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ABSTRACT: Lung transplantation has been one of the great medical advances as the last option for the treatment of end-stage pulmonary disease. Optimal pulmonary care of potential donors and recipients can definitely increase the number of successful lung retrievals and reduce the incidence of complications.
The use of a lung-protective ventilatory strategy, associated with recruitment maneuvers, has a profound clinical impact, doubling the number of lungs available for transplant. Postoperatively, it is important to use a lung-protective ventilation strategy, whereas for patients with life-threatening reperfusion injury, extracorporeal membrane oxygenation can ensure a survival rate between 50 and 80%. Pumpless extracorporeal carbon dioxide removal system allows the maintenance of normal gas exchange and can be maintained in the perioperative period.
Perioperative ventilatory care of the transplanted patient still represents a challenge for the ICU clinician. The lung-protective strategy and the early application of carbon dioxide removal systems can increase the number of lung donor eligibility. Further studies are needed to increase the viability of other organs and to develop new strategies that reduce the risk of ischemia-reperfusion injury, which still represents the most common complication in the postoperative period.
Current opinion in anaesthesiology 04/2012; 25(2):170-4.
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American Journal of Respiratory and Critical Care Medicine 04/2012; 185(7):699-701. · 11.08 Impact Factor
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Salvatore Grasso,
Pierpaolo Terragni,
Alberto Birocco,
Rosario Urbino, Lorenzo Del Sorbo,
Claudia Filippini,
Luciana Mascia,
Antonio Pesenti,
Alberto Zangrillo,
Luciano Gattinoni,
V Marco Ranieri
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ABSTRACT: To assess whether partitioning the elastance of the respiratory system (E (RS)) between lung (E (L)) and chest wall (E (CW)) elastance in order to target values of end-inspiratory transpulmonary pressure (PPLAT(L)) close to its upper physiological limit (25 cmH(2)O) may optimize oxygenation allowing conventional treatment in patients with influenza A (H1N1)-associated ARDS referred for extracorporeal membrane oxygenation (ECMO).
Prospective data collection of patients with influenza A (H1N1)-associated ARDS referred for ECMO (October 2009-January 2010). Esophageal pressure was used to (a) partition respiratory mechanics between lung and chest wall, (b) titrate positive end-expiratory pressure (PEEP) to target the upper physiological limit of PPLAT(L) (25 cmH(2)O).
Fourteen patients were referred for ECMO. In seven patients PPLAT(L) was 27.2 ± 1.2 cmH(2)O; all these patients underwent ECMO. In the other seven patients, PPLAT(L) was 16.6 ± 2.9 cmH(2)O. Raising PEEP (from 17.9 ± 1.2 to 22.3 ± 1.4 cmH(2)O, P = 0.0001) to approach the upper physiological limit of transpulmonary pressure (PPLAT(L) = 25.3 ± 1.7 cm H(2)O) improved oxygenation index (from 37.4 ± 3.7 to 16.5 ± 1.4, P = 0.0001) allowing patients to be treated with conventional ventilation.
Abnormalities of chest wall mechanics may be present in some patients with influenza A (H1N1)-associated ARDS. These abnormalities may not be inferred from measurements of end-inspiratory plateau pressure of the respiratory system (PPLAT(RS)). In these patients, titrating PEEP to PPLAT(RS) may overestimate the incidence of hypoxemia refractory to conventional ventilation leading to inappropriate use of ECMO.
European Journal of Intensive Care Medicine 03/2012; 38(3):395-403. · 5.17 Impact Factor
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ABSTRACT: Despite a very large body of investigations, no effective pharmacological therapies have been found to cure acute lung injury. Hence, supportive care with mechanical ventilation remains the cornerstone of treatment. However, several experimental and clinical studies showed that mechanical ventilation, especially at high tidal volumes and pressures, can cause or aggravate ALI. Therefore, current clinical recommendations are developed with the aim of avoiding ventilator-induced lung injury (VILI) by limiting tidal volume and distending ventilatory pressure according to the results of the ARDS Network trial, which has been to date the only intervention that has showed success in decreasing mortality in patients with ALI/ARDS. In the past decade, a very large body of investigations has determined significant achievements on the pathophysiological knowledge of VILI. Therefore, new perspectives, which will be reviewed in this article, have been defined in terms of the efficiency and efficacy of recognizing, monitoring and treating VILI, which will eventually lead to further significant improvement of outcome in patients with ARDS.
