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PubMed1990

Protein kinase C activates the respiratory burst of fertilization, but not cortical granule exocytosis, in ionophore-stimulated sea urchin eggs.

In a "respiratory burst", fertilized sea urchin eggs consume oxygen to produce H2O2 as an extracellular oxidant to crosslink their protective surface envelopes. The egg generates H2O2 via a NADPH-specific oxidase that requires protein kinase C for activation. To further study the physiological regulation of the respiratory burst and cortical granule exocytosis, we have measured azide-insensitive oxygen uptake and fertilization envelope assembly in ionophore-stimulated eggs. Procaine, trifluoperazine, staurosporine, and H-7, which inhibit protein kinase C by different mechanisms, suppressed egg oxygen consumption without affecting fertilization envelope assembly. In contrast, both exocytosis and oxygen uptake were blocked in N-ethylmaleimide-treated eggs. When the eggs were stimulated with ionophore in Na-free artificial seawater, which prevents the increase in pHi, oxidase activity was inhibited. This effect was reversed by elevation of cytoplasmic pH with the membrane-permeant base NH4Cl. We conclude that protein kinase C was not involved in the events downstream from the ionophore-dependent elevation of Ca2+ which induced cortical granule exocytosis. However, the respiratory burst was inhibited despite the increase in Ca2+ that triggered exocytosis. The likely target for inhibition of the burst was protein kinase C. Cytoplasmic alkalinization was necessary for optimal rates of H2O2 synthesis, further implicating pHi as a regulator of the egg oxidase.

Animals↗

PubMed1999

Preservation solutions for transplantation.

Eurocollins has almost been abandoned because of the glucose disadvantage. UW is certainly the most used preservation solution for livers, kidneys, and pancreases with excellent clinical and experimental preservation data. UW can certainly be considered the current golden standard solution. However, the disadvantage of high viscosity, high price, uneasy handling of many 1-L bags, and the fact that the radical scavenger glutathion cannot be detected in the bags by chemical analysis (presumably due to diffusion) encourage competitors to produce new compounds with better cost to effect ratios. HTK has a firm place in cardiac preservation; by demonstration of equal safety and efficacy in preserving livers and kidneys, at least in the middle and lower range of cold ischemia time, HTK will be sued more frequently, particularly with the consideration of lower price and more easy handling aspects. The suggested high volume perfusion is not really necessary, calculation based on a total volume of 10 L for a multiorgan donor show significant cost reductions. Celsior is current only used for cardiac preservation. Beyond all aspects of conservation and preservation potencies of all these fluids, it must not be forgotten that cold ischemia itself is a risk factor for organ function. Therefore, cold ischemia time should be kept as short as possible. People are willing to accept 24 hours or more cold ischemia time in kidney transplantation because organ failure can be treated by dialysis. In other organs, where immediate organ function is essential, like in clinical heart transplantation, cold ischemia is hardly ever extended beyond 6 hours. Why are hearts and kidneys so different? Very likely, there is no difference, and the outstanding results in living unrelated kidney transplants is mostly due to short cold ischemia time.

Adenosine↗

PubMed1984

The influence of 2-chloroprocaine on the subsequent analgesic potency of bupivacaine.

Isolated rat sciatic nerves were used to study the interaction between 2-chloroprocaine (2-CP) and bupivacaine (BP). Five nerves studied as controls were treated with 5 X 10(-4) M BP and the amplitude of the compound action potential (CAP) evoked by suprathreshold stimulation was measured. This concentration of BP completely blocked nerve conduction; but, following washout with normal Krebs-Ringer solution, the CAP amplitude recovered to 50% of initial values in 50 (+/- 4) min with a rate of recovery of 1.7 (+/- 0.6) %/min. In another series of experiments, five nerves were blocked first with 5 X 10(-4) M 2-CP, allowed to fully recover, and then were blocked with BP under the same conditions as the controls. Under these conditions, the half time for the recovery of CAP amplitude following BP was shortened to 25 (+/- 5) min, with a rate of recovery of 2.8 (+/- 0.3) %/min. When five nerves were exposed to a 5 X 10(-4) M solution of a 2-CP metabolite, 4-amino-2-chlorobenzoic acid, no nerve blockade was produced. When these nerves subsequently were blocked with BP, recovery to 50% of initial values occurred in 22 (+/- 5) min, with a rate of recovery of 2.0 (+/- 0.2) %/min. Although pretreatment with either 2-CP or 4-amino-2-chlorobenzoic acid significantly shortened the duration of BP-induced nerve blockade, neither drug had a significant effect on the rate of recovery once the CAP amplitude returned to measurable values.

