Involvement of the βγ subunits of G proteins in the cAMP response induced by stimulation of the histamine H<Subscript>1</Subscript> receptor

Stimulation of the histamine H₁ receptor has been shown to enhance adenosine 3′, 5′-cyclic monophosphate (cAMP) accumulation in various cell types but, to date, the mechanism by which this occurs is still unclear. In the present study, we examined the possibility that the βγ subunits of G proteins (Gβγ) are involved in this process in cultured Chinese hamster ovary cells transfected with the human histamine H₁ receptor (CHO-H₁). Histamine increased intracellular cAMP levels in a concentration-dependent manner in CHO-H₁ cells, and this histamine action was abolished by pyrilamine (1 μM). Inhibition of histamine H₁ receptor-G_q protein coupling by stable expression of the C-terminal peptide of Gα_q protein significantly attenuated the cAMP accumulation induced by histamine. By comparison, neither BAPTA/AM (50 μM), an intracellular Ca²⁺ chelator, nor GF 109203X (1 μM), an inhibitor of protein kinase C, influenced the cAMP response. Histamine H₁ receptor-mediated cAMP accumulation was significantly inhibited by transient transfection of CHO-H₁ cells with the C-terminal peptide of β-adrenoceptor kinase I (residues 542–685), a scavenger of Gβγ. Stable expression of the C-terminal peptide of the Gα_s protein, but not treatment with pertussis toxin (200 ng/ml for 24 h), attenuated the histamine H₁ receptor-mediated cAMP accumulation. These results suggest that stimulation of histamine H₁ receptors activates adenylyl cyclase through the release of Gβγ subunits from G proteins, thereby elevating intracellular cAMP levels.     

Accessibility of ‘essential’ alcohol in the time of COVID‐19: Casting light on the blind spots of licensing?

Among the Australian and UK governments' responses to the COVID‐19 pandemic has been the designation of outlets selling alcohol for off‐premise consumption as ‘essential’ services, allowing them to remain open while pubs, hotels and restaurants have been forced to close. In a context of restrictions on movement outside the home in both countries, and where alcohol providers are trying to find new ways to reach their customers, this may lead to an intensification of the social and health harms associated with home drinking. By examining the current situation in both Australia and the UK, we argue that heightened risks from home drinking amid COVID‐19 bring into sharp focus long‐standing weaknesses within licensing systems in both countries: the regulation of off‐premise outlets to minimise harms from drinking at home. We call for critical conversations on how licensing systems should be revised to take more responsibility for protecting people from the health and social harms associated with home drinking, both under COVID‐19 and in the future.     

What is the long‐term outcome of the different subgroups of functional dyspepsia?

BACKGROUND: Functional dyspepsia is often a long-lasting disorder that accounts for substantial healthcare costs. It has been classified into subgroups assuming that it can guide management of dyspepsia. AIM: To evaluate the clinical significance of subgrouping functional dyspepsia in a long-term perspective study. METHODS: Consecutive patients with dyspepsia identified by general practitioners were investigated. Those patients with functional dyspepsia (n=201) were enrolled in this study. Initially, patients were divided into five subgroups (ulcer-like, dysmotility-like, reflux-like, unspecified, and irritable bowel syndrome-like). Patients' medical histories were reviewed after 6-7 years, and the number and outcome of repeated investigations were analysed. At the end of follow-up, patients filled in a questionnaire similar to that at baseline, and were invited for gastroscopy. RESULTS: Only 2% of patients developed peptic ulcer during follow-up, none of them were in the ulcer-like subgroup. When referrals to hospital and examinations during follow-up were registered, no statistically significant differences existed between subgroups. Patients with reflux-like dyspepsia made fewer revisits than others (P=0.02), but had used antidyspepsia drugs during the previous year more often (P=0.036). Stability of the subgroups over time was poor. CONCLUSIONS: Functional dyspepsia is a long-lasting disorder with a very good prognosis. Subgroups of functional dyspepsia play only a minor role in prediction of the long-term outcome, and their usefulness in clinical practice is also hampered by subgroup instability over time.     

Predicting the Oxidative Metabolism of Statins: An Application of the <Emphasis Type="Italic">MetaSite</Emphasis>® Algorithm

Purpose This study was undertaken to examine the MetaSite algorithm by comparing its predictions with experimentally characterized metabolites of statins produced by cytochromes P450 (CYPs). Methods Seven statins were investigated, namely atorvastatin, cerivastatin, fluvastatin, pitavastatin and pravastatin which are (or were) used in their active hydroxy-acid form, and lovastatin and simvastatin which are used as the lactone prodrug. But given the fast lactone-hydroxy-acid equilibrium undergone by statins, both forms were investigated for each of the seven drugs. The MetaSite version 2.5.3 used here contains the homology 3D-models of CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. In addition, we also used the crystallographic 3D-structure of human CYP2C9 and CYP3A4. To allow a better interpretation of results, the probability function P _SM i calculated by MetaSite (namely the probability of atom i to be a site of metabolism) was explicitly decomposed into its two components, namely a recognition score Ei (the accessibility of atom i) and the chemical reactivity Ri of atom i toward oxidation reactions. Results The current version of MetaSite is known to work best with prior experimental knowledge of the cytochrome(s) P450 involved. And indeed, experimentally confirmed sites of oxidation were correctly given a high priority by MetaSite. In particular 77% of correct predictions (including false positive but, as discussed, this is not necessarily a shortcoming) were obtained when considering the first five metabolites indicated by MetaSite. Conclusion To the best of our knowledge, this is the first independent report on the software. It is expected to contribute to the development of improved versions, but above all it demonstrates that the usefulness of such softwares critically depends on human experts. Electronic Supplementary Material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Comparison of the subjective effects of Δ<Superscript>9</Superscript>-tetrahydrocannabinol and marijuana in humans

