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PubMed2005

5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis.

More than any other brain neurotransmitter system, the indolamine serotonin (5-HT) has been linked to aggression in a wide and diverse range of species, including humans. The nature of this linkage, however, is not simple and it has proven difficult to unravel the precise role of this amine in the predisposition for and execution of aggressive behavior. The dogmatic view that 5-HT inhibits aggression has dominated both pharmacological research strategies to develop specific and effective novel drug treatments that reduce aggressive behavior and the pharmacological mechanistic interpretation of putative serenic drug effects. Our studies on brain serotonin and aggression in feral wild-type rats using the resident-intruder paradigm have challenged this so-called serotonin deficiency hypothesis of aggressive behavior. The well-known fact that certain 5-HT(1A/1B) receptor agonists potently and specifically reduce aggressive behavior without motor slowing and sedative effects is only consistent with this hypothesis under the assumption that the agonist mainly acts on the postsynaptic 5-HT(1A/1B) receptor sites. However, systemic injections of anti-aggressive doses of 5-HT(1A) and (1B) agonists robustly decrease brain 5-HT release due to their inhibitory actions at somatodendritic and terminal autoreceptors, respectively. The availability of the novel benzodioxopiperazine compound S-15535, which acts in vivo as a preferential agonist of the somatodendritic 5-HT(1A) auto-receptor and as an antagonist (weak partial agonist) at postsynaptic 5-HT(1A) receptors, allows for a pharmacological analysis of the exact site of action of this anti-aggressive effect. It was found that, similar to other prototypical full and partial 5-HT(1A) and/or 5-HT(1B) receptor agonists like repinotan, 8-OHDPAT, ipsapirone, buspirone, alnespirone, eltoprazine, CGS-12066B and CP-93129, also S-15535 very effectively reduced offensive aggressive behavior. Unlike the other ligands, however, a remarkable degree of behavioral specificity was observed after treatment with S-15535, in that the anti-aggressive effects were not accompanied by inhibiting (like other 5-HT(1A) receptor agonist with moderate to high efficacy at postsynaptic 5-HT(1A) receptors) or enhancing (like agonists with activity at 5-HT(1B) receptors and alnespirone) non-aggressive motor behaviors (e.g., social exploration, ambulation, rearing, and grooming) beyond the range of undrugged animals with corresponding levels of aggression. The involvement of 5-HT(1A) and/or 5-HT(1B) receptors in the anti-aggressive actions of these drugs was convincingly confirmed by showing that the selective 5-HT(1A) receptor antagonist WAY-100635 and/or the 5-HT(1B) receptor antagonist GR-127935, while inactive when given alone, effectively attenuated/prevented these actions. Furthermore, combined administration of S-15535 with either alnespirone or CGS-42066B elicited a clear additive effect, indicated by a left-ward shift in their dose-effect curves, providing further support for presynaptic sites of action (i.e., inhibitory somatodendritic 5-HT(1A) and terminal 5-HT(1B) autoreceptors). These findings strongly suggest that the specific anti-aggressive effects of 5-HT(1A) and 5-HT(1B) receptor agonists are predominantly based on reduction rather than enhancement of 5-HT neurotransmission during the combative social interaction. Apparently, normal display of offensive aggressive behavior is positively related to brief spikes in serotonergic activity, whereas an inverse relationship probably exists between tonic 5-HT activity and abnormal forms of aggression only.

Aggression↗
PubMed2005

Detailed pharmacological characterization of GT-2331 for the rat histamine H3 receptor.

