Methyl-laudanosine: A new pharmacological tool to investigate the function of small-conductance Ca2+-activated K+ channels

ABSTRACT Small-conductance Ca 2ϩ -activated K ϩ channels (SK channels) underlie the prolonged postspike afterhyperpolarization (AHP) observed in many central neurons and play an important role in modulating neuronal activity. However, a lack of specific and reversible blockers of these channels hampers their study in various experimental conditions. Because previous work has shown that bicuculline salts block these channels, we examined whether related alkaloids, namely laudanosine quaternary derivatives, would produce similar effects. Intracellular recordings were performed on rat midbrain dopaminergic neurons and hippocampus CA1 pyramidal cells. Binding experiments were performed on rat cerebral cortex membranes. Laudanosine, methyl-laudanosine, and ethyl-laudanosine blocked the apamin-sensitive AHP of dopaminergic neurons with mean IC 50 values of 152, 15, and 47 M, respectively. The benzyl and butyl derivatives were less potent. Methyl-laudanosine had no effect on the I h current, action potential parameters, or membrane resistance of dopaminergic cells, or on the decrease in input resistance induced by muscimol, indicating a lack of antagonism at GABA A receptors. Interestingly, 100 M methyllaudanosine induced a significant increase in spiking frequency of dopaminergic neurons but not of CA1 pyramidal cells, suggesting the possibility of regional selectivity. Binding experiments on laudanosine derivatives were in good agreement with electrophysiological data. Moreover, methyl-laudanosine has no affinity for voltage-gated potassium channels, and its affinity for SK channels (IC 50 4 M) is superior to its affinity for muscarinic (IC 50 114 M) and neuronal nicotinic (IC 50 Ն367 M) receptors . Methyl-laudanosine may be a valuable pharmacological tool to investigate the role of SK channels in various experimental models. Other than neurotransmitter receptors and transporters, ion channels constitute an attractive target to develop new drugs that will be active on the central nervous system. Currently, the only ion channel that is well established as a central nervous system target is the voltage-gated Na ϩ channel, which is blocked by antiepileptic drugs such as phenytoin, carbamazepine, and lamotrigine Evidence suggests that SK-channel modulation may be interesting in a range of central nervous system disorders, This work was supported in part by Grant 3.4525.98 from the National Fund for Scientific Research (Brussels, Belgium). This work has been presented in meeting abstract form: Scuvée-Moreau J, Liégeois JF, and Seutin V (2002) Effect of laudanosine derivatives on the apamin-sensitive afterhyperpolarization of rat dopaminergic neurons-identification of methyl-laudanosine as a new specific blocker (Abstract). Fundam Clin Pharmacol 16:67

Mechanisms of caffeine-induced diuresis

Caffeine is an alkaloid which belongs to the family of methylxanthines and is present in beverages, food and drugs. Caffeine competitively antagonizes the adenosine receptors (AR), which are G protein-coupled receptors largely distributed throughout the body, including brain, heart, vessels and kidneys. Caffeine consumption has a well-known diuretic effect. The homeostasis of salt and water involves different segments of the nephron, in which adenosine plays complex roles depending on the differential expression of AR. Hence, caffeine increases glomerular filtration rate by opposing the vasoconstriction of renal afferent arteriole mediated by adenosine via type 1 AR during the tubuloglomerular feedback. Caffeine also inhibits Na(+) reabsorption at the level of renal proximal tubules. In addition, caffeine perturbs the hepatorenal reflex via sensory nerves in Mall's intrahepatic spaces. Here, we review the physiology of caffeine-induced natriuresis and diuresis, as well as the putative pathological implications