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PubMed1984

[Animal experimental studies on the pharmacology of a new anti-arrhythmic of the imino-cycloheptane series, stirocainide].

The action of 2- benzal -1-(2'-diisopropyl-amino-ethoxy-imino)- cycloheptane hydrogenfumarate ( Stirocainide , Th 494) has been investigated on isolated guinea-pig atria and papillary muscles and on the circulation of the anaesthetized and conscious cat. Th 494 is characterized as a Na+-inhibitory antiarrhythmic agent in isolated atria and papillary muscles. 1-10 mumol/l Th 494 induces only a small increase in action potential duration in both preparations, whereas no change in resting potential or amplitude of the action potential is observed. The action on the maximal rate of rise of the action potential (Vmax) depends on the rate of stimulation ("use-dependence"), this effect being somewhat smaller in atria as compared to papillary muscles. The increase in threshold of alternating current induced arrhythmias and in functional refractory period is also smaller in atria. Isometric force of contraction is reduced by Th 494 in guinea-pig atria and papillary muscles to a greater extent than in rabbit and cat. In the anaesthetized cat 2 mg/kg Th 494 i.v. induces a transient decrease in heart rate and a decrease in the maximal rise of left ventricular pressure. In addition, 4 mg/kg i.v. induces a transient decrease in systolic and diastolic blood pressure as well as a broadening of the QRS complex in the ECG. High doses of 4 and 8 mg/kg, respectively, lead to arrhythmias and apnoea, 8 mg/kg to exitus. Atropine does not influence the action of Th 494. 2 and 4 mg/kg Th 494 do not alter the action of norepinephrine on heart and circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1981

Convulsant and possible anticholinergic actions of dendrotoxin in the amphibian spinal cord.

1 Dendrotoxin (DTOX)6, 6a and 5,6-1, fractions of the venom isolated from the green mamba (Dendroaspis viridis) promoted both spontaneous and stimulus-coupled rhythmic activity and antagonized the cholinergically mediated ventral root-dorsal root potential (VR-DRP) of frog spinal cord. The different time course and reversibility of these two effects indicates that the toxin has two entirely separate sites of action on the frog spinal cord. 2 Since DTOX 6 neither blocked nor enhanced responses of ventral and dorsal roots to glutamate, gamma-aminobutyric acid (GABA), beta-alanine, glycine or aspartate, it is unlikely that its convulsant action resulted from an alteration of the postsynaptic actions of inhibitory or excitatory amino acids. 3 An alteration in the threshold for action potential generation could perhaps contribute to the convulsant action of DTOX 6, although other mechanisms such as blockade of the release of unspecified inhibitory substances cannot be excluded. 4 In addition to the lack of effect on amino acid responses, DTOX failed to block the polysynaptic DR-VRP or DR-DRP pathways, which are mediated at least in part by amino acid neurotransmitters. Although this would be consistent with a specific action of DTOX at the cholinergic synapse of the VR-DRP pathway, this site of action has not yet been demonstrated unequivocally. Other possible mechanisms whereby DTOX could block VR-DRP are discussed.

Animals↗
PubMed1992

Thapsigargin inhibits contraction and Ca2+ transient in cardiac cells by specific inhibition of the sarcoplasmic reticulum Ca2+ pump.

Regulation of the level of ionized calcium, [Ca2+]i, is critical for its use as an important intracellular signal. In cardiac and skeletal muscle the control of fluctuations of [Ca2+]i depend on sarcolemmal and sarcoplasmic reticulum ion channels and transporters. We have investigated the sesquiterpine lactone, thapsigargin (TG), because of its reported action to alter cellular calcium regulation in diverse cell types, including striated muscle cells. We have combined biochemical and physiological methods at the cellular level to determine the site of action of this agent, its specificity, and its cellular effects. Using a patch-clamp method in whole cell configuration while measuring [Ca2+]i with Indo-1 salt, we find that TG (100 nM) largely blocks the contraction and the [Ca2+]i transient in rat ventricular myocytes. Analysis of these data indicate that no sarcolemmal current or transport system is directly altered by TG, although indirect [Ca2+]i-dependent processes are affected. In permeabilized myocytes, TG blocked oxalate-stimulated calcium uptake (half-maximal effect at 10 nM) into the SR. However, TG (100 microM) had no effect on Ca(2+)-induced Ca(2+)-release in purified muscle (ryanodine-receptor enriched) vesicles while clearly blocking Ca(2+)-ATPase activity in purified (longitudinal SR) vesicles. We conclude that in striated muscle TG markedly alters calcium metabolism and thus alters contractile function only by its direct action on the Ca(2+)-ATPase.