RATIONALE: There has been controversy about whether the subjective, behavioral or therapeutic effects of whole plant marijuana differ from the effects of its primary active ingredient, Delta(9)-tetrahydrocannabinol (THC). However, few studies have directly compared the effects of marijuana and THC using matched doses administered either by the smoked or the oral form.OBJECTIVE: Two studies were conducted to compare the subjective effects of pure THC to whole-plant marijuana containing an equivalent amount of THC in normal healthy volunteers. In one study the drugs were administered orally and in the other they were administered by smoking.METHODS: In each study, marijuana users (oral study: n=12, smoking study: n=13) participated in a double-blind, crossover design with five experimental conditions: a low and a high dose of THC-only, a low and a high dose of whole-plant marijuana, and placebo. In the oral study, the drugs were administered in brownies, in the smoking study the drugs were smoked. Dependent measures included the Addiction Research Center Inventory, the Profile of Mood States, visual analog items, vital signs, and plasma levels of THC and 11-nor-9-carboxy-THC.RESULTS: In both studies, the active drug conditions resulted in dose-dependent increases in plasma THC levels, and the levels of THC were similar in THC-only and marijuana conditions (except that at the higher oral dose THC-only produced slightly higher levels than marijuana). In both the oral study and the smoking study, THC-only and whole plant marijuana produced similar subjective effects, with only minor differences.CONCLUSION: These results support the idea that the psychoactive effects of marijuana in healthy volunteers are due primarily to THC.     

Discovery of 4′′-Ether Linked Azithromycin-Quinolone Hybrid Series: Influence of the Central Linker on the Antibacterial Activity

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The Role of the Acidity of N-Heteroaryl Sulfonamides as Inhibitors of Bcl-2 Family Protein–Protein Interactions

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Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of the Dopamine D<Subscript>2</Subscript> Receptor Occupancy of Olanzapine in Rats

Purpose  

A mechanism-based PK-PD model was developed to predict the time course of dopamine D₂ receptor occupancy (D₂RO) in rat striatum following administration of olanzapine, an atypical antipsychotic drug.     

Comparison of the α-adrenoceptor-mediated effects of β<Subscript>3</Subscript>-adrenoceptor ligands in rat pulmonary artery

We have recently shown that the -adrenoceptor ligands CGP 12177, bupranolol, and SR 59230A (aryloxypropanolamines), but not BRL 37344 and CL 316243 (phenylethanolamines), exhibit significant affinity for ₁-adrenoceptors and that CGP 12177 displays partial agonist properties at -adrenoceptors in rat pulmonary artery. In this study, bupranolol and SR 59230A were further evaluated for their potential -adrenoceptor mediated effects (i.e., agonist and/or antagonist properties) in rat intralobar pulmonary artery and compared with BRL 37344 and CL 316243. Bupranolol induced a relaxation in phenylephrine-precontracted arteries, but had no effect in prostaglandin -precontracted ones. SR 59230A also elicited a relaxation in phenylephrine-precontracted arteries. In -precontracted arteries, SR 59230A induced a contractile response that was insensitive to the irreversible -adrenoceptor antagonist phenoxybenzamine. BRL 37344 at high concentrations, but not CL 316243, produced slight relaxation in both phenylephrine- and -precontracted arteries. The contractile response to phenylephrine was antagonized by bupranolol and SR 59230A in a competitive manner (pA₂: 6.38 and 7.08 respectively). The concentration–response curve to phenylephrine was also shifted to the right by BRL 37344 (mean pK_b: 4.45), but not by CL 316243 (100 M). This study indicates that the aryloxypropanolamine derivatives bupranolol and SR 59230A exhibit competitive antagonist, but no agonist properties on ₁-adrenoceptors, SR 59230A also inducing -adrenoceptor-independent contraction. Among the phenylethanolamines, BRL 37344 but not CL 316243, also exerts an antagonist effect on ₁-adrenoceptors, with a much lower potency than the aryloxypropanolamines studied.     

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2–p53 Interaction

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Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABA<Subscript>A</Subscript>/α<Subscript>1</Subscript>-preferring antagonist β-CCt in squirrel monkeys

Abstract Rationale. Delineation of the receptor mechanisms underlying the behavioral effects of benzodiazepines should allow for the development of drugs with improved clinical utility and reduced side effects. Objectives. The purpose of the present study was to investigate the role of GABA_A/α₁ receptors in the sedative and motor-impairing effects of benzodiazepines. Methods. Squirrel monkeys were tested with the GABA_A/α₁-preferring agonist zolpidem and the nonselective benzodiazepine agonist triazolam alone and in combination with the GABA_A/α₁-preferring antagonist β-CCt and the nonselective benzodiazepine antagonist flumazenil. During 30-min experimental sessions, all occurrences of normal behaviors like locomotion, environment- and self-directed behaviors, as well as side effects such as ataxia, rest and procumbent postures were scored. Results. Zolpidem and triazolam produced dose-dependent reductions in locomotion and environment-directed behavior and increased ataxia and procumbent posture. Triazolam, but not zolpidem, also engendered species-typical rest posture at some doses. Flumazenil antagonized all of the behavioral effects of zolpidem and triazolam, whereas β-CCt antagonized only zolpidem- and triazolam-induced ataxia. Conclusions. GABA_A/α₁ receptor mechanisms appear to play a key role in the ataxic effects of benzodiazepine agonists in squirrel monkeys, similar to recent results with transgenic mice. In contrast to the findings of these recent studies, GABA_A mechanisms other than or in addition to those mediated at the α₁ subunit may play a more important role in the sedative/hypnotic effects of benzodiazepines in squirrel monkeys. Electronic Publication