La Presse Médicale 11/2011; 40(12 Pt 2):e569-83. · 0.67 Impact Factor
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ABSTRACT: Despite improvements in outcome due to lung protective ventilation strategies using low tidal volumes, the mortality rate from acute respiratory distress syndrome (ARDS) remains unacceptably high, ranging from 34 to 64%. The predominant cause of death in ARDS is not severe hypoxemia, which is one of the defining criteria of ARDS, but multiple organ failure (MOF).
In view of the relationship between ARDS and MOF, two different but complementary pathophysiological perspectives will be developed in this article: ARDS as a consequence of MOF, and ARDS as the cause of MOF. This framework may be useful in guiding the development of novel therapeutic strategies that ultimately improve the outcome of ARDS and sepsis patients.
ARDS is a severe lung disease characterized by a very complex pathophysiology, involving not only the respiratory system but also nonpulmonary distal organs. Elucidation of the pathophysiological mechanisms bi-directionally linking MOF to ARDS appears to be a promising area of research that hopefully will lead to improved outcomes for these devastating conditions.
Current opinion in critical care 02/2011; 17(1):1-6. · 2.67 Impact Factor
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Vito Fanelli,
Valeria Puntorieri,
Barbara Assenzio,
Erica L Martin,
Vincenzo Elia,
Martino Bosco,
Luisa Delsedime, Lorenzo Del Sorbo,
Andrea Ferrari,
Stefano Italiano,
Alessandra Ghigo,
Arthur S Slutsky,
Emilio Hirsch,
V Marco Ranieri
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ABSTRACT: Ventilator-induced lung injury (VILI) occurs in part by increased vascular permeability and impaired alveolar fluid clearance. Phosphoinositide 3-kinase gamma (PI3Kγ) is activated by mechanical stress, induces nitric oxide (NO) production, and participates in cyclic adenosine monophosphate (cAMP) hydrolysis, each of which contributes to alveolar edema. We hypothesized that lungs lacking PI3Kγ or treated with PI3Kγ inhibitors would be protected from ventilation-induced alveolar edema and lung injury.
Using an isolated and perfused lung model, wild-type (WT) and PI3Kγ-knockout (KO) mice underwent negative-pressure cycled ventilation at either -25 cmH₂O and 0 cmH₂O positive end-expiratory pressure (PEEP) (HIGH STRESS) or -10 cmH₂O and -3 cmH₂O PEEP (LOW STRESS).
Compared with WT, PI3Kγ-knockout mice lungs were partially protected from VILI-induced derangement of respiratory mechanics (lung elastance) and edema formation [bronchoalveolar lavage (BAL) protein concentration, wet/dry ratio, and lung histology]. In PI3Kγ-knockout mice, VILI induced significantly less phosphorylation of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), production of nitrate and nitrotyrosine, as well as hydrolysis of cAMP, compared with wild-type animals. PI3Kγ wild-type lungs treated with AS605240, an inhibitor of PI3Kγ kinase activity, in combination with enoximone, an inhibitor of phosphodiesterase-3 (PDE3)-induced cAMP hydrolysis, were protected from VILI at levels comparable to knockout lungs.
Phosphoinositide 3-kinase gamma in resident lung cells mediates part of the alveolar edema induced by high-stress ventilation. This injury is mediated via altered Akt, eNOS, NO, and/or cAMP signaling. Anti-PI3Kγ therapy aimed at resident lung cells represents a potential pharmacologic target to mitigate VILI.