Animals↗
PubMed2000

Prevention of monensin-induced hyperpolarization in NG108-15 cells.

The NG 108-15 (neuroblastoma X glioma hybrid) cell line was used as an in vitro neuronal model to evaluate potential antagonists of the Na+-selective carboxylic ionophore monensin. Changes in membrane electrical characteristics induced by monensin with and without the simultaneous administration of antagonists were measured using intracellular microelectrode techniques. Bath application of monensin (3 microM) produced a hyperpolarization of approximately = 35 mV. Monensin also altered the generation of action potentials in response to electrical stimulation in 14 of 24 (58%) exposed cells, as evident in a partial or complete loss of action potentials or in an alteration of action potential waveform. The antagonists used were Na+-K+ pump inhibitor ouabain (1-3 microM), the Ca2+dependent K+ channel blocker quinine (3-30 microM) or drugs known to influence Ca2+ signaling in cells, i.e., trifluoperazine (3-10 microM), verapamil (1-10 microM) or chlorpromazine (3-30 microM). On a molar basis, ouabain was the most and trifluoperazine the least effective of the antagonists. Quinine, verapamil and chlorpromazine all prevented the development of the hyperpolarization in an approximate concentration-dependent manner. However, none of these drugs was able to block the effects of monensin on action potentials. Indeed, high concentrations of the antagonists that were most effective in preventing the hyperpolarization accentuated impairments in action potential generation and also reduced input resistance in many cells. Thus, none of these antagonists appears suitable for transition to in vivo antidotal protection studies.

Action Potentials↗
PubMed1991

Reduced calcium and inhibition of protein kinase C mimic the enhancement of ornithine decarboxylase activity of prolactin in Ambystoma tigrinum tissues.

We previously reported that prolactin (PRL) could increase the activity of ornithine decarboxylase (ODC) in liver slices taken from larval tiger salamanders (Ambystoma tigrinum). This action of the hormone was inhibited by oxytocin (OT), the calcium ionophore A23187, and diacyglycerol (DG) and was duplicated by 10 microM verapamil (VML), a calcium channel blocker. Here, we expand these results to show that 1) a higher dose of VML (50 microM) produces an additive effect with PRL; 2) addition of small amounts of calcium (0.1 mM) to the liver culture medium blocks PRL action; 3) neither nifedipine (NIF), a different type of calcium channel blocker, nor EDTA alter PRL action; and 4) gossypol, a reported inhibitor of protein kinase C, mimics PRL action. Additionally, we show that PRL increases ODC activity in tiger salamander tail skin in vitro, a tissue previously demonstrated to be a PRL target tissue in this species. The same set of treatments which we have shown to modify PRL effects on ODC in liver slices affects PRL action in the tail skin in a parallel manner. Thus, the mechanism whereby PRL enhances ODC activity appears to be the same in both these tissues. These results are discussed in conjunction with the findings from similar studies using mammalian tissues in an attempt to assess the current picture of the mechanism of PRL action and the possible role of inositol phospholipid turnover, calcium, and protein kinase C in the action of this hormone.

Ambystoma↗
PubMed1988

Phospholipid composition modulates the Na+-Ca2+ exchange activity of cardiac sarcolemma in reconstituted vesicles.