Action Potentials↗

PubMed2004

Sodium bisulfite: scapegoat for chloroprocaine neurotoxicity?

BACKGROUND: Neurologic deficits after apparent intrathecal injection of 3% Nesacaine-CE intended for epidural administration created concern about the potential toxicity of chloroprocaine and the preservative sodium bisulfite. Although bisulfite-free formulations of chloroprocaine were subsequently introduced into clinical practice, the relative toxicities of this anesthetic and preservative were never clearly established. The current studies used a relevant functional and histologic model to investigate the intrathecal neurotoxicity of these two compounds. METHODS: In the first experiment, rats implanted with intrathecal catheters were given one of two commercially available solutions of chloroprocaine, one of which contained sodium bisulfite; control animals received saline. Animals were assessed for sensory impairment 7 days after administration using the tail-flick test and were killed to obtain histologic specimens to quantify nerve injury. In the second experiment, identical methodology was used to investigate the effects of freshly prepared solutions of chloroprocaine, chloroprocaine with sodium bisulfite, sodium bisulfite, and saline. RESULTS: The two experiments yielded similar results. In experiment 1, tail-flick latencies and nerve injury scores after administration of plain chloroprocaine were significantly greater than those of chloroprocaine containing bisulfite. Injury scores for animals receiving chloroprocaine with bisulfite were elevated compared with those for animals given saline. In experiment 2, animals receiving plain chloroprocaine developed elevations in tail-flick latencies and nerve injury scores that were significantly greater than those for all other groups. Nerve injury scores with chloroprocaine containing bisulfite were greater than with saline or bisulfite alone. Tail-flick latencies and nerve injury scores with bisulfite alone were similar to those with saline. CONCLUSIONS: Clinical deficits associated with unintentional intrathecal injection of chloroprocaine likely resulted from a direct effect of the anesthetic, not the preservative. The data also suggest that bisulfite can reduce neurotoxic damage induced by intrathecal local anesthetic.

Anesthetics, Local↗

PubMed1984

Antitussive effect of RU-20201--central and peripheral actions.

The antitussive effect of the new compound 1, 2, 3, 4a, 9b-hexahydro-8, 9b-dimethyl-4-[3-(4-methyl-piperazine-1-yl) propionamide] dibenzofuran-3-one dihydrochloride (RU-20201) was investigated in dogs and guinea pigs, including its sites of action. The antitussive effect of RU-20201 was about 1/10 as potent as that of codeine phosphate in dogs with the puncture electrode-induced cough (PEC) method and about 1/12 and 1/4 as potent as that of codeine phosphate in guinea pigs with the PEC and chemical stimulation methods, respectively. When RU-20201 was administered in a dose range of 1 to 10 mg into the vertebral artery toward the brain in lightly anesthetized dogs, no antitussive effect was observed against the coughing elicited by electrical stimulation of the central cut end of the superior laryngeal nerve. However, a stimulative effect on respiration, especially on respiratory rate occurred. The peripheral effect of RU-20201 on the cough was investigated using the in situ upper trachea perfusion preparation which allows a direct drug administration to the local site around the tracheal mucosa, this site being electrically stimulated to induce coughing. A close i.a. infusion of RU-20201 in doses of 1 and 3 mg/min into the tracheal vascular bed for 5 min inhibited the cough response elicited by mucosal stimulation. The above findings suggest that RU-20201 has a significant antitussive activity, the site of action being probably, at least, at the cough receptor level.

Animals↗

PubMed1997

Ion transport and membrane potential in CNS myelinated axons. II. Effects of metabolic inhibition.

