Effects of hypothalamic lesions on active sodium-potassium transport in the extensor digitorum longus muscles of hypokalemic rat

The CNS-induced suppression on muscle Na+-K+ pump was studied in "twitch" muscle, extensor digitorum longus (EDL), of hypokalemic rats which were fed a K+ deficient diet for several weeks. Peripheral nerve section or bilateral lesion of the ventromedial hypothalamic nucleus had no effect on the Na+ and K+ contents in EDL of hypokalemic rats. However, lesions of the paraventricular nucleus caused the net Na+ loss and the net K+ uptake in the muscles. Lesions in either the dorsomedial nucleus or anterior hypothalamus also caused significant net K+ uptake but the net Na+ loss was not significant. The results were compared with those of "tonic" muscle, soleus, reported previously.     

Change of intracellular K+ activity in rat soleus muscle during hypokalemia

The relationship between intracellular total K+ concentration [( K]i) as determined by a flame spectrophotometer and intracellular K+ activity (aKi) as determined by an ion-selective microelectrode was studied in soleus muscle of rats on a diet deficient in K+ for 40 days. [K]i began to fall immediately from the initial stage of hypokalemia, while aKi was well-maintained for 15 days. Then, aKi decreased gradually. The measured resting potential (Em) hyperpolarized beyond the EK was calculated from aKi in hypokalemic rat muscle from day 20 to 40. A rapid increase in aKi occurred over 3 hours in soleus muscle of hypokalemic rats for 5 to 6 weeks. It was concluded that the bound intracellular K+ acts as a buffer for aKi in hypokalemic rat muscle, that Em exceeds EK because the Na+-K+ pump is stimulated by increased [Na]i and that the increase in aKi after denervation is due to the removal of a Na+-K+ pump inhibitor normally released from nerve ending.     

Ouabain binding sites in skeletal muscle from normal and dystrophic mice.

The specific binding of tritiated ouabain was used to estimate the density of Na+-K+-ATPase sites ("Na+-pump" sites) in segments of skeletal muscle from normal and dystrophic mice. Ouabain binding was approximately 4 times greater in red (soleus) muscle than in white (superficial gastrocnemius) muscle from normal animals. In dystrophic soleus muscles, ouabain binding was decreased by nearly one-half. Because Na+-K+-ATPase activity is associated with plasma membranes, these observations constitute further evidence for a sarcolemmal abnormality in dystrophic mice.     

A HYPOTHALAMIC DIGOXIN-MEDIATED MODEL FOR CONSCIOUS AND SUBLIMINAL PERCEPTION

The human hypothalamus produces an endogenous membrane Na+-K+ ATPase inhibitor digoxin. Digoxin can modulate multiple neurotransmitter systems. It can play a role in perceptual binding, focused attention and short term memory important in conscious perception. It can also mediate subliminal or quantal perception. A hypothalamic digoxin-mediated model for conscious and quantal perception is postulated.     

Hypothalamic digoxin,hemispheric dominance,and neurobiology of love and affection

The human hypothalamus produces an endogenous membrane Na+-K+ ATPase inhibitor, digoxin, which can regulate neuronal transmission. The digoxin status and neurotransmitter patterns were studied in individuals with a predilection to fall in love. It was also studied in individuals with differing hemispheric dominance to find out the role of cerebral dominance in this respect. In individuals with a predilection to fall in love there was decreased digoxin synthesis, increased membrane Na+-K+ ATPase activity, decreased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern correlated with that obtained in left hemispheric chemical dominance. Hemispheric dominance and hypothalamic digoxin could regulate the predisposition to fall in love.     

HYPOTHALAMIC DIGOXIN,HEMISPHERIC DOMINANCE,AND NEUROBIOLOGY OF LOVE AND AFFECTION

The human hypothalamus produces an endogenous membrane Na+-K+ ATPase inhibitor, digoxin, which can regulate neuronal transmission. The digoxin status and neurotransmitter patterns were studied in individuals with a predilection to fall in love. It was also studied in individuals with differing hemispheric dominance to find out the role of cerebral dominance in this respect. In individuals with a predilection to fall in love there was decreased digoxin synthesis, increased membrane Na+-K+ ATPase activity, decreased tryptophan catabolites (serotonin, quinolinic acid, and nicotine), and increased tyrosine catabolites (dopamine, noradrenaline, and morphine). This pattern correlated with that obtained in left hemispheric chemical dominance. Hemispheric dominance and hypothalamic digoxin could regulate the predisposition to fall in love.     