Histamine H(3) receptor antagonists are potential therapeutic agents for cognitive dysfunction, epilepsy, hypersomnia and obesity. GT-2331 (4-[(R,R)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl]-1H-imidazole) was originally identified as a potent histamine H(3) receptor antagonist. However, recent reports demonstrated a complex pharmacology for GT-2331. To further understand the pharmacological profile of GT-2331, we characterized GT-2331 using various in vitro and in vivo assays. In vitro, GT-2331 behaved as a full agonist on adenylyl cyclase inhibition and as a partial agonist on [(35)S]GTPgammaS binding at the recombinant rat histamine H(3) receptor. In contrast, in vivo, GT-2331 had no effect on brain histamine turnover while the histamine H(3) receptor agonist R-alpha-methylhistamine significantly decreased histamine turnover. Furthermore, GT-2331 completely blocked R-alpha-methylhistamine-induced water intake, suggesting that GT-2331 behaves as a full antagonist. Thus, GT-2331 displayed the spectrum of pharmacological activities from full agonism to full antagonism, these observations suggest that histamine H(3) receptor ligands need to be carefully evaluated in various paradigms.

Adenylyl Cyclase Inhibitors↗
PubMed2006

In vitro and in vivo pharmacological characterization of the nociceptin/orphanin FQ receptor ligand Ac-RYYRIK-ol.

It was recently reported that the hexapeptide Ac-RYYRIK-ol binds with high affinity nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors and competitively antagonizes N/OFQ actions in the mouse vas deferens assay. Here we further describe the in vitro and in vivo pharmacological features of this NOP receptor ligand. In mouse brain homogenate the degradation half life of Ac-RYYRIK-ol (2.48 min) was significantly higher than that of the parent compound Ac-RYYRIK-NH2 (1.20 min). In the electrically stimulated mouse vas deferens, Ac-RYYRIK-ol (10-1000 nM) competitively antagonized the inhibitory effect of N/OFQ (pA2=8.46), while in the isolated mouse colon the hexapeptide mimicked N/OFQ contractile effects thus behaving as a NOP receptor agonist (pEC50=9.09). This latter effect was no longer evident in colon tissues taken from mice knock out for the NOP receptor gene (NOP-/-). In vivo in mice, similarly to N/OFQ, Ac-RYYRIK-ol (dose range 0.001-1 nmol) produced: i) pronociceptive effects after intracerebroventricular (i.c.v.) administration and antinociceptive actions when given intrathecally (i.t.) in the tail withdrawal assay; ii) inhibition of locomotor activity and iii) stimulation of food intake after supraspinal administration. Finally, in the forced swimming test, Ac-RYYRIK-ol was inactive per se, but reversed the antidepressant-like effects elicited by the NOP receptor selective antagonist UFP-101 ([Nphe(1),Arg(14),Lys(15)]N/OFQ-NH2). Thus, in all these in vivo assays Ac-RYYRIK-ol mimicked the actions of N/OFQ showing however higher potency. In conclusion, Ac-RYYRIK-ol displayed a complex pharmacological profile which is likely due to the low efficacy agonist nature of this novel ligand of the NOP receptor. The high potency, selectivity of action, and in vivo effectiveness make Ac-RYYRIK-ol a useful pharmacological tool for future studies in the field of N/OFQ and its NOP receptor.

Animals↗
PubMed2006

Pharmacological characterisation of strychnine and brucine analogues at glycine and alpha7 nicotinic acetylcholine receptors.

Strychnine and brucine from the plant Strychnos nux vomica have been shown to have interesting pharmacological effects on several neurotransmitter receptors, including some members of the superfamily of ligand-gated ion channels. In this study, we have characterised the pharmacological properties of tertiary and quaternary analogues as well as bisquaternary dimers of strychnine and brucine at human alpha1 and alpha1beta glycine receptors and at a chimera consisting of the amino-terminal domain of the alpha7 nicotinic receptor (containing the orthosteric ligand binding site) and the ion channel domain of the 5-HT3A serotonin receptor. Although the majority of the analogues displayed significantly increased Ki values at the glycine receptors compared to strychnine and brucine, a few retained the high antagonist potencies of the parent compounds. However, mirroring the pharmacological profiles of strychnine and brucine, none of the analogues displayed significant selectivity between the alpha1 and alpha1beta subtypes. The structure-activity relationships for the compounds at the alpha7/5-HT3 chimera were significantly different from those at the glycine receptors. Most strikingly, quaternization of strychnine and brucine with substituents possessing different steric and electronic properties completely eliminated the activity at the glycine receptors, whereas binding affinity to the alpha7/5-HT3 chimera was retained for the majority of the quaternary analogues. This study provides an insight into the structure-activity relationships for strychnine and brucine analogues at these ligand-gated ion channels.

