An uptake system for dietary alkaloids in poison frogs (Dendrobatidae).

The skin of poison frogs (Dendrobatidae) contains a wide variety of alkaloids that presumably serve a defensive role. These alkaloids persist for years in captivity, but are not present in captive-raised frogs. Alkaloids fed to poison frogs (Dendrobates, Phyllobates, Epipedobates) are readily accumulated into skin, where they remain for months. The process can be selective; an ant indolizidine is accumulated, while an ant pyrrolidine is not. Frogs (Colostethus) of the same family, which do not normally contain alkaloids, do not accumulate alkaloids. Such an alkaloid uptake system provides a means of maintaining skin alkaloids and suggests that some if not all such 'dendrobatid alkaloids' may have a dietary origin.

Structure-activity relationships for 2-substituted adenosines at A1 and A2 adenosine receptors.

A series of 55 2-alkyloxy-, 2-aryloxy- and 2-aralkyloxy-adenosines was screened as inhibitors of the binding of [3H]R-phenyl-isopropyladenosine to A1 adenosine receptors in rat cerebral cortical membranes, and of the binding of [3]N-ethylcarboxamidoadenosine to A2 adenosine receptors in rat striatal membranes and as agonists at A2 adenosine receptors coupled to adenylate cyclase in rat pheochromocytoma PC12 cell membranes. The activities are consonant with a hydrophobic binding site in the A2 receptors at a distance from the 2-position of the adenine ring corresponding to a spacer chain of -O-CH2-CH2-. These is little lateral steric tolerance in the region occupied by the spacer chain. Interaction with the hydrophobic binding site is greatest in the 2-alkyloxy series for 2-cyclohexylethoxy-, 2-cyclohexylpropoxy- and 2-cyclohexylbutoxyadenosines and in the 2-aralkoxy series for 2-phenylethoxy-, 2-(4-methylphenyl)ethoxy-, 2-(4-chlorophenyl)ethoxy-, and 2-naphthylethoxy-adenosine. The affinities of the 2-substituted adenosines for the rat cerebral cortical A1 receptors are not as markedly altered by structural changes and are in almost all cases two- to hundredfold less than the affinity of the 2-substituted adenosine for the rat striatal A2 receptor. There is excellent correspondence of the present data on rat A2 receptors with reported potencies of these 2-substituted adenosines as coronary vasodilators in guinea pig heart preparations.

Variability in alkaloid profiles in neotropical poison frogs (Dendrobatidae): genetic versus environmental determinants.

Dendrobatid frogs produce a diverse set of alkaloids, whose profiles appear characteristic of frogs of each species or, in the case of variable species, of each population. In the case of one widespread species, Dendrobates auratus, alkaloid profiles in extracts of skin are markedly different in three populations, one from a Pacific island, Isla Taboga, Panama, one from central mountains in Panama, and the third from the Caribbean coast in Costa Rica. The first contains three major classes of dendrobatid alkaloids, the histrionicotoxins, the pumiliotoxin-A class and the decahydroquinolines. The second contains mainly histrionicotoxins, pumiliotoxin-A class alkaloids and one indolizidine. The third contains histrionicotoxins, a homopumiliotoxin, one decahydroquinoline, and a variety of indolizidines, quinolizidines and pyrrolizidines. Frogs from Isla Taboga or a nearby island were introduced into the Manoa Valley, Oahu, Hawaii, in 1932. Remarkably, although alkaloids of the pumiliotoxin-A class and one decahydroquinoline are still major constituents in skin extracts of Hawaiian frogs descended from the 1932 founding population, histrionicotoxins are absent and a novel tricyclic alkaloid is present. Offspring of wild-caught parents from Hawaii, Panama or Costa Rica raised in indoor terrariums on a diet of crickets and fruit flies do not contain detectable amounts of skin alkaloids. Offspring raised in large outside terrariums in Hawaii and fed mainly wild-caught termites and fruit flies do contain the same profile of alkaloids as their wild-caught parents in Hawaii, but at reduced levels. The genetic, environmental and dietary determinants of alkaloid profiles in dendrobatid frogs remain obscure, in particular the underlying cause for total absence in terrarium-reared frogs.

Pyrethroids: involvement of sodium channels in effects on inositol phosphate formation in guinea pig synaptoneurosomes.

The effects of pyrethroids were studied on phosphoinositide breakdown in guinea pig synaptoneurosomes. Similar to other agents that activate voltage-dependent sodium channels, type I and type II pyrethroids stimulated phosphoinositide breakdown. Type II pyrethroids, like deltamethrin and fenvalerate, were more potent and, at least for deltamethrin, more efficacious than type I pyrethroids, like allethrin, resmethrin and permethrin. The effects of type II pyrethroids could be partially inhibited by the sodium channel blocker tetrodotoxin. The effects of allethrin and resmethrin were not affected by 5 microM tetrodotoxin. Stimulation of phosphoinositide breakdown by fenvalerate was additive to the stimulation elicited by the receptor agonists carbamylcholine and norepinephrine, but not to the stimulation elicited by sodium channel agents (batrachotoxin, scorpion venom and pumiliotoxin B). Stimulation by allethrin was not additive to the stimulation elicited either by receptor agonists or sodium channel agents. A submaximal concentration of allethrin, a type I pyrethroid, did not greatly affect the dose-dependent stimulation elicited by a type II pyrethroid, deltamethrin, while a higher concentration of allethrin prevented further stimulation by type II pyrethroids. A local anesthetic, dibucaine, which inhibits sodium channel activation, inhibited phosphoinositide breakdown induced by type II, but not by type I pyrethroids, except at higher concentrations. Thus, type II pyrethroids appear to stimulate phosphoinositide breakdown in synaptoneurosomes in a manner analogous to other sodium channel agents, while type I pyrethroids elicit phosphoinositide breakdown by a different mechanism, probably not involving sodium channels.