve lobectomy or bilobectomy (33), or with standard lobectomy (19). Immediate and long-term postoperative evaluation included spirometry, echocardiography, perfusion lung scans, computed tomography, and PA angiography. The follow-up ranged between 27 and 96 months and is complete for all patients. RESULTS: We had one specific postoperative complication (PA thrombosis) and no mortality. Perfusion scans and PA angiography were normal in all but the 1 patient having thrombosis. Mean forced expiratory volume (FEV) in 1 s and forced vital capacity (FVC) were, respectively, 72% and 80% preoperatively, 65% and 76% 1 month after surgery, and then they plateaued at 70% and 78% after 6 months. Echocardiography showed patterns in the normal range and normal estimates of PA pressures in all but 2 patients. Five-year survival was 38.3% for the entire group, 18.6% for stages IIIA and B, and 64.4% for stages I and II. CONCLUSIONS: Morbidity, mortality, and functional data do not differ from what is currently reported for standard lobectomy. Long-term survival is in line with that reported for standard resection. These data support PA reconstruction as a viable option in the treatment of lung cancer.

Adult↗
PubMed1999

Induction chemotherapy for T4 centrally located non-small cell lung cancer.

OBJECTIVE: We used induction chemotherapy in a prospective, single-institution clinical trial intended to achieve resectability in patients with centrally located, unresectable T4 non-small cell lung cancer. Other types of IIIB disease were excluded. METHODS: Between January 1990 and April 1996, we enrolled 57 patients with histologically confirmed non-small cell lung cancer. Eligibility criteria for T4 were clinical (superior vena cava syndrome, 9 patients), vocal cord paralysis (6 patients), dysphagia from esophageal involvement (1 patient), radiologic (computed tomography and magnetic resonance evidence of infiltration, 10 patients), bronchoscopic (tracheal infiltration, 11 patients), and thoracoscopic (histologically proven mediastinal infiltration, 20 patients). After 3 cycles of cisplatin (120 mg/m2), vinblastine (4 mg/m2), and mitomycin (2 mg/m2), patients were reevaluated. RESULTS: Forty-two patients (73%; 36 men, 6 women; age range, 42-75 years; mean, 58 years) responded to therapy and underwent thoracotomy; 11 patients did not respond, and 4 patients had major toxicity. Thirty-six patients (63% of the entire group) had complete resection. We performed 4 exploratory thoracotomies, 6 pneumonectomies, 32 lobectomies (20 procedures were associated with reconstruction of hilar-mediastinal structures). Overall, 4 patients had no histologic evidence of disease. We had 2 bronchopleural fistulas with 1 death and 5 other major complications. Overall survival at 1 and 4 years is 61.4% and 19.5%, respectively. Forty-two patients (73%) underwent exploratory operation, with a 4-year survival of 25.9%; 36 patients (63%) had complete resection, with a 4-year survival of 30.5%. CONCLUSIONS: Induction chemotherapy is effective for downstaging and surgical reconversion of centrally located T4 non-small cell lung cancer. Survival is promising, especially in patients whose disease becomes resectable.

Adenocarcinoma↗
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↗