Cell Line↗
PubMed2006

Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery.

Pregabalin (Lyrica) is a new antiepileptic drug that is active in animal seizure models. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the alpha2-delta (alpha2-delta) protein, an auxiliary subunit of voltage-gated calcium channels. Pregabalin subtly reduces the synaptic release of several neurotransmitters, apparently by binding to alpha2-delta subunits, and possibly accounting for its actions in vivo to reduce neuronal excitability and seizures. Several studies indicate that the pharmacology of pregabalin requires binding to alpha2-delta subunits, including structure-activity analyses of compounds binding to alpha2-delta subunits and pharmacology in mice deficient in binding at the alpha2-delta Type 1 protein. The preclinical findings to date are consistent with a mechanism that may entail reduction of abnormal neuronal excitability through reduced neurotransmitter release. This review addresses the preclinical pharmacology of pregabalin, and also the biology of the high affinity binding site, and presumed site of action.

Amines↗
PubMed2005

Manipulating REM sleep in older adults by selective REM sleep deprivation and physiological as well as pharmacological REM sleep augmentation methods.

Experimental approaches to manipulate REM sleep within the cognitive neuroscience of sleep are usually based on sleep deprivation paradigms and focus on younger adults. In the present study, a traditional selective REM sleep deprivation paradigm as well as two alternative manipulation paradigms targeting REM sleep augmentation were investigated in healthy older adults. The study sample consisted of 107 participants, male and female, between the ages of 60 and 82 years, who had been randomly assigned to five experimental groups. During the study night, a first group was deprived of REM sleep by selective REM sleep awakenings, while a second group was woken during stage 2 NREM sleep in matched frequency. Physiological REM sleep augmentation was realized by REM sleep rebound after selective REM sleep deprivation, pharmacological REM sleep augmentation by administering an acetylcholinesterase inhibitor in a double-blind, placebo-controlled design. Deprivation and augmentation paradigms manipulated REM sleep significantly, the former affecting more global measures such as REM sleep minutes and percentage, the latter more organizational aspects such as stage shifts to REM sleep, REM latency, REM density (only pharmacological augmentation) and phasic REM sleep duration. According to our findings, selective REM sleep deprivation seems to be an efficient method of REM sleep manipulation in healthy older adults. While physiological rebound-based and pharmacological cholinergic REM sleep augmentation methods both failed to affect global measures of REM sleep, their efficiency in manipulating organizational aspects of REM sleep extends the traditional scope of REM sleep manipulation methods within the cognitive neuroscience of sleep.

Aged↗
PubMed2006

Pharmacologic management of ischemic stroke: relevance to stem cell therapy.

Pharmacologic management of the acute phase of the ischemic stroke includes treating the physical and medical conditions that can worsen cerebral injury; administering intravenous thrombolytic therapy (recombinant tissue plasminogen activator) in those who meet current guidelines; instituting prophylactic measures to prevent medical complications; and initiating passive rehabilitation measures. New approaches under investigation include intra-arterial thrombolytic therapy; endovascular embolectomy and clot disruption; and neuroprotective treatments to preserve surviving ischemic tissue. One neuroprotective agent given within 6 h after stroke onset, NXY059, recently met the primary outcome measure in a phase III clinical trial. Pharmacologic management of the subacute and chronic phases involves treatment of risk factors for recurrent stroke and other forms of cardiovascular disease, including hypercholesterolemia, hypertension, and diabetes mellitus. In this phase, antiplatelet therapy can be initiated or continued; smoking, obesity and alcohol intake can be managed; and active rehabilitation can begin through physical, occupational, and speech therapy. A few medications to augment rehabilitation have shown promising results in small clinical trials, but none have been tested in large phase III trials or approved by the US or European regulatory agencies. Thus, there are no pharmacologic measures available to enhance central nervous system restorative processes after acute stroke, and implantation of stem cells provides one promising approach, not only for cell replacement but also for the provision of therapeutic molecules.

