Ion-channels on parasite muscle: pharmacology and physiology

Ion-channels are essential components of excitable cells. This fact has been exploited in the development of anthelmintic agents; the majority of which act on nematode ion channels. The purpose of this review is to describe the site of action of some frequently used anthelmintic compounds: nAChRs and levamisole/pyrantel; Glu-Cls and avermectins/mylbemycins; GABA receptors and piperazine. Also described is some of the physiological and pharmacological data on other nematode muscle ion-channels which may prove attractive targets for future anthelmintic development: Ca²⁺ activated Cl⁻ channels; peptide gated chloride Cl⁻ channels; Ca²⁺ channels and potassium channels. Emphasis is placed on the pharmacological and physiological data from parasite tissue. Information on the genes involved in ion-channel formation and modulation are reviewed in detail elsewhere in this issue.     

Two dopamine receptors: biochemistry, physiology and pharmacology

In 1979, two categories of dopamine (DA) receptors (designated as D-1 and D-2) were identified on the basis of the ability of a limited number of agonists and antagonists to discriminate between these two entities. In the past 5 years agonists and antagonists selective for each category of receptor have been identified. Using these selective drugs it has been possible to attribute the effects of DA upon physiological and biochemical processes to the stimulation of either a D-1 or a D-2 receptor. Thus, DA-induced enhancement of both hormone release from bovine parathyroid gland and firing of neurosecretory cells in the CNS of Lymnaea stagnalis has been attributed to stimulation of a D-1 receptor. Likewise, the DA-induced inhibition of the release of prolactin and alpha-MSH from the pituitary gland, as well as of acetylcholine, DA and beta-endorphin from brain, the DA-induced inhibition of chemo-sensory discharge in rabbit carotid body and the DA-induced hyperpolarization of neurosecretory cells in the CNS of Lymnaea stagnalis have been attributed to stimulation of a D-2 receptor. Independently two categories of DA receptors (designated as DA-1 and DA-2) were identified in the cardiovascular system. Stimulation of a DA-1 receptor increases the vascular cyclic AMP content and causes a relaxation of vascular smooth muscle in renal blood vessels, whereas stimulation of a DA-2 receptor inhibits the release of norepinephrine from certain postganglionic sympathetic neurons. Recent studies with the newly developed drugs discriminating between D-1 and D-2 receptors suggest however that the independently developed schemata for classification of dopamine receptors in either the central nervous and endocrine systems or the cardiovascular system are similar although maybe not completely identical.     

Rat genetics: attaching physiology and pharmacology to the genome

During the past five years, the Rat Genome Project has been rapidly gaining momentum, especially since the announcement in August 2000 of plans to sequence the rat genome. Combined with the wealth of physiological and pharmacological data for the rat, the genome sequence should facilitate the discovery of mammalian genes that underlie the physiological pathways that are involved in disease. Most importantly, this combined physiological and genomic information should also lead to the development of better pre-clinical models of human disease, which will aid in the development of new therapeutics.     

Molecular pharmacology of calmodulin pathways in the cell functions.

In this paper we summarize much of the pharmacological evidence that has led to our current understanding of calmodulin-regulated cell function, with emphasis on aspects that may be relevant to drug design. These newly developed compounds are one of the most powerful tools as molecular probes for pharmacological approach, and will shed light on the physiological significance and molecular mechanisms of calmodulin-dependent pathways in various cell functions.     

Cancer stem cell hypotheses: impact on modern molecular physiology and pharmacology research

Although questioned on several occasions, the existence of cancer stem cells (CSCs) has been confirmed by a number of studies on experimental animal models. Nevertheless, it was shown that CSC hypotheses have several limitations and inconsistencies regarding the explanation of CSC origin, CSC identification and isolation, possible heterogeneity within CSC population, as well as methodology issues in some studies that were carried out in order to prove CSC existence. The aim of this article is to give a short and comprehensive review of recent advances concerning CSC hypothesis and to describe its impact on modern molecular physiology and pharmacology research.     

TRP channels as target sites for insecticides: physiology,pharmacology and toxicology

Transient receptor potential (TRP) channels are attracting attention from various research areas including physiology, pharmacology and toxicology. Our group has focused on TRPA1 channels and revealed their expression pattern, ion channel kinetics and pharmacological characteristics. From Integrated Pest Management point of view, TRP channels could be a possible new target site of pest control agents as well as the primary or secondary target site for known insecticides. We have examined expressed TRPA1 channels using physiological and pharmacological methods to clarify the function of these channels. Here, we show that the TRPA1 is activated by the insecticide and natural toxin allyl isothiocyanate which is known as insecticide.     