European Journal of Intensive Care Medicine 11/2010; 36(11):1935-45. · 5.17 Impact Factor
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ABSTRACT: Mechanical ventilation is a lifesaving treatment delivered to patients with a wide spectrum of medical and surgical diseases. However, significant limitations of the clinical application of mechanical ventilation in current practice have emerged, prompting the definition of novel therapeutic perspectives, especially concerning the prevention and treatment of acute respiratory failure. In the past few decades, there has been a consistent scientific and technologic effort to develop alternative strategies to avoid the need for mechanical ventilation. In particular, several studies have explored the feasibility and efficacy of extracorporeal oxygenation and carbon dioxide removal. Furthermore, promising results on the prevention of the occurrence of severe acute respiratory failure have been provided by clinical studies on the noninvasive application of continuous positive airway pressure as well as by experimental investigations in basic science. Therefore, further development in this direction will occur only with a permanent integration and exchange of knowledge among industry, clinicians, and scientific investigators.
Critical care medicine 10/2010; 38(10 Suppl):S555-8. · 6.37 Impact Factor
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Erica L Martin,
Danielle G Souza,
Caio T Fagundes,
Flavio A Amaral,
Barbara Assenzio,
Valeria Puntorieri, Lorenzo Del Sorbo,
Vito Fanelli,
Martino Bosco,
Luisa Delsedime,
Jose F Pinho,
Virginia S Lemos,
Fabricio O Souto,
Jose C Alves-Filho,
Fernando Q Cunha,
Arthur S Slutsky,
Thomas Ruckle,
Emilio Hirsch,
Mauro M Teixeira,
V Marco Ranieri
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ABSTRACT: Sepsis is a leading cause of death in the intensive care unit, characterized by a systemic inflammatory response (SIRS) and bacterial infection, which can often induce multiorgan damage and failure. Leukocyte recruitment, required to limit bacterial spread, depends on phosphoinositide-3 kinase γ (PI3Kγ) signaling in vitro; however, the role of this enzyme in polymicrobial sepsis has remained unclear.
This study aimed to determine the specific role of the kinase activity of PI3Kγ in the pathogenesis of sepsis and multiorgan damage.
PI3Kγ wild-type, knockout, and kinase-dead mice were exposed to cecal ligation and perforation-induced sepsis and assessed for survival; pulmonary, hepatic, and cardiovascular damage; coagulation derangements; systemic inflammation; bacterial spread; and neutrophil recruitment. Additionally, wild-type mice were treated either before or after the onset of sepsis with a PI3Kγ inhibitor and assessed for survival, neutrophil recruitment, and bacterial spread.
Both genetic and pharmaceutical PI3Kγ kinase inhibition significantly improved survival, reduced multiorgan damage, and limited bacterial decompartmentalization, while modestly affecting SIRS. Protection resulted from both neutrophil-independent mechanisms, involving improved cardiovascular function, and neutrophil-dependent mechanisms, through reduced susceptibility to neutrophil migration failure during severe sepsis by maintaining neutrophil surface expression of the chemokine receptor, CXCR2. Furthermore, PI3Kγ pharmacological inhibition significantly decreased mortality and improved neutrophil migration and bacterial control, even when administered during established septic shock.
This study establishes PI3Kγ as a key molecule in the pathogenesis of septic infection and the transition from SIRS to organ damage and identifies it as a novel possible therapeutic target.
American Journal of Respiratory and Critical Care Medicine 09/2010; 182(6):762-73. · 11.08 Impact Factor
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ABSTRACT: Acute respiratory failure and its most severe form, the acute respiratory distress syndrome, are relatively common in the ICU setting and have a high morbidity and mortality. This article will discuss ongoing research in this area, with a focus on relatively novel approaches in terms of pathophysiology, diagnosis and therapeutic advancements.
Several novel diagnostic and therapeutic tools, such as electrical impedance tomography, high frequency oscillatory ventilation, minimally invasive extracorporeal CO2 removal devices and neurally adjusted ventilatory assist, have recently been studied to minimize ventilator-induced lung injury. A brief review of these studies is presented in this article.
