Self-reported exercise tolerance can be used to predict in-hospital perioperative risk, even when using relatively simple and familiar measures.

Whole-cell voltage-clamp techniques were used to study the effects of the protein kinase C (PKC) activators phorbol esters and OAG on Ca and K currents in differentiated neurons acutely dissociated from adult hippocampus and in tissue-cultured neurons from fetal hippocampus. PKC activators had selective depressant effects on K currents, with persistent currents (IK and IK-Ca) being reduced and transient current (IA) being unaffected. In both cell types we recorded both high-voltage- activated, noninactivating (L-type) and high-voltage-activated, rapidly inactivating (N-type) Ca current. A low-voltage-activated, rapidly inactivating (T-type) Ca current was also recorded in tissue-cultured neurons but not in acutely dissociated neurons. PKC activators markedly reduced N-type current with less effect on L-type and no effect on T- type Ca current. Effects of PKC activators could be reversed with washing or with application of PKC inhibitors H-7 or polymyxin-B, an effect that could not be attributed to inhibition of cAMP-dependent protein kinase. The Ca/calmodulin inhibitor calmidazolium was ineffective in reversing the actions of PKC activators. Using whole- cell voltage-clamp techniques, we have demonstrated that hippocampal neurons possess 3 distinguishable components of calcium current. Distinct K currents were also observed. Our data strongly support the hypothesis that both Ca and K currents are selectively regulated by PKC and that these effects occur directly on the postsynaptic neuron.

Despite their widespread use in investigations of protein kinase C (PKC), concern is often expressed regarding the specificity of action of phorbol esters. We have extensively compared the effects of PDBu, a phorbol ester that activates PKC, with those of its inactive analog, 4 alpha-PDBu, on calcium (Ca) channel regulation in acutely isolated guinea pig hippocampal neurons and found that PKC-dependent and -independent actions could be clearly distinguished. While both phorbol esters depressed whole-cell barium current through Ca channels (IBa), PDBu was approximately 100-fold more potent than 4 alpha-PDBu. PKC-independent effects began to appear in the range of 5-10 microM, doses that, while high, have been used in some investigations. Moreover, only PDBu (1) was active when applied intracellularly, (2) had effects that were blocked by the PKC inhibitor H-7, and (3) induced PKC translocation with potency similar to its potency in depressing IBa. The finding that 4 alpha-PDBu acted only extracellularly was unexpected and suggested either that it acted via an extracellular binding site or that its orientation in the membrane was crucial to its effects on Ca channels. Finally, (4) PDBu alone caused a hyperpolarizing shift in the voltage dependence of the high-voltage-activated, rapidly inactivating (N type) component of Ca current. This result extends our previous finding that the N-type current component was depressed by PDBu to a greater extent than the L-type component and may represent an important new mode of neurotransmitter regulation of ion channels in the brain via PKC.

No abstract

No abstract