No abstract

Mutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca2+, inhibits halothane- and isoflurane-induced Ca2+ release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and prevents or reverses the fulminant MH crisis induced by isoflurane anesthesia and rescues animals from heat stroke caused by environmental heat stress. Notably, Cpd1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Cpd1 has the potential to be a promising candidate for effective treatment of patients carrying RyR1 mutations.

No abstract

1. The effects of nicardipine on the secretion of pancreatic juice were investigated in dog isolated, blood-perfused pancreas, and compared with those of papaverine, aminophylline and secretin. 2. Intra-arterial administration of nicardipine (1-10 micrograms) elicited a dose-dependent increase in pancreatic secretion. Papaverine (0.1-1 mg), aminophylline (0.3-3 mg) and secretin (0.03-0.1 units) also elicited increased secretion. The secretory activity of nicardipine (10 micrograms) was approximately equal to that of 0.5 mg of papaverine, 1.5 mg of aminophylline and 0.03 units of secretin. 3. The concentration of bicarbonate in the pancreatic juice induced by nicardipine was increased, but the protein concentration was only increased slightly. These effects are analogous to those of secretin. 4. Nicardipine-induced secretion was not modified by pretreatment with relatively large doses of phentolamine, propranolol, atropine, guanethidine, haloperidol or metiamide. 5. Secretin-induced secretion was significantly potentiated by infusion of papaverine, but not by infusion of nicardipine or aminophylline. 6. These results suggest that nicardipine acts on the exocrine cells in the dog pancreas, at least in part, through the increase of intracellular cyclic AMP concentration by inhibiting phosphodiesterase activity.

Kaolin induced a clear and reproducible writhing reaction when intraperitoneally injected into mice. A simultaneous injection (i.p.) of soybean trypsin inhibitor (SBTI) significantly suppressed the kaolin-induced writhing reaction. This writhing reaction was markedly potentiated by a simultaneous injection (i.p.) of captopril. In an in vitro experiment kaolin caused kinin-release in mouse plasma, possibly through the activation of prekallikrein. This activation of plasma prekallikrein and kinin-release were inhibited in the presence of SBTI. Some non-steroidal anti-inflammatory agents inhibited the kaolin-induced writhing reaction dose-dependently. These results suggest that kaolin-induced writhing reaction may be caused by the released bradykinin through activation of the plasma kallikrein-kinin system. This model is a novel and simple tool for assessment of analgesic agents.