Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca-ATPase 2a axis and Na-Ca exchanger function in Ca extrusion. This resulted in reduced sarcoplasmic reticulum Ca content, diastolic Ca overload, systolic dysfunction and impaired contractile force. Furthermore, saxagliptin reduced protein kinase C-mediated delayed rectifier K current that prolonged action potential duration and consequently QTc interval. Importantly, saxagliptin aggravated pre-existing cardiac dysfunction induced by ischemia/reperfusion injury. In conclusion, our novel results provide mechanisms for the off-target deleterious effects of saxagliptin on cardiac function and support the outcome of SAVOR-TIMI 53 trial that linked saxagliptin with the risk of heart failure.

all 10 cities including the rural areas of the province of Kerman. All data were finally analyzed by SPSS software (version 11.5). Results On the basis of recorded statistical analysis, the mortality cases of human rabies in the province of Kerman during one decade was 10 persons (eight males and two females). One-half of them (50%) were bitten by dogs and the others (50%) by foxes. Among the reported deaths, 40% were from Kahnooj county (Jiroft region). The reported data indicated that 21,546 persons were bitten by animals during 10 years in the province of Kerman. The mean of age of the people who were bitten by dogs was 24.80 years (SD = ±14.6), while the mean age of the people who were bitten by foxes was 57.25 years (SD = ±1.50). There was a significant difference between the mean age of these two groups of the people (P < 0.05). The most frequent rate of injured people was reported in the age group 10-19 years old and the frequency rate of males (76.00%) was more than females (24.00%). Therefore, there was a statistically significant difference between males and females in this study (P < 0.01). About 60% of all persons that were bitten by animals were from rural areas and 40% of them were from urban areas (P < 0.05). Among the people who were bitten and injured by animals during one decade in the province of Kerman, 85.70% of them were not treated by the rabies prophylaxis treatment regimen. Among all of them who were bitten by animals, 50% were injured through hands and feet, 40% of them through heads and faces, and 10% of them through trunks, cervical regions and other organs of the bodies. In the persons who were bitten by animals in the head region, the mean latency period for rabies was 33 days (SD = ±12.2 days), while the mean latency period in the persons who were bitten through hands and feet was 77 days (SD = ±45.8 days). The P value was <0.1. The results of this study showed that there is a significant reciprocal correlation between annual raining level and the frequency rate of animal bites in the province of Kerman (r = 0.5, P < 0.01). Conclusions According to this study, the role of foxes in the epidemiology of human rabies in the province of Kerman, located in the southeast of Iran, seems very important. Since most of the animal bite individuals, during the one-decade survey in this region of Iran, did not seem aware of the risk of exposure to the viral infection of rabies through animal bites, the public education of preventive measurements of rabies seems imperative by the public health authorities as well as vaccination of animals against rabies, especially dogs and cats, as well as mass vaccination of wild animals by means of distribution of oral vaccines in the vast and scattered forests by helicopters belonging to Veterinary Organization Authorities being recommended. Collaboration of intersectional public health relationships of medical science universities of the province of Kerman as well as all related authorities to control rabies prevalence in the regional and interregional provi...

The present study demonstrates that most of the electrophysiological properties of ICa,L in ventricular myocytes isolated from children with tetralogy of Fallot resemble those of adult ventricular cells. The existence of a big calcium window current could be involved in the occurrence of early afterdepolarizations which could lead to the high incidence of arrhythmias after surgical repair of tetralogy of Fallot.

Ox-LDL induced cell damage and irregular electrical activity in ventricular myocytes. These effects were dependent on the lipid hydroperoxide content of ox-LDL and were similar to oxidative stress (OS) induced by various OS-generating systems. The observed effects may play a role for functional cardiac abnormalities in patients with increased ox-LDL levels.

Our study revealed the presence of I(f) in left atrial myocytes and showed that I(f) parameters depend on atrial region. I(f) current densities were sufficient to convert the mathematical model of a quiescent human atrial cell into a "pacemaker cell". These data support the hypothesis of I(f) as a contributor to abnormal automaticity in human atrial tissue.

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The electrophysiological characteristics of right ventricular myocytes isolated from children with tetralogy of Fallot resemble in most cases subendocardial myocytes from adults. The most prominent difference is a fast recovery from inactivation as well as a small rate dependent reduction of Itol. The observed EADs may have clinical implications.

1 The aim of this study was to investigate the effect of nicotinamide-adenine dinucleotide (NADH) supplementation on the metabolic condition of isolated guinea-pig ventricular cardiomyocytes. The pinacidil-primed ATP-dependent potassium current I K(ATP) was used as an indicator of subsarcolemmal ATP concentration and intracellular adenine nucleotide contents were measured. 2 Membrane currents were studied using the patch-clamp technique in the whole-cell recording mode at 36 -371C. Adenine nucleotides were determined by HPLC.