Brain Ischemia↗
PubMed2005

Pharmacological profiles of recombinant and native insect nicotinic acetylcholine receptors.

Nicotinic acetylcholine receptors (nAChRs) are targets for insect-selective neonicotinoid insecticides exemplified by imidacloprid (IMI) and mammalian-selective nicotinoids including nicotine and epibatidine (EPI). Despite their importance, insect nAChRs are poorly understood compared with their vertebrate counterparts. This study characterizes the [(3)H]IMI, [(3)H]EPI, and [(3)H]alpha-bungarotoxin (alpha-BGT) binding sites in hybrid nAChRs consisting of Drosophila melanogaster (fruit fly) or Myzus persicae (peach-potato aphid) alpha2 coassembled with rat beta2 subunits (Dalpha2/Rbeta2 and Mpalpha2/Rbeta2) and compares them with native insect and vertebrate alpha4beta2nAChRs. [(3)H]IMI and [(3)H]EPI bind to Dalpha2/Rbeta2 and Mpalpha2/Rbeta2 hybrids but [(3)H]alpha-BGT does not. In native Drosophila receptors, [(3)H]EPI has a single high-affinity binding site that is independent from that for [(3)H]IMI and, interestingly, overlaps the [(3)H]alpha-BGT site. In the Mpalpha2/Rbeta2 hybrid, [(3)H]IMI and [(3)H]EPI bind to the same site and have similar pharmacological profiles. On considering both neonicotinoids and nicotinoids, the Dalpha2/Rbeta2 and Mpalpha2/Rbeta2 receptors display intermediate pharmacological profiles between those of native insect and vertebrate alpha4beta2 receptors, limiting the use of these hybrid receptors for predictive toxicology. These findings are consistent with the agonist binding site being located at the nAChR subunit interface and indicate that both alpha and beta subunits influence the pharmacological properties of insect nAChRs.

Animals↗
PubMed2004

Impact of curative ablation on pharmacologic management in children with reentrant supraventricular tachycardias.

BACKGROUND: The introduction of radiofrequency catheter ablation as a curative treatment option has led to a much better outlook for children with recurrent supraventricular reentrant tachycardias (SVT). This study sought to evaluate the impact of ablation on pharmacologic treatment of SVT. METHODS: Two time periods were retrospectively compared with regard to number of episodes of SVT in different age groups, number of acute drug conversions of SVT, chronic antiarrhythmic drug treatments prescribed: in the first period (1989-1994) management of SVT was exclusively pharmacological whereas during the second period (1995-2000) ablation was an option for patients aged 5 years or older. RESULTS: The study included 88 pediatric patients with recurrent SVT, 40 in the first period, 48 in the latter. Of these, 16 children (all >5 years of age) had an ablation procedure during the second time period. In patients aged >5 years, the number of documented SVT fell from a mean of 3.7/patient to two episodes. The number of acute drug conversions of SVT decreased from a mean of 1.1/patient to 0.2 (p<0.05) during the second period. In the group of children aged >5 years chronic antiarrhythmic treatment was given during a mean of 15 months/patient in period one compared to 4.6 months (p<0.05) in the second period. CONCLUSION: In the current era with increasing use of ablation as first-line treatment in older children with recurrent SVT, acute as well as chronic pharmacologic intervention for SVT has become significantly less frequent.

Adolescent↗
PubMed2006

Non-pharmacological treatments in the management of rapid cycling bipolar disorder.

