Stretch of cardiac muscle is known to activate various physiological processes that result in changes to cardiac function, contractility and electrophysiology. To date, however, the precise relationship between mechanical stretch and changes in the electrophysiology of the heart remain unclear. This relationship, termed mechanoelectric feedback (MEF), is thought to underlie many cardiac arrhythmias associated with pathological conditions. These electrophysiological changes are observed not only in the whole heart, but also at the single cardiomyocyte level, and can be explained by the presence of stretch-activated ion channels (SACs). Most investigations of the actions of stretch have concentrated on these sacrolemmal ionic currents thought responsible for the proposed MEF-induced changes in contractility. While these studies have provided some useful insight into possible mechanisms, the inappropriate use of solutions and non-physiological degrees of stretch, may have caused somewhat misleading results. Currently, little is known about the involvement or contribution of non-selective or K+ selective SACs to the normal cardiac cycle. Here, I investigate the concept that stretch-induced changes in cardiac electrophysiology (MEF) are important in normal cardiac cycle and demonstrate the effects of stretch on the Frank-Starling mechanism (stretch induced increases in cardiac contractility) while pharmacologically manipulating stretch-activated ion currents. Experiments were conducted using a number of agents known to influence stretch-activated channels either in a positive or antagonistic manner. Results proved somewhat negative toward MEF theory with only substantial or pathological levels of stretch being able to elicit any electrophysiological change in the heart. Furthermore, where electrophysiological changes were associated with pathological stretch they were not consistently modulated by stretch-activated ion channel activators or blockers. Of equal importance was the observation that smaller levels of myocardial stretch associated with positive changes in contractility via the Frank-Starling mechanism were not associated with any electrophysiological changes in the Langendorff perfused heart (as observed by monophasic action potentials) nor in isolated muscle preparations (as observed through transcellular membrane potential recordings). As such, the present research undertaken in this thesis confirms an absence of electrophysiological changes with stretch except under extreme conditions suggesting that MEF is not a robust and necessarily repeatable phenomenon in the mammalian heart. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1320476 / Thesis (Ph.D.) - University of Adelaide, School of Molecular and Biomedical Science, 2008

The mammalian Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitously expressed membrane protein that regulates myocardial intracellular pH. Inhibition of NHE1 prevents hypertrophy and reduces ischemia-reperfusion (I/R) injury in animal models. To understand the regulation of NHE1 in the myocardium by phosphorylation we constructed adenoviruses, which express wild type or mutant cDNA for NHE1. Additionally, wild type and mutant NHE1 had mutations Leu163Phe/Gly174Ser, which increases NHE1 resistance to EMD87580 (NHE1 inhibitor) by 100-fold. This allowed measurement of exogenous NHE1 activity while inhibiting endogenous NHE1 activity. We examined the effects of a series of mutations of phosphorylation sites in the cytosolic domain of NHE1. Sustained intracellular acidosis and phenylephrine caused an ERK-dependent activation of NHE1 activity and phosphorylation levels. We demonstrated that amino acids Ser770 and Ser771 were essential for activation of NHE1 activity in isolated rat cardiomyocytes by sustained intracellular acidosis and phenylephrine. Furthermore, mutation of Ser770 and Ser771 to Ala prevented increased NHE1 phosphorylation by sustained intracellular acidosis and phenylephrine. This was found to occur in an ERK-dependent manner. Taken together, our results demonstrate that both sustained intracellular acidosis and phenylephrine rapidly activate the NHE1 protein in isolated cardiac cells via an ERK-dependent pathway that acts on the common amino acids Ser770 and Ser771 of the C-terminal tail of NHE1.

No description available.