Na+-Ca2+ exchange activity in cardiac sarcolemmal vesicles is known to be sensitive to charged, membrane lipid components. To examine the interactions between membrane components and the exchanger in more detail, we have solubilized and reconstituted the Na+-Ca2+ exchanger into membranes of defined lipid composition. Our results indicate that optimal Na+-Ca2+ exchange activity requires the presence of certain anionic phospholipids. In particular, phosphatidylserine (PS), cardiolipin, or phosphatidic acid at 50% by weight results in high Na+-Ca2+ exchange activity, whereas phosphatidylinositol and phosphatidylglycerol provide a poor environment for exchange. In addition, incorporation of cholesterol at 20% by weight greatly facilitates Na+-Ca2+ exchange activity. Thus, for example, an optimal lipid environment for Na+-Ca2+ exchange is phosphatidylcholine (PC, 30%)/PS (50%)/cholesterol (20%). Na+-Ca2+ exchange activity is also high when cardiac sarcolemma is solubilized and then reconstituted into asolectin liposomes. We fractionated the lipids of asolectin into subclasses for further reconstitution studies. When sarcolemma is reconstituted into vesicles formed from the phospholipid component of asolectin, Na+-Ca2+ exchange activity is low. When the neutral lipid fraction of asolectin (including sterols) is also included in the reconstitution medium, Na+-Ca2+ exchange activity is greatly stimulated. This result is consistent with the requirement for cholesterol described above. Proteinase treatment, high pH, intravesicular Ca2+ and dodecyl sulfate all stimulate Na+-Ca2+ exchange in native sarcolemmal vesicles. We examined the effects of these interventions on exchange activity in reconstituted vesicles of varying lipid composition. In general, Na+-Ca2+ exchange could be stimulated only when reconstituted into vesicles of a suboptimal lipid composition. That is, when reconstituted into asolectin or PC/PS/cholesterol (30:50:20), the exchanger is already in an activated state and can no longer be stimulated. The one exception was that the Na+-Ca2+ exchanger responded to altered pH in an identical manner, independent of vesicle lipid composition. The mechanism of action of altered pH on the exchanger thus appears to be different from other interventions.

Animals↗
PubMed1999

Loss of antiallodynic and antinociceptive spinal/supraspinal morphine synergy in nerve-injured rats: restoration by MK-801 or dynorphin antiserum.

The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical analgesic utility of this drug. In animals with peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine is significantly decreased. Here, the possible loss of spinal/supraspinal morphine antinociceptive synergy and relationship to elevation of spinal dynorphin content was studied. Ligation of lumbar spinal nerves resulted in elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham-operated rats supraspinal/spinal co-administration of morphine produced synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1-17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive synergy and elicited a dose-related i.th. morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter morphine actions in sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal morphine appear to be due to the elevation across multiple spinal segments of dynorphin following nerve injury. Pathological actions of elevated dynorphin may directly or indirectly modulate the NMDA receptor, result in a loss of supraspinal/spinal morphine synergy and may thus account for the decreased clinical analgesic efficacy of morphine in peripheral neuropathies.

Analgesics, Opioid↗
PubMed2003

Age-related changes in the distribution of Na(v)1.1 and Na(v)1.2 in rat cerebellum.

Modification of sodium channel availability and behavior is obviously a good candidate for alteration of action potential observed during aging. In the present study, we revealed age-related alterations in the expression of voltage-gated Na+ (Na(v)) channel in rat cerebellum by immunohistochemistry. In the cerebellar cortex of aged rats, Na(v)1.1 immunoreactivity in Purkinje cell bodies was highly increased, whereas granule cells showed lower staining intensity. In the cerebellar nuclei of aged rats, Na(v)1.1 and Na(v)1.2 expression was specifically increased in the cerebellar output neurons, which was confirmed by image analysis. The first demonstration of age-related changes in Na(v) channel expression contributes to our understanding of the mechanisms responsible for alteration in synaptic transmission during aging.

Aging↗
PubMed1988

Mechanisms of secretory responses to gonadotropin-releasing hormone and phorbol esters in cultured pituitary cells. Participation of protein kinase C and extracellular calcium mobilization.

The role of protein kinase C in luteinizing hormone (LH) release was analyzed in studies on the actions of gonadotropin releasing hormone (GnRH) and phorbol esters in cultured pituitary cells. During incubation in normal medium, GnRH stimulated LH release with an ED50 of 0.35 nM. Incubation in Ca2+-deficient medium (Ca2+-free, 10 microM) substantially decreased but did not abolish the LH responses to GnRH. The extracellular Ca2+-dependent component of GnRH action could be mimicked by high K+ concentrations, consistent with the presence of voltage-sensitive calcium channels (VSCC) in pituitary gonadotrophs. Ca2+ channel agonist (Bay K 8644) and antagonist (nifedipine) analogs, respectively, enhanced or partially inhibited LH responses to GnRH and also to K+, the latter confirming the participation of two types of VSCC (dihydropyridine-sensitive and -insensitive) in K+-induced secretion. Phorbol esters, including 12-O-tetradecanoylphorbol-13-acetate (TPA), 4 beta-phorbol-12,13-dibenzoate, and 4 beta-phorbol-12,13-diacetate, stimulated LH release with ED50s of 5, 10, and 1000 nM, respectively, and with about 70% of the efficacy of GnRH. Phorbol ester-stimulated LH secretion was decreased but not abolished by progressive reduction of [Ca2+]e in the incubation medium, and the residual LH response was identical with that elicited by GnRH in Ca2+-deficient medium. TPA increased [Ca2+]i to a peak after 20 s in normal medium but not in the absence of extracellular Ca2+, indicating that protein kinase C (Ca2+/phospholipid-dependent enzyme) promotes calcium entry but can also mediate secretory responses without changes in calcium influx and [Ca2+]i. The extracellular Ca2+-dependent action of TPA on LH release was blocked by Co2+. However, nifedipine did not alter TPA action on [Ca2+]i and LH release. These observations indicate that protein kinase C can participate in GnRH-induced LH release that is independent of Ca2+ entry, but also promotes the influx of extracellular Ca2+ through dihydropyridine-insensitive Ca2+-channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Demonstration of an autoreceptor modulating the release of [3H]5-hydroxytryptamine from a synaptosomal-rich spinal cord tissue preparation.