It is increasingly evident that only integration of physiological, clinical and technological approaches will lead to improvement in the outcome of patients with acute respiratory failure.
Current opinion in critical care 11/2009; 16(1):1-7. · 2.67 Impact Factor
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ABSTRACT: Tidal hyperinflation may occur in patients with acute respiratory distress syndrome who are ventilated with a tidal volume (VT) of 6 ml/kg of predicted body weight develop a plateau pressure (PPLAT) of 28 < or = PPLAT < or = 30 cm H2O. The authors verified whether VT lower than 6 ml/kg may enhance lung protection and that consequent respiratory acidosis may be managed by extracorporeal carbon dioxide removal.
PPLAT, lung morphology computed tomography, and pulmonary inflammatory cytokines (bronchoalveolar lavage) were assessed in 32 patients ventilated with a VT of 6 ml/kg. Data are provided as mean +/- SD or median and interquartile (25th and 75th percentile) range. In patients with 28 < or = PPLAT < or = 30 cm H2O (n = 10), VT was reduced from 6.3 +/- 0.2 to 4.2 +/- 0.3 ml/kg, and PPLAT decreased from 29.1 +/- 1.2 to 25.0 +/- 1.2 cm H2O (P < 0.001); consequent respiratory acidosis (Paco2 from 48.4 +/- 8.7 to 73.6 +/- 11.1 mmHg and pH from 7.36 +/- 0.03 to 7.20 +/- 0.02; P < 0.001) was managed by extracorporeal carbon dioxide removal. Lung function, morphology, and pulmonary inflammatory cytokines were also assessed after 72 h.
Extracorporeal assist normalized Paco2 (50.4 +/- 8.2 mmHg) and pH (7.32 +/- 0.03) and allowed use of VT lower than 6 ml/kg for 144 (84-168) h. The improvement of morphological markers of lung protection and the reduction of pulmonary cytokines concentration (P < 0.01) were observed after 72 h of ventilation with VT lower than 6 ml/kg. No patient-related complications were observed.
VT lower than 6 ml/Kg enhanced lung protection. Respiratory acidosis consequent to low VT ventilation was safely and efficiently managed by extracorporeal carbon dioxide removal.
Anesthesiology 09/2009; 111(4):826-35. · 5.36 Impact Factor
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ABSTRACT: Postregistration trials or postmarketing or phase IV trials are tools to investigate any treatment that is already approved and is, therefore, available for prescription use. The main objectives of these trials are typical effectiveness, more structured surveillance for uncommon or rare side effects, and the potential development of new indications. Several issues need to be addressed in the postregistration phase of the evaluation of a therapeutic treatment. Among those we will focus on two ethical challenges: reporting bias from industry-sponsored research and use of placebo as one of the arms in controlled studies where proven treatment already exists. The review of this topic is particularly relevant in the field of critical care because it is ongoing in the debate about the opportunity to perform a new placebo-controlled study with the recombinant human activated protein C (activated drotrecogin alfa-activated protein C). In fact, despite the approval of activated protein C for treatment of patients with severe sepsis and high risk of death, several issues regarding the efficacy and safety of its administration have been recognized by several investigators to the point that the European Medicines Agency asked for a new placebo-controlled study to further clarify the benefit/risk profile of activated protein C.
Critical care medicine 02/2009; 37(1 Suppl):S154-8. · 6.37 Impact Factor
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ABSTRACT: An overview of the main features of cerebral vasospasm is provided in this report, highlighting the possible future direction of development in the diagnosis and management of this severe complication of aneurysmal subarachnoid hemorrhage.
F1000 Medicine Reports 01/2009; 1.
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ABSTRACT: All original research contributions published in Critical Care in 2007 in the field of respirology and critical care medicine are summarized in this article. Fifteen papers were grouped in the following categories: acute lung injury and acute respiratory distress syndrome, mechanical ventilation, ventilator-induced lung injury, imaging, and other topics.
