Preconditioning by isoflurane induces lasting sensitization of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel by a protein kinase C-delta-mediated mechanism

BACKGROUND: Cardioprotective effects of volatile anesthetics in anesthetic-induced preconditioning involve activation of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium (sarcKATP) channels. This study addressed the memory phase of anesthetic preconditioning by investigating whether brief exposure to isoflurane produces lasting sensitization of the sarcKATP channel and whether protein kinase C mediates this effect. METHODS: Whole cell sarcKATP channel current (IKATP) was monitored from single isolated rat ventricular cardiomyocytes. Pinacidil was used to open the channel, and the magnitude of activated IKATP was an indicator of channel's ability to open. Involvement of protein kinase C was investigated using chelerythrine and isoform-specific peptide inhibitors and activators of protein kinase C-delta and protein kinase C-epsilon. RESULTS: The mean density of IKATP elicited by pinacidil (5 microm) in anesthetic-free conditions was 3.8 +/- 3.7 pA/pF (n = 11). After 10 min of exposure to isoflurane (0.56 mm) and 10 or 30 min of anesthetic washout, pinacidil-elicited IKATP was increased to 15.6 +/- 11.3 pA/pF (n = 12; P < 0.05) and 11.8 +/- 3.9 pA/pF (n = 6; P < 0.05), respectively. In the presence of chelerythrine (5 microm), isoflurane did not potentiate channel opening, and IKATP was 6.6 +/- 4.6 pA/pF (n = 11). Application of protein kinase C-delta peptide inhibitor also abolished isoflurane-induced sensitization of sarcKATP channel, and IKATP was 7.7 +/- 5.4 pA/pF (n = 12). In contrast, protein kinase C-epsilon peptide inhibitor did not affect channel sensitization, and pinacidil-elicited current was 14.8 +/- 9.6 pA/pF (n = 12). Interestingly, when both protein kinase C-delta and protein kinase C-epsilon activators were applied instead of isoflurane, they sensitized the channel to the same extent as isoflurane (18.9 +/- 7.2 pA/pF, n = 11, and 18.6 +/- 11.1 pA/pF, n = 10, respectively). CONCLUSION: Isoflurane induces prolonged sensitization of the sarcKATP channel to opening that persists even after anesthetic withdrawal. Our results indicate that protein kinase C-delta, rather than protein kinase C-epsilon, is a likely mediator of isoflurane effects, although both protein kinase C-delta and protein kinase C-epsilon can modulate the channel function.     

Visual attention affects temporal estimation in anticipatory motor actions

The production of accurate motor actions requires successful extraction of relevant information about the target of that action. By the same token, it also requires the successful exclusion of potentially distracting, irrelevant information. This study sought to determine the impact of transient visual distractions on performance in an anticipatory timing task, in particular the temporal and spatial relationship between distractor and target at which maximal distraction occurs. The results support the notion of a critical temporal and spatial window of distraction which provides insight into the visuomotor processes underlying distraction.     

Malignant insulinoma: Can we predict the long-term outcomes?

Insulinomas are the most frequent type of functional pancreatic neuroendocrine tumors with a variety of neuroglycopenic and autonomic symptoms and well-defined diagnostic criteria; however, prediction of their clinical behavior and early differentiation between benign and malignant lesions remain a challenge. The comparative studies between benign and malignant cases are limited, suggesting that short clinical history, early hypoglycemia during fasting, high proinsulin, insulin, and C-peptide concentrations raise suspicion of malignancy. Indeed, malignant tumors are larger with higher mitotic count and Ki-67 proliferative activity, but there are no accurate histological criteria to distinguish benign from malignant forms. Several signaling pathways have been suggested to affect the pathophysiology and behavior of insulinomas; however, our knowledge is limited, urging a further understanding of molecular genetics. Therefore, there is a need for the identification of reliable markers of metastatic disease that could also serve as therapeutic targets in patients with malignant insulinoma. This opinion review reflects on current gaps in diagnostic and clinical aspects related to the malignant behavior of insulinoma.     

