scholarly journals Thermoresponsive Hydrogel Containing Viscum album Extract for Topic and Transdermal Use: Development, Stability and Cytotoxicity Activity

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 37
Author(s):  
João V. D. C. Batista ◽  
Ana Paula S. Matos ◽  
Adriana P. Oliveria ◽  
Eduardo Ricci Júnior ◽  
Zaida M. Freitas ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Skin Permeation ◽  
Abies Alba ◽  
Viscum Album ◽  
Poloxamer 407 ◽  
In Vitro Assays ◽  
In Vitro Toxicity ◽  
Antitumoral Activity ◽  
Clinical Experiments

Viscum album L. (Santalaceae), also known as European mistletoe, is a semi-parasitic plant that grows on different host trees. Our group recently demonstrated the antitumoral activity of ethanolic V. album extracts in vitro, depending on the dose and the host tree, V. album ssp abietis from Abies alba being the most active extract. The goal of this work focused on the development of a new topical formulation containing V. album extracts, evaluation of in vitro toxicity and ex vivo skin permeation assays. The Poloxamer 407 hydrogel containing 5% of dry (VA_DEH) or aqueous (VA_AEH) extract presented dermal compatible pH and microbiological stability for 180 days. The hydrogels flow curve presented a non-linear relation, characteristic of non-Newtonian fluids, and the mean viscosity for the VA_DEH and VA_AEH was 372.5 ± 7.78 and 331.0 ± 2.83 Pa.s, respectively, being statistically different (Welch’s t test; p < 0.01). Additionally, WST-1 in vitro assays revealed a dose-dependent toxicity for both formulations and VA_DEH presented a higher activity than the VA_AEH. The promising cytotoxic potential of VA_DEH lead to the ex vivo skin permeation assay with 2.73 ± 0.19 µg/cm2 of chlorogenic acid, which permeated at 8 h, showing a transdermal potential. These in vitro results support the idea that VA_DEH is a novel promising candidate for mistletoe therapy. Therefore, further in vivo and pre-clinical experiments should be performed to evaluate the safety and efficacy of this new dermic delivery system.

scholarly journals Απομόνωση δραστικών εκχυλισμάτων, τμημάτων των φυτών Abies alba και Viscum album subsp. abietis και μελέτη των επιδράσεών τους στον πολλαπλασιασμό κακοηθών σαρκωματικών κυττάρων και σαρκωμάτων επιμύων

2011 ◽  
Author(s):  
Ιωάννης Ζελοβίτης
Keyword(s):  
Ex Vivo ◽  
Abies Alba ◽  
Viscum Album

Μελετήσαμε τις βιολογικές δράσεις ενός μικτού εκχυλίσματος από τους ιστούς των φυτών Viscum album & Abies alba σε μια σειρά in vitro, in vivo και ex vivo μοντέλων καρκίνου. Ως εκχυλιστικό μέσο χρησιμοποιήσαμε κυρίως την αιθυλική αλκοόλη, αλλά και το υποζέον νερό (95 οC) σε συνδυασμό με τη λειοφυλίωση. Οι νεοπλασματικές σειρές που χρησιμοποιήθηκαν για τα in vitro πειράματα ήταν μια σειρά λειομυοσαρκωματικών κυττάρων (LMS) επίμυος Wistar και η λευχαιμική σειρά L–210. Επίσης χρησιμοποιήθηκε για την μελέτη της κυτταροτοξικότητας των λεμφοκυττάρων ΝΚ η ερυθρολευχαιμική σειρά Κ-562. Τα εκχυλίσματα φυτικών ιστών που μελετήθηκαν ήταν: φύλλων, βλαστών, καρπών (Viscum album) και φύλλων, φλοιού, ξύλου (Abies alba). Τέλος μελετήθηκε ένα μικτό εκχύλισμα των δύο φυτών, τόσο ως προς τη κυτταροτοξικότητά του in vitro, όσο και προς τις αντικαρκινικές και αντικαρκινογόνες του ιδιότητες in vivo. Ακόμη μελετήθηκε η δράση του μικτού εκχυλίσματος α) επί της κυτταροτοξικής ικανότητας των NK λεμφοκυττάρων του ανθρώπου, εναντίον νεοπλασματικών κυττάρων της σειράς K-562 και LMS κυττάρων επίμυος Wistar. β) Η αντιμεταστατική του δράση σε ένα in vivo μοντέλο μετάστασης με ενδοφλέβια έγχυση LMS κυττάρων και σε ένα in vitro μοντέλο αιματογενούς μεταστατικής διασποράς, περιλαμβάνον τις αλληλεπιδράσεις μεταξύ νεοπλασματικών κυττάρων και αιμοπεταλίων. γ) Η ολική αντιοξειδωτική του ικανότητα, η ικανότητα αναστολής του ενζύμου 5–LOX, η ικανότητα αναστολής της παραγωγής θρομβοξάνης Α2 και προσταγλανδίνης Ε2 από ανθρώπινα αιμοπετάλια, όπως και από καρκινικά κύτταρα. Τα δεδομένα που προέκυψαν μας δείχνουν ότι το μικτό εκχύλισμα από τους ιστούς των δύο φυτών: 1) Εμφανίζει κυτταροτοξικές ιδιότητες εναντίον των LMS κυττάρων του επίμυος Wistar in vitro. 2) Είναι ισχυρά κυτταροτοξικό απέναντι στην L–210. 3) Είναι ισχυρά κυτταροτοξικό απέναντι στα νεοπλασματικά κύτταρα των όγκων που αναπτύσσονται σε επίμυες Wistar είτε μέσω ενοφθαλμισμού LMS κυττάρων, είτε μέσω έγχυσης 3,4–βενζοπυρενίου. 4) Είναι αντικαρκινογόνο καθόσον αναστέλλει σημαντικά την καρκινογόνο δράση του Β[a]Ρ, μειώνοντας το ποσοστό εμφάνισης κακοηθών όγκων, αλλά και αυξάνοντας το προσδόκιμο επιβίωσης των καρκινοπαθών ζώων. 5) Ενισχύει τη κυτταροτοξική δράση των ΝΚs του ανθρώπου εναντίον καρκινικών κυττάρων Κ-562 και LMS κυττάρων ως στόχων. 6) Αναστέλλει τη μεταστατική διαδικασία στο in vivo μοντέλο μετάστασης στον επίμυ Wistar, αλλά και στο in vitro μοντέλο το σχετικό με τη συσσωρευτική δράση των LMS κυττάρων επί των αιμοπεταλίων του ανθρώπου. 7) Αναστέλλει δοσοεξαρτώμενα την 5-LOX in vitro, καθώς και την κυκλοξυγονάση των ανθρώπινων αιμοπεταλίων και των LMS κυττάρων ex vivo και in vitro αντίστοιχα. 8) Παρουσιάζει αξιόλογη ολική αντιοξειδωτική ισχύ. 9) Διαθέτει πολύ χαμηλή χρόνια τοξικότητα.