Intrahypothalamic 5,7-dihydroxytryptamine: Temporal analysis of effects on 5-hydroxytryptamine content in brain nuclei and on facilitated lordosis behavior

The long-term relationship between serotonin (5-HT) levels in discrete hypothalamic nuclei and female rat sexual behavior, the lordosis response, was examined following intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). One week following 5,7-DHT injection, 5-HT levels in the ventromedial hypothalamic nucleus, dorsomedial nucleus, anterior hypothalamic nucleus and the medial preoptic nucleus were approximately 90% depleted as compared to sham animals. Other hypothalamic and preoptic areas including the arcuate-median eminence, vertical nucleus of diagonal band and lateral septal nucleus showed smaller reductions in 5-HT, from 40 to 70% of sham values. At this time estrogen-dependent lordosis behavior in the lesioned group was facilitated. Behavioral facilitation was greatest at 4 weeks post lesion when depletion of 5-HT in the VMN was maximal. 5-HT levels increased at 57 days after 5,7-DHT treatment in most areas, and by 71 days post lesion, no significant differences in 5-HT levels were found between sham and 5,7-DHT-treated groups. Concomitant with the increases in 5-HT, facilitated lordosis behavior gradually decreased. Loss of behavioral facilitation appeared to be most closely related to increases in content of 5-HT in the ventromedial nucleus. These results further support the hypothesis that 5-HT endings in the hypothalamus exert tonic inhibitory regulation over hormone-dependent lordosis in the female rat. They also indicate that regenerating 5-HT fibers in the hypothalamus can reinstate a normal pattern of hormone-dependent behavioral function.     

A serotonin agonist-antagonist reversible effect on Na+-K+-ATPase activity in the developing rat brain

In brain of adult and developing rats the Na+-K+-adenosine triphosphatase (Na+-K+-ATPase) system seems to react to serotonin (5-HT) changes induced pharmacologically. A 5-HT agonist (quipazine) elicits a response of the enzyme activity in the cerebral cortex in vivo, which is neutralized with a 5-HT antagonist (methysergide). This effect was observed from day 21 to adulthood. Also in a state of 5-HT receptor hypersensitivity (rats treated early with 5,6-dihydroxytryptamine), the response of Na+-K+-ATPase to the 5-HT agonist was higher than without neurotoxic lesion of 5-HT paths. These data suggest an involvement of the Na+-K+-ATPase system in 5-HT receptor sensitivity in the rat brain.     

A hypothalamic digoxin-mediated model for conscious and subliminal perception

The human hypothalamus produces an endogenous membrane (Na+)-K+ ATPase inhibitor digoxin. Digoxin can modulate multiple neurotransmitter systems. It can play a role in perceptual binding, focused attention and short term memory important in conscious perception. It can also mediate subliminal or quantal perception. A hypothalamic digoxin-mediated model for conscious and quantal perception is postulated.     

A hypothalamic digoxin-mediated model for autism

The isoprenoid pathway and its metabolites--digoxin, dolichol, and ubiquinone--were assessed in autism. The isoprenoid pathway and digoxin status was also studied for comparison in individuals of differing hemispheric dominance to determine the role of cerebral dominance in the genesis of autism. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity in autism. Digoxin, an endogenous Na+-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na+-K+ ATPase activity was found to be reduced in autism. Membrane Na+-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced magnesium levels. Hypothalamic digoxin can modulate conscious and subliminal perception and its dysfunction may lead to autism. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarizing tryptophan catabolites--serotonin, quinolinic acid (NMDA agonist), strychnine (blocks glycinergic inhibitory transmission), and nicotine (promotes dopamine release) and decreased levels of hyperpolarizing tyrosine catabolites--dopamine, noradrenaline, and morphine--contributing to membrane Na+-K+ ATPase inhibition. Increased nicotine levels can produce increased dopaminergic transmission in the presence of low dopamine levels. NMDA excitotoxicity could result from hypomagnesemia induced by membrane Na+-K+ ATPase inhibition and quinolinic acid, an NMDA agonist acting on the NMDA receptor. Hypomagnesemia and increased dolichol level can affect glycoconjugate metabolism and membranogenesis leading on to disordered synaptic connectivity in the limbic allocortex and defective presentation of viral antigens and neuronal antigens contributing to autoimmunity and viral persistence important in the pathogenesis. Membrane Na+-K+ ATPase inhibition can produce immune activation, a component of autoimmunity. Mitochondrial dysfunction consequent to altered calcium/magnesium ratios and reduced ubiquinone levels can result in increased free radical generation and reduced free radical scavenging and defective apoptosis leading to abnormal synaptogenesis. Autism can thus be considered a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway. The biochemical patterns including hyperdigoxinemia observed in autism correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for autism.