Critical care (London, England) 11/2008; 12(5):231. · 4.61 Impact Factor
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ABSTRACT: We evaluated the potential benefit of continuous positive airway pressure (CPAP) to prevent postoperative pulmonary complications (PPCs), atelectasis, pneumonia, and intubation in patients undergoing major abdominal surgery.
PPCs are common during the postoperative period and may be associated with a high morbidity rate. Efficacy of CPAP to prevent PPCs occurrence is controversial.
Medical literature databases were searched for randomized controlled trials examining the use of CPAP versus standard therapy in patients undergoing abdominal surgery. The meta-analysis estimated the pooled risk ratio and the number needed to treat to benefit (NNTB) for PPCs, atelectasis, and pneumonia.
The meta-analysis was carried out over 9 randomized controlled trials. Overall, CPAP significantly reduced the risk of (1) PPCs (risk ratio, 0.66; 95% confidence interval [CI], 0.52-0.85) with a corresponding NNTB of 14.2 (95% CI, 9.9-32.4); (2) atelectasis (risk ratio, 0.75; 95% CI, 0.58-0.97; NNTB, 7.3; 95% CI, 4.4-64.5); (3) pneumonia (risk ratio, 0.33; 95% CI, 0.14-0.75; NNTB, 18.3; 95% CI, 14.4-48.8). In all cases the variation in risk ratio attributable to heterogeneity was negligible, although there was some evidence of publication bias.
This systematic review suggests that CPAP decreases the risk of PPCs, atelectasis, and pneumonia and supports its clinical use in patients undergoing abdominal surgery.
Annals of Surgery 05/2008; 247(4):617-26. · 7.49 Impact Factor
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Critical Care Medicine 07/2007; 35(6):1623-4. · 6.33 Impact Factor
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ABSTRACT: Human neutrophil peptides (HNP) exert immune-modulating effects. We hypothesized that HNP link innate and adaptive immunity through activation of costimulatory molecules. Human lung epithelial cells and CD4+ lymphocytes were treated with HNP separately or in coculture. Stimulation with HNP induced an increase in cell surface expression of CD54 (ICAM-1), CD80, and CD86 on lung epithelial cells and the corresponding major ligands, CD11a (LFA-1), CD152 (CTLA-4), and CD28 on CD4+ lymphocytes. There was an increased nuclear expression of the transcription factor p53 in human alveolar A549 cells and an elevated NF-kappaB (p50) and a degradation of I-kappaB protein in CD4+ lymphocytes following HNP stimulation. HNP enhanced the interaction between A549 cells and CD4+ lymphocytes by increasing cell adhesion and release of IFN-gamma, IL-2, and IL-8. This was attenuated by using an alpha1-proteinase inhibitor to neutralize HNP. We conclude that HNP play an important role in linking innate to acquired immunity by activation of costimulatory molecules in lung epithelial cells and CD4+ lymphocytes.
Journal of Leukocyte Biology 05/2007; 81(4):1022-31. · 4.99 Impact Factor
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ABSTRACT: We sought to investigate the potential role of elevated levels of thrombopoietin (TPO) in platelet activation during unstable angina (UA).
Thrombopoietin is a humoral growth factor that does not induce platelet aggregation per se, but primes platelet activation in response to several agonists. No data concerning its contribution to platelet function abnormalities described in patients with UA are available.
We studied 15 patients with UA and, as controls, 15 patients with stable angina (SA) and 15 healthy subjects. We measured TPO and C-reactive protein (CRP), as well as monocyte-platelet binding and the platelet expression of P-selectin and of the TPO receptor, c-Mpl. The priming activity of patient or control plasma on platelet aggregation and monocyte-platelet binding and the role of TPO in this effect also were studied.
Patients with UA showed higher circulating TPO levels, as well as increased monocyte-platelet binding, platelet P-selectin expression, and CRP levels, than those with SA and healthy control subjects. The UA patients also showed reduced platelet expression of the TPO receptor, c-Mpl. In vitro, the plasma from UA patients, but not from SA patients or healthy controls, primed platelet aggregation and monocyte-platelet binding, which were both reduced when an inhibitor of TPO was used.