The influence of varying inspired fractions of O₂ and CO₂ on the development of involuntary breathing movements during maximal apnoea

The growing urge to breathe that occurs during breath-holding results in development of involuntary breathing movements (IBMs). The present study determined whether IBMs are initiated at critical levels of hypercapnia and/or hypoxia during maximal apnoea. Arterial blood gasses at the onset of IBM were monitored during maximal voluntary breath-holds. Eleven healthy men performed breath holds after breathing air, hyperoxic–normocapnia, hypoxic–normocapnia, and normoxic–hypercapnia. Pre-breathing of the gas mixtures facilitated the IBM onset, reducing the time-to-onset for ∼46% (hyperoxic condition) and for ∼80% (hypoxic condition) compared to the normoxic air breathing time. A strong correlation (R = 0.83, P = 0.002) between arterial partial pressure of CO₂ (Pa_CO2${\text{Pa}}_{{\text{CO}}_2}$) at IBM onset after pre-breathing hyperoxic and hypercapnic gas mixtures was observed, suggesting the existence of a possible IBM Pa_CO2${\text{Pa}}_{{\text{CO}}_2}$ threshold level of ∼6.5 ± 0.5 kPa. No clear “threshold” was observed for partial pressure of arterial O₂ (Pa_O2${\text{Pa}}_{{\text{O}}_2}$). However, we observed that IBM onset was influenced, in part, by an interaction between Pa_O2${\text{Pa}}_{{\text{O}}_2}$ and Pa_CO2${\text{Pa}}_{{\text{CO}}_2}$ levels during maximal apnoea. This study demonstrated the complex interaction between arterial blood-gases and the physiological response to maximal breath holding.     

Increased corticospinal excitability induced by unpleasant visual stimuli

Pleasant and unpleasant emotional stimuli are frequently conceptualized as motivators for action. This notion was examined using focal transcranial magnetic stimulation (TMS). Ten healthy participants viewed pleasant, neutral, and unpleasant pictures from the International Affective Picture System (IAPS). During picture viewing, focal TMS was applied to the right motor cortex over the area innervating the first dorsal interosseous muscle of the left hand. Corticomotor excitability was larger while viewing negative pictures than while viewing neutral or positive images, as evidenced by greater motor evoked potentials. No difference was found between pleasant and neutral pictures. These results are consistent with models of emotion in which the neural networks underlying negative emotions have selective, direct connections to brain structures that mediate motor responses.     

The impact of consecutive freshwater trimix dives at altitude on human cardiovascular function

Self‐contained underwater breathing apparatus (SCUBA) diving is regularly associated with numerous asymptomatic changes in cardiovascular function. Freshwater SCUBA diving presents unique challenges compared with open sea diving related to differences in water density and the potential for dive locations at altitude. The aim of this study was to evaluate the impact of freshwater trimix diving at altitude on human cardiovascular function. Ten divers performed two dives in consecutive days at 294 m altitude with the surface interval of 24 h. Both dives were at a depth of 45 m with total dive time 29 and 26 min for the first and second dive, respectively. Assessment of venous gas embolization, hydration status, cardiac function and arterial stiffness was performed. Production of venous gas emboli was low, and there were no significant differences between the dives. After the first dive, diastolic blood pressure was significantly reduced, which persisted up to 24 h. Left ventricular stroke volume decreased, and heart rate increased after both dives. Pulse wave velocity was unchanged following the dives. However, the central and peripheral augmentation index became more negative after both dives, indicating reduced wave reflection. Ejection duration and round trip travel time were prolonged 24 h after the first dive, suggesting longer‐lasting suppression of cardiac and endothelial function. This study shows that freshwater trimix dives with conservative profiles and low venous gas bubble loads can result in multiple asymptomatic acute cardiovascular changes some of which were present up to 24 h after dive.