Chloride channel blocker IAA-94 increases myocardial infarction by reducing calcium retention capacity of the cardiac mitochondria.

Indanyloxyacetic acid-94 (IAA-94), an intracellular chloride channel blocker, is shown to ablate cardioprotection rendered by ischemic preconditioning (IPC), N (6)-2-(4-aminophenyl) ethyladenosine or the PKC activator phorbol 12-myristate 13-acetate and cyclosporin A (CsA) in both ex-vivo and in-vivo ischemia-reperfusion (IR) injury. Thus signifying the role of the IAA-94 sensitive chloride channels in mediating cardio-protection upon IR injury. Although IAA-94 sensitive chloride currents are recorded in cardiac mitoplast, there is still a lack of understanding of the mechanism by which IAA-94 increases myocardial infarction (MI) by IR injury. Mitochondria are the key arbitrators of cell life and death pathways. Both oxidative stress and calcium overload in the mitochondria, elicit pathways resulting in the opening of mitochondrial permeability transition pore (mPTP) leading to cell death. Therefore, in this study we explored the role of IAA-94 in MI and in maintaining calcium retention capacity (CRC) of cardiac mitochondria after IR. IAA-94 inhibited the CRC of the isolated cardiac mitochondria in a concentration-dependent manner as measured spectrofluorimetrically using calcium green-5 N. Interestingly, IAA-94 did not change the mitochondrial membrane potential. Further, CsA a blocker of mPTP opening could not override the effect of IAA-94. We also showed for the first time that IAA-94 perfusion after ischemic event augments MI by reducing the CRC of mitochondria. To conclude, our results demonstrate that the mechanism of IAA-94 mediated cardio-deleterious effects is via modulating the mitochondria CRC, thereby playing a role in mPTP opening. These findings highlight new pharmacological targets, which can mediate cardioprotection from IR injury.

[Effect of phenobarbital on the embryotoxic action of 2-methyl-4-chlorophenoxyacetic acid]. / Vliianie fenobarbitala na émbriotoksicheskoe deistvie 2-metil-4-khlorfenoksiuksusnoi kisloty.

Single administration of 2-methyl-4-chlorophenoxyacetic acid (2M-4C) to albino rats on the 9th and 10th day of gestation produces a teratogenic and embryotoxic action. A preliminary administration of phenobarbital in a dose of 80 mg/kg for 3 days largely reduced the embryotoxic effect of the drug, this manifesting itself in a lower general embryonal and post-implantation mortality, greater size and mass of the fetuses. It is suggested that the stimulation of the microsomal oxidation with phenobarbital led to a higher speed of the 2M-4C molecule decomposition and, consequently, to its lessened embryotoxic effect.

[Effect of serotonin and monoamine oxidase inhibitors on corneal anesthesia produced by celnovocaine and novocaine]. / Vliianie serotonina i ingibitorov monaaminaksidazy no anesteziiu rogovitsy, vyzyvaemuiu tselnovokainom i novokainom.

In experiments on guinea pigs it is shown that a preliminary intraperitoneal administration of monoamine oxidase inhibitors (MAOI) -- transamine (10 mg/kg) or malic acid benzyldihydrazide (50 mg/kg) antagonizes the local anesthetic action of celnovocaine (CC) and novocaine (NC). An analogous effect is also observed following instillation of transamine (a 0.1% solution) and malic acid benzyldihydrazide (a 0.23% solution) into the eye 10 minutes before administration of the anesthetic. Instillation of a 0.1% serotonin creatinine sulphate solution also antagonizes anesthesia produced by CC and NC, while MAOI potentiates the effect of serotonin.