A superfusion system employed to measure the K+-stimulated release of [3H]5-hydroxytryptamine [(3H]5-HT, [3H]serotonin) from a synaptosomal-rich spinal cord tissue preparation was carefully characterized, then used to examine the regulation of spinal 5-HT release. Spinal 5-HT release is apparently modulated by an autoreceptor. Exogenous 5-HT depressed, in a concentration-dependent manner, the K+-stimulated release of [3H]5-HT. Similarly, lysergic acid diethylamide (LSD) produced a concentration-dependent decrease in [3H]5-HT release. Methiothepin and quipazine blocked the inhibition of release induced by exogenous 5-HT. The 5-HT2 receptor antagonists spiperone and ketanserin failed to alter the action of 5-HT at the spinal 5-HT autoreceptor. Spiperone and ketanserin were shown, however, to alter the storage of [3H]5-HT. When used in concentrations greater than 10 nM, the drugs evoked increases in basal [3H]5-HT and [3H]5-hydroxyindoleacetic acid ( [3H]5-HIAA) effluxes which were independent of the presence of calcium ions. A good agreement existed between the potencies of drugs for modifying autoreceptor function and their abilities to compete for high-affinity [3H]5-HT binding in the spinal cord (designated 5-HT1). Furthermore quipazine, in concentrations that preferentially interact with the 5-HT1B subtype, antagonized the actions of exogenous 5-HT on K+-stimulated release. Spiperone, in a concentration that approximated the affinity constant of 5-HT1A sites for the drug, was ineffective in altering the ability of exogenous 5-HT to modulate K+-stimulated [3H]5-HT release. These results suggest that 5-HT1B sites are associated with serotonergic autoreceptor function in the spinal cord.

Animals↗
PubMed2005

Anti-obese action of raspberry ketone.

Raspberry ketone (4-(4-hydroxyphenyl) butan-2-one; RK) is a major aromatic compound of red raspberry (Rubus idaeus). The structure of RK is similar to the structures of capsaicin and synephrine, compounds known to exert anti-obese actions and alter the lipid metabolism. The present study was performed to clarify whether RK helps prevent obesity and activate lipid metabolism in rodents. To test the effect on obesity, our group designed the following in vivo experiments: 1) mice were fed a high-fat diet including 0.5, 1, or 2% of RK for 10 weeks; 2) mice were given a high-fat diet for 6 weeks and subsequently fed the same high-fat diet containing 1% RK for the next 5 weeks. RK prevented the high-fat-diet-induced elevations in body weight and the weights of the liver and visceral adipose tissues (epididymal, retroperitoneal, and mesenteric). RK also decreased these weights and hepatic triacylglycerol content after they had been increased by a high-fat diet. RK significantly increased norepinephrine-induced lipolysis associated with the translocation of hormone-sensitive lipase from the cytosol to lipid droplets in rat epididymal fat cells. In conclusion, RK prevents and improves obesity and fatty liver. These effects appear to stem from the action of RK in altering the lipid metabolism, or more specifically, in increasing norepinephrine-induced lipolysis in white adipocytes.

Adipose Tissue↗
PubMed1976

Pathophysiologic and pharmacologic alterations in the release and action of ADH.