Compound resting membrane potential was recorded by the grease gap technique (37 degrees C) during glycolytic inhibition and chemical anoxia in myelinated axons of rat optic nerve. The average potential recorded under control conditions (no inhibitors) was -47 +/- 3 (SD) mV and was stable for 2-3 h. Zero glucose (replacement with sucrose) depolarized the nerve in a monotonic fashion to 55 +/- 10% of control after 60 min. In contrast, glycolytic inhibition with deoxyglucose (10 mM, glucose omitted) or iodoacetate (1 mM) evoked a characteristic voltage trajectory consisting of four distinct phases. A distinct early hyperpolarizing response (phase 1) was followed by a rapid depolarization (phase 2). Phase 2 was interrupted by a second late hyperpolarizing response (phase 3), which led to an abrupt reduction in the rate of potential change, causing nerves to then depolarize gradually (phase 4) to 75 +/- 9% and 55 +/- 6% of control after 60 min, in deoxyglucose and iodoacetate, respectively. Pyruvate (10 mM) completely prevented iodoacetate-induced depolarization. Effects of glycolytic inhibitors were delayed by 20-30 min, possibly due to continued, temporary oxidative phosphorylation using alternate substrates through the tricarboxylic acid cycle. Chemical anoxia (CN- 2 mM) immediately depolarized nerves, and phase 1 was never observed. However a small inflection in the voltage trajectory was typical after approximately 10 min. This was followed by a slow depolarization to 34 +/- 4% of control resting potential after 60 min of CN-. Addition of ouabain (1 mM) to CN--treated nerves caused an additional depolarization, indicating a minor glycolytic contribution to the Na+-K+-ATPase, which is fueled preferentially by ATP derived from oxidative phosphorylation. Phases 1 and 3 during iodoacetate exposure were diminished under nominally zero Ca2+ conditions and abolished with the addition of the Ca2+ chelator ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA; 5 mM). Tetraethylammonium chloride (20 mM) also reduced phase 1 and eliminated phase 3. The inflection observed with CN- was eliminated during exposure to zero-Ca2+/EGTA. A Ca2+-activated K+ conductance may be responsible for the observed hyperpolarizing inflections. Block of Na+ channels with tetrodotoxin (TTX; 1 microM) or replacement of Na+ with the impermeant cation choline significantly reduced depolarization during glycolytic inhibition with iodoacetate or chemical anoxia. The potential-sparing effects of TTX were less than those of choline-substituted perfusate, suggesting additional, TTX-insensitive Na+ influx pathways in metabolically compromised axons. The local anesthetics, procaine (1 mM) and QX-314 (300 microM), had similar effects to TTX. Taken together, the rate and extent of depolarization of metabolically compromised axons is dependent on external Na+. The Ca2+-dependent hyperpolarizing phases and reduction in rate of depolarization at later times may reflect intrinsic mechanisms designed to limit axonal injury during anoxia/ischemia.

Animals↗

PubMed2004

Effects of repeated injection of local anesthetic on sciatic nerve blocks response.

In order to examine whether repeated sciatic nerve blocks showed tachyphylaxis and continuity of sciatic nerve with spinal cord affected development of tachyphylaxis when assayed in vivo by duration of depression compound action potentials (CAP), rats were anesthetized with halothane, ventilated, monitored and supported with stable hemodynamics and temperature. Posterior tibial nerve distally and sciatic nerve in thigh were exposed, placed on bipolar silver electrodes for stimulation and recording respectively. Three sequential sciatic nerve blocks were performed between these electrodes using 0.15 ml of 3% chloroprocaine. Nine rats were chosen to observe the effects of repeated sciatic nerve blocks on CAP. In another 18 rats, a second investigator exposed the sciatic nerve near its origin at spinal cord and randomly performed nerve cut and sham (n=9), and closed the incision blinding the electrophysiologic investigator. The results showed that electrical stimulated tibial nerve induced sciatic nerve Aalpha/beta, Adelta, C fiber mediated CAP waves. CAP amplitudes were remained stable during whole experimental procedure. CAP amplitudes were decreased completely with 3% chloroprocaine blocked sciatic nerve and recovered fully. The duration of CAP depression were reduced with repeated blocks. There were no selective blocked effects on Aalpha/beta, Adelta, C fiber mediated CAP. With sciatic nerve cut proximally, there was no statistical significant tachyphylaxis with 3% chloroprocaine repeated blocked sciatic nerve, and the duration of first and third blocked Adelta fiber mediated CAP was 108+/-20 and 92+/-14 min respectively (P>0.05). In normal rats the duration of first and third blocked Adelta fiber mediated CAP was 110+/-20 and 75+/-16 min respectively (P<0.05). It was suggested that tachyphylaxis to local anesthetics can occur in rats repeated blocked sciatic nerve when assayed in vivo by duration of depression CAP. The continuity of sciatic nerve with spinal cord is one of the important factors affecting the development of tachyphylaxis.

