1,721,155 research outputs found
Neutral/negative α 1 -AR antagonists and calcium channel blockers at comparison in functional tests on guinea-pig smooth muscle and myocardium
No full textBackground: Constitutive (agonist-independent) activity is a prerogative of many G protein-coupled receptors (GPCRs) including α 1 -adrenoceptors (α 1 -ARs). Inhibition of such an activity at α 1 -AR subtypes by antagonists with negative efficacy is difficult to be adequately tested. Methods: In the present experimental approach, we compared the activity of three calcium channel blockers (nifedipine, diltiazem and verapamil) and of three potent benzodioxane-based α 1 -AR antagonists, differing for subtype selectivity and inverse agonist properties, in producing smooth muscle relaxation and negative inotropy under the same test conditions. We selected, as benzodioxane derivatives, (S)-WB4101, inverse agonist with slight α 1A /α 1B -α 1D AR selectivity, and two previously developed analogues. Both of these are potent antagonists at α 1D -AR, that is the α 1 - AR subtype suspected of the highest susceptibility to inverse agonists for its high degree of basal activity, but only one is inverse agonist. Results: We found that all the three benzodioxane-related α 1 -AR antagonists have significant intrinsic relaxant activity on non-vascular smooth muscle and moderate negative inotropic effect, while they do not relax aorta. Their potency is always lower than that of three calcium channel blockers. Conclusions: Intrinsic myorelaxant and negative inotropic activity of the three benzodioxane-based α 1 -AR antagonist is related neither to a particular profile of α 1 -AR subtype selectivity nor to whether or not being an inverse agonist, but it parallels the calcium antagonists effects indicating a direct interaction of the three α 1 -AR antagonists with L-type Ca 2+ channels
Hibiscus Sabdariffa L. Flowers and Olea Europea L. Leaves Extract-Based Formulation for Hypertension Care: In Vitro Efficacy and Toxicological Profile
No full textOlea europaea L. leaves extract (Oe) and Hybiscus sabdariffa L. flowers extract (Hs) have calcium antagonistic properties. Aim of this work was to study the cardiovascular effects of Pres Phytum(®), a nutraceutical formulation containing a mixture of the two extracts and the excipients, and investigate its possible off-target effects, using in vitro biological assays on guinea pig isolated organs. Cardiovascular effects were assessed using guinea pig atria and aorta. The effects of Pres Phytum on spontaneous gastrointestinal, urinary, and respiratory tracts smooth muscle contractility were evaluated. Pres Phytum exerted a vasorelaxant effect (IC50 = 2.38 mg/mL) and a negative chronotropic effect (IC50 = 1.04 mg/mL) at concentrations lower than those producing smooth muscle spontaneous contractility alterations in the other organs. Compared to Pres Phytum, the mixture did not exert negative inotropic activity, while it maintained a negative chronotropic efficacy (IC50 = 1.04 mg/mL). These experimental data suggest a possible nutraceutical use of this food supplement for the management of preclinical hypertension
Advancements in the Research of New Modulators of Nitric Oxide Synthases Activity
Full text linkNitric oxide (NO) has been defined as the "miracle molecule" due to its essential pleiotropic role in living systems. Besides its implications in physiologic functions, it is also involved in the development of several disease states, and understanding this ambivalence is crucial for medicinal chemists to develop therapeutic strategies that regulate NO production without compromising its beneficial functions in cell physiology. Although nitric oxide synthase (NOS), i.e., the enzyme deputed to the NO biosynthesis, is a well-recognized druggable target to regulate NO bioavailability, some issues have emerged during the past decades, limiting the progress of NOS modulators in clinical trials. In the present review, we discuss the most promising advancements in the research of small molecules that are able to regulate NOS activity with improved pharmacodynamic and pharmacokinetic profiles, providing an updated framework of this research field that could be useful for the design and development of new NOS modulators
BIOMECHANICAL CHARACTERIZATION OF SPONTANEOUS AND INDUCED MOTILITY IN SMALL ANIMALS’ GASTROINTESTINAL TISSUE FOR HUMAN NUTRACEUTICAL AND PHARMACEUTICAL PURPOSES
No full textThe correct evaluation of the effects of a new drug or molecule on the tissues it interacts with is essential for fully understanding its benefits and side effects. To date, there is a lack of accurate biomechanical characterization of gastrointestinal tissues, with the effects of active ingredients primarily assessed based on clinical outcomes. While we know a drug is effective, we often fail to understand the underlying mechanisms. Investigating the effects of these substances at the tissue level would improve our understanding of their biochemical and biomechanical properties, allowing the development of more effective drugs or identifying natural molecules with similar benefits but reduced side effects and costs. This study aims to characterize the biomechanical properties of gastrointestinal tissues from small animals. It presents a methodological overview and application using guinea pigs. The research involves biological sample preparation, assessment of spontaneous and induced motility, and evaluation of passive elastic behavior. The study focuses on tissues extracted ex vivo from the ileum and colon of healthy guinea pigs, analyzing their behavior in longitudinal and circular directions. Stress–strain curves were generated for circular samples. Our findings demonstrate the reliability of the proposed method for predicting the activity of compounds and extracts. The clinical efficacy of Otilonium Bromide (OB), tested in our models, highlights the method’s validity. This evidence supports biomechanical characterization as a complementary approach to clinical outcomes, enhancing our understanding of how active ingredients affect gastrointestinal function
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