The physiologic factors involved in vaseopressin (ADH) release and action are reviewed with emphasis on the interaction between osmotic and volume stimuli to the discharge of ADH. Abnormalities in reception of stimuli to ADH release, and in the impaired synthesis and release of ADH, are reviewed in relation to the causes of diabetes insipidus, and information on the biochemical changes which have been described in patients with nephrogenic diabetes insipidus is also discussed. We summarize the pathologic lesions and associated diseases found in 54 of our patients with diabetes insipidus. Criteria for establishing the diagnosis of diabetes insipdus are reviewed with emphasis on the dehydration test, including the importance of measuring plasma osmolality at the conclusion of water deprivation. Treatment of diabetes insipidus is briefly discussed with emphasis on the use of DDAVP and oral agents. The syndrome of inappropriate ADH secretion (SIADH) is reviewed including our experience with 39 patients. The differential diagnosis of SIADH, including the value of water loading and the measurement of ADH levels, is discussed. We comment on treatment of these patients including the use of investigational drugs. Lastly, we review the pharmacologic features and clinical relevance of some drugs which alter the release and action of ADH.

Analgesics↗
PubMed2001

The role of lipids in the pathogenesis of muscle insulin resistance and beta cell failure in type II diabetes and obesity.

This review considers evidence for, and putative mechanisms of, lipid-induced muscle insulin resistance. Acute free fatty acid elevation causes muscle insulin resistance in a few hours, with similar muscle lipid accumulation as accompanies more prolonged high fat diet-induced insulin resistance in rodents. Although causal relations are not as clearcut in chronic human insulin resistant states such as obesity and type 2 diabetes, it is now recognised that muscle lipids also accumulate in these states. The classic Randle glucose-fatty acid cycle is only one of a number of mechanisms by which fatty acids might influence muscle glucose metabolism and insulin action. A key factor is seen to be accumulation of muscle long chain acyl CoAs, which could alter insulin action via several mechanisms including chronic activation of protein kinase C isoforms or ceramide accumulation. These interactions are fundamental to understanding metabolic effects of new insulin "sensitizers", e.g. thiazolidinediones, which alter lipid metabolism and improve muscle insulin sensitivity in insulin resistant states. Recent work has also pointed to a possible role of lipids in beta cell deterioration ("lipotoxicity") associated with type 2 diabetes.

Animals↗
PubMed1988

Recent data on the structure of rabbit milk protein genes and on the mechanism of the hormonal control of their expression.

Mammary explants or isolated mammary cells from rabbit have been cultured in the presence of insulin, prolactin and cortisol alone or in combination. The cellular content in alpha s1-casein, beta-casein and whey acidic protein (WAP) mRNA have been evaluated using the corresponding cDNA as probes. In all cases alpha s1-casein mRNA was the most abundant and WAP mRNA the least abundant mRNA. The three genes showed essentially similar dependency towards hormones. Prolactin stimulated mRNA accumulation and insulin and cortisol amplified this stimulation. The induction by prolactin was rapid whereas stimulation by insulin was slower. Fragments of rabbit genomic DNA inserted in lambda phage and containing alpha s1-casein, and WAP genes have been cloned. The primary sequence around the CAP site of the three genes has been established. A comparison of the sequences located upstream from the CAP site shows several striking homologies with the corresponding genes from cow, rat and guinea-pig. This suggests that these sequences participate in the transcriptional control of the genes by hormones. The mechanism involved in the transduction of the prolactin message to milk protein genes in unknown. Using mammary explants in culture, several classical mechanisms of transduction have been examined. Phorbol ester, phorbol -12, 13-dibutyrate (PdiBu) inhibited prolactin action. However, another tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA), did not alter prolactin action. Kinase C inhibitor H7 did not prevent prolactin action and did not overcome the inhibition by PdiBu. Kinase C is therefore not essential for the transduction of the prolactin message to milk protein gene. Neomycin, which inhibits phosphatidylinositol hydrolysis by phosphorylase C, prevented prolactin action, whereas other inhibitors of phosphatidylinositol metabolism remained uneffective. Degradation of phosphatidylinositol is therefore likely not an essential step of prolactin action on milk protein genes. Inhibitors of tyrosine kinase and phosphatase exhibited a poor capacity to modify the prolactin response. Hence, transduction mechanisms using tyrosine kinase activity likely cannot account for prolactin action.

Animals↗
PubMed1983

Mechanism of biphasic contractions in strontium-treated ventricular muscle.