BACKGROUND: Rapid cycling (RC) bipolar disorder is often treatment-resistant to pharmacotherapy. Non-pharmacological methods, however, are reasonable considerations in treatment refractory cases of bipolar patients. Thus, such methods may be useful in the management of RC, especially when drugs are not shown to be effective. METHOD: This review is based on studies of all major non-pharmacological methods which are used in the management of bipolar disorder, by focusing on data regarding patients with a RC pattern of the illness. RESULTS: Regarding biological treatments, for electroconvulsive therapy and sleep deprivation, there exists some evidence that they might be efficacious in RC patients for acute treatment as well as for prophylaxis from recurrences. Light therapy has not been shown to be efficacious in RC, while no published data exist for transcranial magnetic stimulation and vagus nerve stimulation. The non-biological treatments include psychotherapeutic and psychosocial interventions; these have not been tried particularly on RC patients, but their use should be expected to contribute to the overall management of the RC pattern as it does to that of mood disorder in general. LIMITATIONS: Many data on which this review is based are drawn from case reports or non-randomised trials. CONCLUSIONS: Non-pharmacological methods, either biological or non-biological (psychotherapies and psychoeducation), may be applied in the management of RC patients. These methods might be used in combination with the administration of drug treatment, based on the clinical experience of the physician and the individual characteristics of the patient.

Activity Cycles↗
PubMed2005

Brain-derived neurotrophic factor bound with lecithin derivative showed a markedly enhanced pharmacological potency due to its potent cell membrane affinity followed by prolonged MAPK activation.

We synthesized lecithinized brain-derived neurotrophic factor (lecithinized-BDNF), in which an average of three molecules of a lecithin derivative were bound to recombinant human BDNF. We evaluated its pharmacological activity in C57BL/KsJ-db/db mice, and assessed its targetability and affinity for the nervous system. Subcutaneously administered lecithinized-BDNF markedly reduced the plasma glucose level, food intake, and body weight in C57BL/KsJ-db/db diabetic mice. Its potency was more than 20 times greater than that of unmodified BDNF. We then studied the mechanism for the markedly enhanced pharmacological activity. In vitro cell growth activity of lecithinized-BDNF using the MTT assay was lower than unmodified BDNF, probably due to steric hindrance of the lecithin moieties. While the plasma BDNF level after subcutaneous administration of lecithinized-BDNF was not higher compared with unmodified BDNF. However, higher amount of lecithinized-BDNF accumulated in the spinal cord was observed. Lastly, we found that in vitro binding capacity of lecithinized-BDNF for PC-pAB1 neural cells was much higher than unmodified BDNF. Moreover, lecithinized-BDNF bound to PC-pAB1 cells did not exchange with an excessive amount of unmodified BDNF or an excess of lecithinized-BDNF. PC-pAB1 cells treated with lecithinized-BDNF showed sustained mitogen-activated protein kinase (MAPK, ERK1/2) activation. These data would indicate that the high affinity of lecithinized-BDNF for the target cells, followed by prolonged MAPK activation, would play an important role in its potent pharmacological activity.

Animals↗
PubMed2004

Paradigms for pharmacologic use as a treatment component in feline behavioral medicine.

Veterinary behavioral medicine remains an under-supported, under-appreciated, and under-taught specialty within veterinary medicine. Neuropsychopharmacology is the aspect that has provided the field with the most scientific legitimacy, but is also one of the most hotly debated. Paradigms for use of pharmacologic intervention include firstly ruling out any underlying medical cause. If a behavioral diagnosis can be made, treatment with psychotropic medication may be considered, although their use is most effective as part of an integrated treatment program that includes behavior modification. Used without an understanding of the mechanism of action, pharmacologic intervention may only blunt or mask behavior without altering processes or environments that produced the behavior. This paper reviews specific drugs, mechanism of action of those drugs, and relevant uses are reviewed for cats. Future advances in treatment in veterinary behavioral medicine will be pharmacological and neurophysiological. As the field of veterinary behavioral medicine expands, its paradigm will enlarge to include routine combination therapy and the implementation of neuropharmacological intervention as a diagnostic tool.

Animals↗
PubMed2005

Pharmacological effects of biotin.