Thrombopoietin may enhance platelet activation in the early phases of UA, potentially participating in the pathogenesis of acute coronary syndromes.
Journal of the American College of Cardiology 01/2007; 48(11):2195-203. · 14.16 Impact Factor
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ABSTRACT: Hemorrhagic shock followed by resuscitation (HSR) commonly triggers an inflammatory response that leads to acute respiratory distress syndrome. Hypothesis: HSR exacerbates mechanical stress-induced lung injury by rendering the lung more susceptible to ventilator-induced lung injury.
Rats were subjected to HSR, and were randomized into an HSR + high tidal volume and zero positive end-expiratory pressure (PEEP) or a HSR + low tidal volume with 5 cm H(2)O PEEP. A sham-operated rat + high tidal volume and zero PEEP served as a control.
HSR increased susceptibility to ventilator-induced lung injury as evidenced by an increase in lung elastance and the wet/dry ratio and a reduction in Pa(O(2)) as compared with the other groups. The lung injury observed in the HSR + high tidal volume group was associated with a higher level of interleukin 6 in the lung and blood, increased epithelial cell apoptosis in the kidney and small intestine villi, and a tendency toward high levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatinine in plasma.
HSR priming renders the lung and kidney more susceptible to mechanical ventilation-induced organ injury.
American Journal of Respiratory and Critical Care Medicine 08/2006; 174(2):178-86. · 11.08 Impact Factor
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ABSTRACT: Antimicrobial human neutrophil peptides (HNPs) play a pivotal role in innate host defense against a broad spectrum of prokaryotic pathogens. In addition, HNPs modulate cellular immune responses by producing the chemokine interleukin-8 (IL-8) in myeloid and epithelial cells and by exerting chemotaxis to T cells, immature dendritic cells, and monocytes. However, the mechanisms by which HNPs modulate the immune responses in the eukaryotic cells remain unclear. We demonstrated that, as with adenosine triphosphate (ATP) and uridine diphosphate (UDP), HNP stimulation of human lung epithelial cells selectively induced IL-8 production in 10 pro- and anti-inflammatory cytokines examined. HNP-induced IL-8 release was inhibited by treatment with the nucleotide receptor antagonists suramin and reactive blue. Transfection of lung epithelial cells with antisense oligonucleotides targeting specific purinergic P2Y receptors revealed that the P2Y6 (ligand of UDP) signaling pathway plays a predominant role in mediating HNP-induced IL-8 production.
Blood 05/2006; 107(7):2936-42. · 9.90 Impact Factor
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Giuseppe Alloatti,
Andrea Marcantoni,
Renzo Levi,
Maria Pia Gallo, Lorenzo Del Sorbo,
Enrico Patrucco,
Laura Barberis,
Daniela Malan,
Ornella Azzolino,
Matthias Wymann,
Emilio Hirsch,
Giuseppe Montrucchio
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ABSTRACT: Cardiac beta-adrenergic and the muscarinic receptors control contractility and heart rate by triggering multiple signaling events involving downstream targets like the phosphoinositide 3-kinase gamma (PI3Kgamma). We thus investigated whether the lack of PI3Kgamma could play a role in the autonomic regulation of the mouse heart. Contractility and ICaL of mutant cardiac preparations appeared increased in basal conditions and after beta-adrenergic stimulation. However, basal and beta-adrenergic stimulated heart rate were normal. Conversely, muscarinic inhibition of heart rate was reduced without alteration of the Gbetagamma-dependent stimulation of IK,ACh current. In addition, muscarinic-mediated anti-adrenergic effect on papillary muscle contractility and ICaL was significantly depressed. Consistently, cAMP level of PI3Kgamma-null ventricles was always higher than wild-type controls. Thus, PI3Kgamma controls the cardiac function by reducing cAMP concentration independently of Gi-mediated signaling.
FEBS Letters 02/2005; 579(1):133-40. · 3.54 Impact Factor
