The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat

Background and Purpose

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions.

Experimental Approaches

Ca²⁺-dependent active force production (F_active), its Ca²⁺ sensitivity (pCa₅₀), the kinetic characteristics of Ca²⁺-regulated activation and relaxation, and Ca²⁺-independent passive force (F_passive) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 μM).

Key Results

In permeabilized cardiomyocytes, OM increased the Ca²⁺ sensitivity of force production (ΔpCa₅₀: 0.11 or 0.34 at 0.1 or 1 μM respectively). The concentration–response relationship of the Ca²⁺ sensitization was bell-shaped, with maximal effects at 0.3–1 μM OM (EC₅₀: 0.08 ± 0.01 μM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased F_passive in the cardiomyocytes with an apparent EC₅₀ value of 0.26 ± 0.11 μM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics.

Conclusions and Implications

OM acted as a Ca²⁺-sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation–relaxation kinetics and at higher OM concentrations increased F_passive production.     

Inhibition of pancreatic secretory and trophic response to caerulein by the H2-receptor antagonist ranitidine in the rat

The effect of ranitidine (20 mg . kg-1) and cimetidine (50 mg . kg-1) on pancreatic secretory and trophic responses to caerulein (1 microgram . kg-1) was studied in the rat. Ranitidine or cimetidine were administered alone or combined with caerulein twice a day for 7 days. Saline-treated rats were used as controls. At the end of treatment animals were anesthetized and pancreatic juice was collected for 1 h after intravenous secretin plus CCK-PZ (8 U . kg-1). Afterwards rats were sacrificed and growth and composition of pancreatic tissue were determined. Compared with control (saline) values, volume of pancreatic juice and output of trypsin and amylase were increased by treatment with caerulein. Ranitidine, when given combined with caerulein, completely abolished the secretory response induced by the peptide, whereas it was totally ineffective when given alone. Cimetidine (alone or combined with caerulein) was always ineffective. Caerulein increased pancreatic weight, total pancreatic trypsin, amylase and RNA content. Here again ranitidine, combined with caerulein, abolished almost completely the trophic effect of caerulein on the pancreas, but when given alone it did not influence pancreatic growth and composition. Also in this case, cimetidine was completely inactive. These results suggest that ranitidine affects exocrine pancreas with an action independent of the H2-receptor blockade.     

Mucocele of the appendix： An unusual cause of lower abdominal pain in a patient with ulcerative colitis-. A case report and review of literature

The authors report the case of a 60-year-old male patient. In November 2001 he developed intestinal symptoms of bloody diarrhea and abdominal pain. Colononoscopy and biopsy established the diagnosis of ulcerative colitis (proctosigmoiditis). The disease activity was moderate at the beginning. No significant laboratory alterations were found (including CEA, CA19-9), and mesalazine was started orally. He was in remission until November 2003, when he was admitted to our Outpatient Clinic for upper and right lower abdominal pain and bloody diarrhea. Colonoscopy found proctosigmoiditis with a moderate activity, gastroscopy revealed chronic gastritis, laboratory data was normal. Treatment was amended with mesalazine clysma and methylprednisolone (16 mg) orally. Symptoms ameliorated; however, right lower abdominal pain persisted. US and CT examinat'on demonstrated a pericecal cystic mass (11 cm×3.5 cm). At first pericecal abscess was suspected, as the previous US examination (6 mo earlier) had revealed normal findings. Fine needie aspiration was performed. Cytology confirmed the diagnosis of mucocele. The patientunderwent partial cecum resection and extirpation of the mucocele. He recovered well and the final histology revealed a cystadenoma of the appendix. Follow up was started. The pati雗t is now free of symptoms. Although primary adenocarcinoma of the appendix is uncommon, the authors emphasize that preoperative diagnosis of an underlying malignancy in a mucocele is important for pati雗t management; however, it is difficult on imaging studies.     

A survey of current practices in the diagnosis of and interventions for inhalational injuries in Canadian burn centres

OBJECTIVE:

To summarize current Canadian practice patterns in the diagnosis of and interventions for inhalation injuries (INHI).

METHODS:

A 10-question survey regarding the diagnosis of and interventions for INHI was sent to the medical directors of all 16 burn centres across Canada.

RESULTS:

The response rate to the survey was 50%. Fibreoptic bronchoscopy is required for the diagnosis of INHI in only four centres (50%). The departments of intensive care, plastic surgery, otolaryngology and respirology are involved in performing fibreoptic bronchoscopy in 87.5%, 37.5%, 12.5% and 12.5% of Canadian burn centres, respectively. Intubation for INHI is most often based on physical examination results (87.5%) and clinical history (75%). The most common physical features believed to be most consistent with INHI are dyspnea (87.5%) and hoarseness (87.5%). Common treatments include intubation (87.5%), routine ventilatory support (87.5%) and chest physiotherapy (75%). None of the centres used nebulized heparin. A total of five centres (62.5%) routinely changed the fluid resuscitation protocol when INHI was diagnosed. Only two centres (25%) routinely used prophylactic antibiotics for INHI.

CONCLUSION:

Prospective, multicentre trials are needed to generate evidence-based consensus in the areas of diagnosis, grading and treatment for INHI in Canada.