In the last few decades, more vitamin-mediated effects have been discovered at the level of gene expression. Increasing knowledge on the molecular mechanisms of these vitamins has opened new perspectives that form a connection between nutritional signals and the development of new therapeutic agents. Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism: Biotin has stimulatory effects on genes whose action favors hypoglycemia (insulin, insulin receptor, pancreatic and hepatic glucokinase); on the contrary, biotin decreases the expression of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme that stimulates glucose production by the liver. The findings that biotin regulates the expression of genes that are critical in the regulation of intermediary metabolism are in agreement with several observations that indicate that biotin supply is involved in glucose and lipid homeostasis. Biotin deficiency has been linked to impaired glucose tolerance and decreased utilization of glucose. On the other hand, the diabetic state appears to be ameliorated by pharmacological doses of biotin. Likewise, pharmacological doses of biotin appear to decrease plasma lipid concentrations and modify lipid metabolism. The effects of biotin on carbohydrate metabolism and the lack of toxic effects of the vitamin at pharmacological doses suggest that biotin could be used in the development of new therapeutics in the treatment of hyperglycemia and hyperlipidemia, an area that we are actively investigating.

Animals↗
PubMed2005

A comparison of the OARSI response criteria with patient's global assessment in patients with osteoarthritis of the hip treated with a non-pharmacological intervention.

OBJECTIVE: To compare the Osteoarthritis Research Society International (OARSI) response criteria for clinical trials with patient's global assessment in patients with osteoarthritis (OA) of the hip receiving a non-pharmacological intervention, i.e., manual therapy or exercise therapy. METHODS: Data of a randomized clinical trial on manual therapy and exercise therapy in patients with OA of the hip (n = 109) were used. Change scores of measures of hip function, range of joint motion and pain were compared between patients who were differently classified by the OARSI response criteria and the patient's global assessment (using a t test, 95% CI). Furthermore, risk ratios (with 95% CI) were calculated for the contrast between treatment outcome, using the OARSI criteria or patient's global assessment. RESULTS: Few patients were classified as improved (i.e., responders) with the OARSI response criteria as compared to patient's global assessment. Significantly worse outcome for hip function and pain was observed in patients who were classified as non-responders (OARSI criteria), but who considered themselves as improved (patient's global assessment). Risk ratios for the contrast between the two treatment programs (manual therapy vs exercise therapy) were similar, when using the OARSI criteria or patient's global assessment. CONCLUSION: The validity of the OARSI response criteria has been previously demonstrated in OA patients treated with pharmacological interventions. The present study demonstrates the validity of the OARSI response criteria in OA patients treated with a non-pharmacological intervention, i.e., manual therapy and exercise therapy.

Aged↗
PubMed2005

Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring.

Maternal exposure to viral infection has been associated with an increased risk of schizophrenia in the offspring, and it has been suggested that the maternal immune response may interfere with normal fetal brain development. Although studies in rodents have shown that perinatal viral infections can lead to neuropathological and behavioral abnormalities considered relevant to schizophrenia, it is not clear whether these consequences are due to the infection itself or to the maternal immune response to infection. We show that an induction of maternal immune stimulation without exposure to a virus by injecting pregnant dams with the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I:C) leads to abnormal behavioral and pharmacological responses in the adult offspring. As in schizophrenia, these offspring displayed excessive behavioral switching, manifested in the loss of latent inhibition and in rapid reversal learning. Consistent with the clinical pharmacology of schizophrenia, both deficits were alleviated by antipsychotic treatment. In addition, these offspring displayed increased sensitivity to the locomotor-stimulating effects of MK-801, pointing to developmental alterations of the dopaminergic and/or glutamatergic systems. Prenatal poly I:C administration did not produce learning deficits in classical fear conditioning, active avoidance, discrimination learning and water maze. These results show that the maternal immune response is sufficient to cause behavioral and pharmacological alterations relevant to schizophrenia in the adult offspring.

Animals↗
PubMed2006

Pharmacologic relaxation of vein grafts is beneficial compared with pressure distention caused by upregulation of endothelial nitric oxide synthase and nitric oxide production.

