Ventricular muscle has a biphasic response to stretch. There is an immediate increase in force that coincides with the stretch which is followed by a second phase that takes several minutes for force to develop to a new steady state. The initial increase in force is due to changes in myofilament properties, whereas the second, slower component of the stretch response (known as the "slow force response" or SFR) is accompanied by a steady increase in Ca 2+ transient amplitude. Evidence shows stretch-dependent Ca 2+ influx during the SFR occurs through some mechanism that is continuously active for several minutes following stretch. Many of the candidate ion channels are located primarily in the t-tubules, which are consequently lost in heart disease. Our aim, therefore, was to investigate the impact of t-tubule loss on the SFR in non-failing cardiac trabeculae in which expression of the different Ca 2+ handling proteins was not altered by any disease process. For comparison, we also investigated the effect of formamide detubulation of trabeculae on β-adrenergic activation (1 µM isoproterenol), since this is another key regulator of cardiac force. Measurement of intracellular calcium ([Ca 2+ ] i) and isometric stress were made in RV trabeculae from rat hearts before, during and after formamide treatment (1.5 M for 5 min), which on washout seals the surface sarcolemmal t-tubule openings. Results showed detubulation slowed the time course of Ca 2+ transients and twitch force, with time-to-peak, maximum rate-of-rise, and relaxation prolonged in trabeculae at optimal length (L o). Formamide treatment also prevented development of the SFR following a step change in length from 90 to 100% L o , and blunted the response to β-adrenergic activation (1 µM isoproterenol).

Background:Hyperbaric oxygen therapy (HBOT) is a treatment option for chronic nonhealing wounds. Transcutaneous oximetry (TCOM) is used for wound assessment. We undertook a randomized prospective controlled trial to evaluate the role of HBOT in healing of chronic nonhealing wounds and to determine whether TCOM predicts healing.Materials and Methods:This study was conducted in 30 consenting patients with nonhealing ulcer. The patients were randomized into group HT (receiving HBOT in addition to conventional treatment) and group CT (receiving only conventional treatment). Duration of treatment in both the groups was 30 days. Wound ulcer was analyzed based on size of the wound, exudates, presence of granulation tissue, and wound tissue scoring. Tissue oxygenation (TcPO2) was measured on 0, 10th, 20th, and 30th day.Results:There was 59% reduction in wound area in group HT and 26% increase in wound area in group CT. Ten patients in group HT showed improvement in wound score as compared to five patients in group CT. Complete healing was seen in three patients in group HT as compared to none in group CT. Surgical debridement was required in 6 patients in group HT and 10 patients in group CT. One patient in group HT required amputation as compared to five patients in group CT. A positive correlation was found between TcPO2 value and various markers of wound healing.Conclusion:HBOT has a definitive adjunctive role in the management of chronic nonhealing ulcers. It decreases the amputation rate and improves patient outcome. Periwound TcPO2 may be used as a predictor of response to HBOT and has a positive correlation with wound healing.

Recently, a family of guanine nucleotide exchange factors have been identified in many cell types as important effectors of cyclic adenosine 3',5'-monophospahte (cAMP) signalling that is independent of protein kinase A (PKA). In the heart, investigation of exchange protein directly activated by cAMP (Epac) has yielded conflicting results. Since cAMP is an important regulator of cardiac contractility, this study aimed to examine whether Epac activation modulates excitation-contraction coupling in ventricular preparations from rat hearts. The study used 8-(4-chlorophenylthio)-2'-O-methyladenosine-3', 5'-cyclic monophosphate (cpTOME), an analogue of cAMP that activates Epac, but not PKA. In isolated myocytes, cpTOME increased Ca(2+) spark frequency from about 7 to 32/100 μm(3)/s (n = 10), P = 0.05 with a reduction in the peak amplitude of the sparks. Simultaneous measurements of intracellular Ca(2+) and isometric force in multicellular trabeculae (n = 7, 1.5 mmol/L [Ca(2+)]o) revealed no effect of Epac activation on either the amplitude of Ca(2+) transients (Control 0.7 ± 0.1 vs cpTOME 0.7 ± 0.1; 340/380 fura-2 ratio, P = 0.35) or on peak stress (Control 24 ± 5 mN/mm(2) vs cpTOME 23 ± 5 mN/mm(2), P = 0.20). However, an effect of Epac in trabeculae was unmasked by lowering extracellular [Ca(2+)]o. In these depotentiated trabeculae, activation of the Epac pathway increased myofilament Ca(2+) sensitivity, an effect that was blocked by addition of KN-93, a Ca(2+)/calmodulin-dependent protein kinase II (CaMK-II) inhibitor. This study suggests that Epac activation may be a useful therapeutic target to increase the strength of contraction during low inotropic states.

Prostaglandins are ubiquitous signaling molecules in the body that produce autocrine/paracrine effects on target cells in response to mechanical or chemical signals. In the heart, long-term exposure to prostaglandin (PG) F2α has been linked to the development of hypertrophy; however, there is no consensus on the acute effect of PGF2α. Our aim was to determine the response to exogenous PGF2α in isolated trabeculae from rat hearts. PGF2α (1 μM) increased both the Ca transients and the isometric stress in trabeculae, reaching steady state after 10-15 minutes, without altering the time course of Ca transient decay. The precursor of PGF2α, arachidonic acid, also stimulated a similar response. The positive inotropic effect of PGF2α was mediated through a protein kinase C signaling pathway that involved activation of the sarcolemmal Na/H exchanger. We also found that the slow force response to stretch was attenuated in the presence of PGF2α and by addition of indomethacin, a blocker of prostaglandin synthesis. In conclusion, PGF2α was positively inotropic when acutely applied to trabeculae and contributed to the increased Ca transients during the slow force response to stretch. Together, these data suggest that PGF2α is important in maintaining homeostasis during volume loading in healthy hearts.