Inhibition of Na+ channels

Inhibition of Na+ channels in the luminal membrane of the tubular epithelial cells... 

Ion channels saxitoxin/ wat --soluble alkaL/inhibition of Na channels Sigma 2000... 

SchlangerLE, KleymanTR, Ling BN. K(+)-sparlng diuretic actions of trimethoprim Inhibition of Na+channels In A6 distal nephron cells. Kidney International. 1994 Apr 45(4) l 070-6. 

Altogether these data demonstrate a complex and dynamic state-dependence for inhibition of Na + channels by mexiletine, with the single generalization that briefer depolarizations maximize stereoselectivity but that the conditions that produce the greatest apparent affinity result in no stereoselectivity. 

XM, and almost complete inhibition of Na" -channels was attained with 400 IM (+)-kavain and the potent Na channel blocker tetrodotoxin (10 XM) (Figure 6.3). The local anesthetic procaine (400 XM) reduced veratridine-elevated [Na i to 30.4% of control, whereas the centrally acting muscle relaxant mephenesin (400 XM) produced no effect. The data indicated a fast and specific inhibition of voltage-dependent Na -channels by (+)-kavain (Gleitz etal., 1995). 

Similar conclusions have been advanced previously to accomodate the voltage-dependent inhibition of Na+ channels by local anesthetics In contrast, nifedipine lacks almost com-... 

Transduction mechanism Inhibition of adenylyl cyclase stimulation of tyrosine phosphatase activity stimulation of MAP kinase activity activation of ERK inhibition of Ca2+ channel activation stimulation of Na+/H+ exchanger stimulation of AM PA/kainate glutamate channels Inhibition of forskol in-stimulated adenylyl cyclase activation of phos-phoinositide metabolism stimulation of tyrosine phosphatase activity inhibition of Ca2+ channel activation activation of K+ channel inhibition of AM PA/ kainate glutamate channels inhibition of MAP kinase activity inhibition of ERK stimulation of SHP-1 and SHP-2 Inhibition of adenylyl cyclase stimulation of phosphoinositide metabolism stimulation of tyrosine phosphatase activation of K+ channel inhibi-tion/stimulation of MAP kinase activity induction of p53 and Bax Inhibition of adenylyl cyclase stimulation of MAP kinase stimulation of p38 activation of tyrosine phosphatase stimulation of K+ channels and phospholipase A2 Inhibition of adenylyl cyclase activation/ inhibition of phosphoinositide metabolism inhibition of Ca2+ influx activation of K+ channels inhibition of MAP kinase stimulation of tyrosine phosphatase... 

Figure 6.2 Diagrammatic representation of a cholinergic synapse. Some 80% of neuronal acetylcholine (ACh) is found in the nerve terminal or synaptosome and the remainder in the cell body or axon. Within the synaptosome it is almost equally divided between two pools, as shown. ACh is synthesised from choline, which has been taken up into the nerve terminal, and to which it is broken down again, after release, by acetylcholinesterase. Postsynaptically the nicotinic receptor is directly linked to the opening of Na+ channels and can be blocked by compounds like dihydro-jS-erythroidine (DH/IE). Muscarinic receptors appear to inhibit K+ efflux to increase cell activity. For full details see text...

The potassium sparing diuretic, amiloride (43), also produces a Class III effect in cardiac tissue. In canine Purkinje fibres APD is increased by 35% after prolonged exposure to 5 /zM of the drug [121]. The authors suggest two potential mechanisms for this effect (1) delay of inactivation of Na+ channels, or (2) inhibition of Na+/Ca + exchange. In infarcted dogs which were subjected to a PES protocol to produce re-entrant ventricular arrhyth-... 

Its activity seems related to the decrease in the release of glutamate, and to the probable inhibition of Na ionic channels. 

Inhibition of Na fast channels, which can inhibit electrically excitable membranes and produce intracardiac conduction delays ( 137)... 

Long-term side effects of lithium treatment include weight gain. The treatment is associated with development of hypothyroidism in about 10-15% of cases. There is an association with kidney disease. Birch has expressed the general view that Li may interact with magnesium-dependent processes, and theoretical chemistry supports this view. Despite the widespread clinical significance of Li, there is presently no consensus on its mode of action. One postulate for the mechanism is termed hyperpolarization . Li affects the conductivity in cell transport channels. Other explanations include modulation of neurotransmitter concentrations and inhibition of Na+/K+/Mg2+/ Ca2+ ATPases. 

These diuretics antagonize the effects of aldosterone at the late distal tubule and cortical collecting tubule. Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone) or by inhibition of Na+ influx through ion channels in the luminal membrane (amiloride, triamterene). 

Stimulate the formation of cGMP. This appears to be the principal mode for mediating the effects of NO in the neurons. However, NO also acts by modifying the transition metal centers of a wide variety of proteins. It can function by selectively and reversibly S-nitrosylating cysteine residues on a wide variety of proteins with precise spatial and temporal resolution. These proteins may be ion channels, pumps, or metabolic enzymes for example, S-nitrosylation activates L-type Ca channels, Ca " -activated K -channels, and GABAA receptors, but it inhibits NMDA receptors and several classes of Na -channels. 

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