OBJECTIVE: Pressure distention of veins during preparation for bypass surgery is believed to impair vascular integrity and reduce graft patency. We previously suggested a combination of pharmacologic vasodilatators as an alternative to distention. Vascular homeostasis is largely regulated by nitric oxide. We investigated the role of distention in comparison with pharmacologic vasorelaxation in the regulation of nitric oxide synthases, nitric oxide bioavailability, and vascular reactivity in vein grafts. METHODS: In a porcine model the internal jugular vein from either side received pressure distention or the combination of vasodilators (alpha-adrenergic antagonist, phenoxybenzamine, 10 micromol/L; Rho-kinase inhibitor, HA-1077 [fasudil], 50 mumol/L; calcium blocker, nicardipine, 1 micromol/L) and then was grafted into the carotid artery. Regulation of nitric oxide synthase, as well as nitrate and nitrite levels, were examined in vein grafts after 2 weeks of implantation. RESULTS: Distention of jugular veins resulted in reduction of vasoconstriction in response to depolarization and agonist stimulation. Arterial grafting doubled inducible nitric oxide synthase expression in both grafts but caused a pronounced upregulation of endothelial nitric oxide synthase protein (by 57.3% +/- 5%) only in drug-treated grafts, whereas in distended grafts the endothelial nitric oxide synthase level was decreased by 27.5% +/- 2.7%. The downregulated endothelial nitric oxide synthase level in the distended grafts was accompanied by a 45.2% +/- 3.1% reduction of phospho-endothelial nitric oxide synthase Ser1177 levels and by a significant reduction in nitric oxide synthase activity (12.1% +/- 1.2%) and nitrate production (48.9% +/- 5.6%) in comparison with that seen in drug-treated grafts. CONCLUSIONS: Pharmacologic preparation of the vein grafts results in upregulation of endothelial nitric oxide synthase and increased nitric oxide production in the vein grafts after arterial implantation. This might provide greater clinical benefit than conventional pressure-distention methods.

Animals↗
PubMed2006

Monitoring ligand-mediated internalization of G protein-coupled receptor as a novel pharmacological approach.

Agonist activation of a G protein-coupled receptor (GPCR) results in the redistribution of the receptor protein away from the cell surface into internal cellular compartments through a process of endocytosis known as internalization. Visualization of receptor internalization has become experimentally practicable by using fluorescent reagents such as green fluorescent protein (GFP). In this study, we examined whether the ligand-mediated internalization of a GPCR can be exploited for pharmacological evaluations. We acquired fluorescent images of cells expressing GFP-labeled GPCRs and evaluated the ligand-mediated internalization quantitatively by image processing. Using beta2-adrenoceptor and vasopressin V1a receptor as model GPCRs that couple to Gs and Gq, respectively, we first examined whether these GFP-tagged GPCRs exhibited appropriate pharmacology. The rank order of receptor internalization potency for a variety of agonists and antagonists specific to each receptor corresponded well with that previously observed in ligand binding studies. In addition to chemical ligand-induced internalization, this cell-based fluorescence imaging system successfully monitored the internalization of the proton-sensing GPCR TDAG8, and that of the free fatty acid-sensitive GPCR GPR120. The results show that monitoring receptor internalization can be a useful approach for pharmacological characterization of GPCRs and in fishing for ligands of orphan GPCRs.

Animals↗
PubMed2004

The molecular determinants of estrogen receptor pharmacology.

The classical models of steroid receptor pharmacology held that agonists functioned by binding to their cognate receptors, facilitating their conversion from an inactive form to one that was capable of activating transcription. By extrapolation, it was believed that antagonists functioned by competitively inhibiting agonist binding, freezing the receptor in an inactive state. However, as early as 1967 when the biologic actions of the "antiestrogen" tamoxifen were first described, it was clear that this simple model did not adequately describe estrogen receptor (ER) pharmacology. Since these initial observations, significant progress has been made in defining the molecular mechanism(s) by which cells distinguish between different ER ligands. The most important of these are: (i) differences in the relative expression level of the two ER subtypes, alpha and beta, in target tissues; (ii) the impact, which the bound ligand has on ER structure; and (iii) the complement of coactivators and corepressors in a target cell, which can interact with the activated receptor. This review describes how these advances have impacted our understanding of the pharmacologic activities of currently available ER ligands.

Female↗