Importance of A-ring substitution of estrogens for the physiology and pharmacology of reproduction

Estrogens substituted in the ortho-position of the phenolic hydroxy-group with an additional hydroxy- or methoxy-group are quantitatively important estrogen metabolites; first isolated and identified from the urine of man and rodents have been demonstrated in blood and different organs, e.g. the pituitary and hypothalamus. The physiological importance of the preeminent representatives of this group, the 2- and 4-hydroxyestrogens, the so-called catecholestrogens, is still equivocal. For example, numerous in vivo investigations in rodents have demonstrated that gonadotrophin secretion is influenced by these catecholestrogens. However, depending on the position of the A-ring substituent, major potency differences have been observed. The significant discrepancies between the quantitative and qualitative effects of catecholestrogens in in vitro and in vivo experiments have been presented and explained on the basis of different receptor affinities and the pharmacokinetics of catecholestrogens. An array of A-ring-substituted steroid model substances has been tested with respect to the effects of 2- and/or 4-substitution on stimulation or blockade of the estrogenic potency.     

Problem of controls in physiology and pharmacology: Psychophysiological and morphofunctional effects of chronic saline administration

The psychophysiological and morphofunctional effects of chronic administration of saline, which is commonly used as an active control, to Wistar rats were analyzed at different levels. The active control proved to be complicated by signs of stress manifested as increased corticosterone levels, changes in the homeostatic system, blood cytometric indices, morphofunctional states of the thymus and spleen, sharp suppression of the cognitive activity, and decrease in the motivational and locomotor activities. Pain expectation developed in animals after the second saline injection in the tail-flick test—pain sensitivity sharply increased in the session prior to the injection. These signs of stress should be taken into account for interpretation of the effects in drug tests.     

Replacing animal use in physiology and pharmacology teaching in selected universities in Eastern Europe--charting a way forward

The aims of this study were to explore the use of animals in teaching and the implementation of innovative technology-based teaching practices across a small sample of universities in Eastern Europe. The research methods used were a questionnaire circulated four weeks before a workshop took place (in October 2009, in Belgrade, Serbia), as well as focused, face-to-face group discussions, led by one of the authors during the workshop. Twenty-two faculty (physiologists and pharmacologists), from 13 Eastern European countries, attended the meeting. Fourteen of the eighteen schools represented at the workshop were making use of animals, in some instances in quite large numbers, for their teaching. For example, a single department at a Romanian university used over 250 animals per annum, and at least 1130 animals were used, per annum, across all of the institutions. The species used in largest numbers were the rat (34%), frog/toad (29%), mouse (22%), rabbit (10%), guinea-pig (4%) and dog (1%). None of the universities sampled had implemented institution-wide virtual learning environments (VLEs), although there were isolated instances of local use of VLEs. There was relatively little current use of technology-based teaching and learning resources, but there was considerable enthusiasm to modernise teaching and to introduce innovative learning and teaching methods. The major perceived barrier to the introduction of replacement alternatives was the lack of versions in local languages. There was a consensus view that developing local language exemplars and evaluating their usefulness was likely to have the greatest impact on animal use, at least in the short-term.     

Reverse pharmacology of orexin: from an orphan GPCR to integrative physiology

Orexins, which were initially identified as endogenous peptide ligands for two orphan G-protein coupled receptors (GPCRs), have been shown to have an important role in the regulation of energy homeostasis. Furthermore, the discovery of orexin deficiency in narcolepsy patients indicated that orexins are highly important factors for the sleep/wakefulness regulation. The efferent and afferent systems of orexin-producing neurons suggest interactions between these cells and arousal centers in the brainstem as well as important feeding centers in the hypothalamus. Electrophysiological studies have shown that orexin neurons are regulated by humoral factors, including leptin, glucose, and ghrelin as well as monoamines and acetylcholin. Thus, orexin neurons have functional interactions with hypothalamic feeding pathways and monoaminergic/cholinergic centers to provide a link between peripheral energy balance and the CNS mechanisms that coordinate sleep/wakefulness states and motivated behavior such as food seeking.