Anesthetics, Local↗

PubMed2000

Physiologic and metabolic results of pancreatic cold storage with Histidine-Tryptophan-Ketoglutarate-HTK solution (Custodiol) in the porcine autotransplantation model.

UNLABELLED: Delayed graft function (DEGF) remains an obscure phenomenon in organ transplantation. For the optimal washing of the compounds of the different organ flush solutions, adequate temperature and equilibrium of electrolytes have to be provided. A total of 29 land-race pigs weighing 37.3-5.4 kg were included in this study. According to the model, the left hemipancreas was perfused with Histidine-Tryptophan-Ketoglutarate (HTK)-solution and autotransplanted after 24 h (G1, n = 13) and 48 h (G2, n = 4) of cold storage (CS). Results were compared with grafts perfused with UW-solution and autotransplanted after 24 h (G3, n = 8) and 48 h (G4, n = 4) CS respectively. Daily measurements of glycemia, glucosuria, amylase and lipase were carried out. HTK perfusion resulted in an increase in wet weight of the grafts after 24 h and 48 h CS (P = 0.031 vs UW). Postoperative glycemia levels in pancreases flushed with HTK-solution were higher after 48 h than after 24 h CS until the 6th postoperative day, when the glycemia returned to normal range (P = 0.02), suggesting a delayed endocrine graft function. The mean IVGTT values attained after full function were comparable in G1 and in G3 (-1.22 +/- 0.23 vs. -1.5 +/- 0.65). The rises in serum amylase and lipase levels were more pronounced after 48 h CS in both HTK and UW groups, (P = n.s.). Appearance of interstitial and intracellular edema after CS and reperfusion did not influence the function. CONCLUSION: HTK-solution is suitable for 24 h pancreatic preservation in vivo; the perfusion requires at least 4 min for electrolyte equilibration. Long preservation time (48 h) resulted in a transitory DEGF.

Animals↗

PubMed1983

The effects of 2-nicotinamidoethyl nitrate on smooth muscle cells of the dog mesenteric artery and trachea.

The effects of 2-nicotinamidoethyl nitrate (nicorandil; 2-NN), a synthesized coronary vasodilator, on smooth muscle cells of dog mesenteric artery or trachea were investigated using microelectrode, double sucrose gap and isometric tension recording methods. Nicorandil hyperpolarized the smooth muscle membrane of the mesenteric artery (5 X 10(-6)M) and the trachea (5 X 10(-5)M). In both these smooth muscle cells, the nicorandil-induced hyperpolarization remained constant in various concentrations of [Cl-]o, but changed with various concentrations of [K+]o. This hyperpolarization was partly inhibited following pretreatment with tetraethylammonium (TEA greater than 1 mM) and was completely inhibited following pretreatment with procaine (1 mM or 5 mM), indicating that the nicorandyl-induced hyperpolarization is due to increase in the K-conductance, in both these membranes. Following pretreatment with TEA (5 mM), outward current pulses evoked an action potential in tracheal smooth muscle cells. Nicorandil inhibited the generation of action potential due to the hyperpolarization of the membrane but not due to inhibition of the spike generating mechanism. Nicorandil (10(-6)M) inhibited the contracture evoked by excess [K]o, in both tissues. The contracture evoked by noradrenaline or repetitive field stimulation with short duration (50 microseconds) pulses was also inhibited in the mesenteric artery, while a higher dose of nicorandil (10(-5)M) was required to inhibit the contracture evoked by acetylcholine or repetitive field stimulation in the trachea. Excitatory junction potentials (e.j.ps) evoked by field stimulation in the mesenteric artery due to the release of noradrenaline, or in the trachea due to release of acetylcholine, were suppressed by 10(-5)M or 5 X 10(-5)M nicorandil, respectively. The reduction in the amplitude of e.j.p. was mainly due to the hyperpolarization of the membrane with increase in the membrane conductance. In the mesenteric artery, following pretreatment with TEA (1 mM) an action potential was generated on the e.j.p.. Nicorandil suppressed the generation of the action potential by reduction in the amplitude of the e.j.p., below the threshold required for generation of the action potential. These results indicate that nicorandil hyperpolarizes the membrane by increasing K-conductance and inhibits the generation of contraction, in both tissues. Higher concentrations of nicorandil are required to suppress the mechanical response in the trachea than in the mesenteric artery. Depression of the mechanical responses in both tissues is partly due to suppression of Ca-mobilization inside the muscle cells and partly to hyperpolarization of the membrane.

Animals↗