Long-term adaptation of cardiovascular system in response to regular physical activity depends not only on its type, intensity and volume, but on arterial blood pressure (ABP) during exercise as well. Although it is proved haemodynamic load is not the only factor responsible for the shaping of athlete's myocardium, both the extent and the type of cardiac remodelling are influenced greatly by the degree of pressure overload during exercise training. The aim of our study was to compare myocardium loading conditions during veloergometric and treadmill interval tests. Methods. Distance runners (all males, n = 16) served as subjects. Their age was 23.6 ± 5.5 yrs, body mass – 70.7 ± 4.7 kg, body mass index – 21.7 ± 1.9 kg/m2, training experience – 8.7 ± 5.6 yrs. Interval tests were applied on separate days. Each of them consisted of increasing intensity exercise interspaced with passive resting period (in seated position) of 4 min in duration. Heart rate (HR) was recorded throughout both tests while ABP was measured during recovery period between treadmill stages. Tests were continued till HR reached 90 percent of age-predicted maximum. Results. Systolic ABP, HR and double product were higher (p<0.05) after the discontinuation of veloergometric workload as compared with treadmill load requiring similar oxygen consumption. Runners' systolic ABP response was bigger to veloergometry as compared with treadmill running eliciting the same HR (p<0.05). Significant correlation was found... [to full text]

Heart failure is an important medical disease and impacts millions of people throughout the world. In order to treat this problem, biomaterial injectable treatment injected into the myocardium of the failing LV are currently being developed. Through this treatment, the biomaterial material injections can reduce wall stresses during the cardiac remodeling process. By using computational techniques to analyze the effects of a treatment involving the injection of biomaterial material into the LV after MI, the material parameters of the hydrogel injections can be optimized. The results shows that the hydrogel injections could reduce the global average fiber stress and the transmural average stress seen from optimization. These results indicated that the hydrogel injections could influence the stiffness in passive LV tissue, but there is still need for more research on the active part of ventricular contraction. Conclusion: hydrogel injection is a viable way to alter ventricular mechanical properties.

Cholecystokinin, or "CCK" peptides, originally identified in the gastrointestinal tract, are now considered to be one of the most abundant peptide systems in the mammalian central nervous system. Prompted by recent findings that implicated the cholecystokinergic system in the pathophysiology of various illnesses, we developed a novel assay system to measure the various forms of cholecystokinin peptides in human plasma and cerebrospinal fluid. The system detects CCK-4, sulfated CCK-8 (CCK-8s) and nonsulfated CCK-8 (CCK-8ns) with equal affinity, with the lower detection limit of 2.7 fmol and an ED50 of 10.6 +/- 2.2 fmol. Using the assay system, we determined that mean CCK-like immunoreactivity (CCK-LI) in the plasma of 12 healthy subjects was 12.9 +/- 2.1 pM CCK-4 equivalents. / After developing the cholecystokinin assay system, we were able to combine our unique methodology with other established techniques to investigate the role of CCK in illnesses such as premenstrual dysphoric disorder (PMDD), anxiety, bulimia nervosa, and cardiomyopathy. / Briefly, we observed no significant differences in plasma CCK levels between women with PMDD and healthy volunteers. However, we found that, independent of diagnosis, plasma cholecystokinin concentrations were higher in women during their first visit to the clinic to participate in the study, as compared to later visits. / In addition, application of our assay system allowed us to determine that oral ingestion of caffeine increased plasma CCK-LI levels 2--4 fold in humans. Moreover, we observed substantial variation in post-caffeine cholecystokinin levels among individuals. / In another study of cholecystokinin and anxiety, we used our CCK assay to determine the effects of ondansetron, a serotonin receptor antagonist, on cholecystokinin levels in plasma. We found that multiple oral doses of ondansetron influence the pharmacokinetic parameters of exogenous CCK. / We also used the three-step assay system to measure CCK-LI in patients with the eating disorder, bulimia nervosa. Baseline fasted cholecystokinin plasma levels were lower in bulimic women as compared to control subjects. However, at "satiety", or the post-binge stage, CCK levels in bulimic women were similar to those of control women. / Finally, our investigation into the role of cholecystokinin in cardiomyopathy revealed that neuronal cholecystokinin receptor density was altered in the cardiomyopathic hamster brain, as compared to age- and sex-matched control animals. (Abstract shortened by UMI.)

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "August 2007" Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Dissertation (PhD)--University of Stellenbosch, 2007. / Bibliography. Also available via the Internet.

Dissertation (Ph.D.)--University of South Florida, 2008. / Title from PDF of title page. Document formatted into pages; contains 140 pages. Includes vita. Includes bibliographical references.