Biphasic contractions were produced in dog trabeculae by replacing 90-95% of the calcium in the bathing solution with strontium. These conditions produced prolonged action potentials accompanied by contractions with two distinct phasic components. The early component disappeared slowly when the remaining Ca++ was removed, whereas the late component was eliminated quickly when Sr++ was removed. Manganese ion (0.25 mM) preferentially decreased the late component without changing the action potential, whereas caffeine and ryanodine decreased or eliminated the early component. Ryanodine did not alter the action potential. Isoproterenol rapidly increased the early component and, more slowly and to a lesser degree, increased the late component. The results suggest that the early component is caused by intracellular release of activator cation, probably from the sarcoplasmic reticulum, whereas the late component is the result of Sr++ entry across the sarcolemma, possibly by way of the slow inward current.

Animals↗
PubMed2001

Decreased leptin uptake in hypothalamic nuclei with ageing in Wistar rats.

Leptin interacts with specific receptors in hypothalamic nuclei and modulates energy balance. Growing evidence has shown the association of obesity and hyperleptinaemia with non-insulin-dependent diabetes mellitus and insulin resistance. The aged Wistar rat shows peripheral insulin resistance in the absence of obesity and alterations of glucose homeostasis. However, it is not known whether, in these animals, the leptin action is altered. Here we studied the effect of ageing on plasma leptin concentration and the ability of hypothalamic nuclei to capture i.c.v.-injected digoxigenin-labelled leptin. Our data indicate that 24-month-old animals are hyperleptinaemic. However, daily food intake was greater in old animals, suggesting that they are leptin resistant. Leptin uptake in the hypothalamus was reduced in old rats. This uptake was a receptor-mediated process as demonstrated by displacement. Leptin accumulation in hypothalamic nuclei was partially colocalized with neuropeptide Y fibres. Immunohistochemical and western blot analyses showed a lower amount of the long form of leptin receptors in the hypothalamus of aged rats. Analysis by RT-PCR also demonstrated a decreased expression of leptin receptor mRNA in old animals. We conclude that the lower leptin uptake may be explained, at least in part, by a decreased amount of receptors in hypothalamic neurones of the aged rats.

Aging↗
PubMed1982

Effects of extracellular potassium accumulation and sodium pump activation on automatic canine Purkinje fibres.

1. Double barrel potassium-sensitive micro-electrodes were used to measure fluctuations in extracellular potassium ion concentration in large automatic canine Purkinje fibres.2. Slow accumulations of potassium were seen in the extracellular space during prolonged beating. Following cessation of prolonged beating, a depletion of extracellular potassium ions was noted.3. The time course of these slow changes in extracellular potassium concentration were shown to be a function of the diffusion properties of the preparation, and the rate and degree of activation of the sodium pump.4. Action potential duration and maximum diastolic potential were simultaneously monitored during and after these periods of rapid stimulation, using conventional intracellular micro-electrodes.5. Initial depolarization and later hyperpolarization of the maximum diastolic potential appeared to occur as a direct result of changes in extracellular potassium concentration and level of pump activation induced by the sudden and prolonged alteration in stimulus rate.6. Following prolonged stimulation, dramatic changes in the automatic beating rate were correlated with changes in extracellular potassium and pump rate, and their effects on the maximum diastolic potential and other parameters of the diastolic potential depolarization.7. For some locations of the potassium-sensitive electrode tip, large fluctuations in extracellular potassium were seen during single beats. Alterations in action potential duration during abrupt rate changes appear to derive in part from modulation by these extracellular potassium concentration fluctuations altering net membrane currents. Slower shifts in action potential duration appear correlated to the degree of sodium pump activation.

Action Potentials↗
PubMedDate not supplied

Physiological changes due to age. Pharmacodynamic changes of drug action and implications for therapy.

The elderly respond differently to drugs than do younger people. Their physiological response is much more variable, and predictability of drug action is much less certain. When all non-pharmacological factors and age-associated pharmacokinetics are taken into account, there is still no full explanation of the potentially altered drug action and increased drug toxicity observed in the elderly. It is only relatively recently that age-associated physiological changes (primary age changes), their interplay with age-associated pathophysiological changes (secondary age changes) and environmental changes (tertiary age changes) have been studied with regard to the effect of those changes on the pharmacodynamics of drug action. In general, age-associated pharmacodynamic changes, i.e. changes in the type, intensity and duration of drug action, have been associated with changes in receptor function (e.g. altered receptor number and affinity, altered second messenger function, altered cell response), changes in the homeostatic mechanisms, and reduced reserve capacity. It is important to realise that these changes, which can differ greatly among patients, may be responsible for an increased incidence of adverse drug reactions and therapeutic failure. They may also mandate a higher dose in some circumstances, as some organs become less responsive to drug action with age.

Adult↗