scholarly journals PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties

2021 ◽  
Vol 22 (5) ◽  
pp. 2731
Author(s):  
Piotr Garnuszek ◽  
Urszula Karczmarczyk ◽  
Michał Maurin ◽  
Arkadiusz Sikora ◽  
Jolanta Zaborniak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Targeted Therapy ◽  
Ex Vivo ◽  
Specific Binding ◽  
Biological Evaluation ◽  
In Vitro Assays ◽  
The Novel ◽  
Distribution Profile ◽  
System L

A new PSMA ligand (PSMA-D4) containing the Glu-CO-Lys pharmacophore connected with a new linker system (L-Trp-4-Amc) and chelator DOTA was developed for radiolabeling with therapeutic radionuclides. Herein we describe the synthesis, radiolabeling, and preliminary biological evaluation of the novel PSMA-D4 ligand. Synthesized PSMA-D4 was characterized using TOF-ESI-MS, NMR, and HPLC methods. The novel compound was subject to molecular modeling with GCP-II to compare its binding mode to analogous reference compounds. The radiolabeling efficiency of PSMA-D4 with 177Lu, 90Y, 47Sc, and 225Ac was chromatographically tested. In vitro studies were carried out in PSMA-positive LNCaP tumor cells membranes. The ex vivo tissue distribution profile of the radioligands and Cerenkov luminescence imaging (CLI) was studied in LNCaP tumor-bearing mice. PSMA-D4 was synthesized in 24% yield and purity >97%. The radio complexes were obtained with high yields (>97%) and molar activity ranging from 0.11 to 17.2 GBq mcmol−1, depending on the radionuclide. In vitro assays confirmed high specific binding and affinity for all radiocomplexes. Biodistribution and imaging studies revealed high accumulation in LNCaP tumor xenografts and rapid clearance of radiocomplexes from blood and non-target tissues. These render PSMA-D4 a promising ligand for targeted therapy of prostate cancer (PCa) metastases.

scholarly journals Fishing for Targets of Alien Metabolites: A Novel Peroxisome Proliferator-Activated Receptor (PPAR) Agonist from a Marine Pest

Marine Drugs ◽  
2018 ◽  
Vol 16 (11) ◽  
pp. 431 ◽  
Author(s):  
Rosa Vitale ◽  
Enrico D'Aniello ◽  
Stefania Gorbi ◽  
Andrea Martella ◽  
Cristoforo Silvestri ◽  
...  
Keyword(s):  
Native Species ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Invasion Biology ◽  
In Vitro Assays ◽  
Bioactive Metabolites ◽  
Peroxisome Proliferator ◽  
Invasive Pests

Although the chemical warfare between invasive and native species has become a central problem in invasion biology, the molecular mechanisms by which bioactive metabolites from invasive pests influence local communities remain poorly characterized. This study demonstrates that the alkaloid caulerpin (CAU)—a bioactive component of the green alga Caulerpa cylindracea that has invaded the entire Mediterranean basin—is an agonist of peroxisome proliferator-activated receptors (PPARs). Our interdisciplinary study started with the in silico prediction of the ligand-protein interaction, which was then validated by in vivo, ex vivo and in vitro assays. On the basis of these results, we candidate CAU as a causal factor of the metabolic and behavioural disorders observed in Diplodus sargus, a native edible fish of high ecological and commercial relevance, feeding on C. cylindracea. Moreover, given the considerable interest in PPAR activators for the treatment of relevant human diseases, our findings are also discussed in terms of a possible nutraceutical/pharmacological valorisation of the invasive algal biomasses, supporting an innovative strategy for conserving biodiversity as an alternative to unrealistic campaigns for the eradication of invasive pests.

scholarly journals Kisspeptin-10 Inhibits Angiogenesis in Human Placental Vessels ex Vivo and Endothelial Cells in Vitro

Endocrinology ◽  
2010 ◽  
Vol 151 (12) ◽  
pp. 5927-5934 ◽  
Author(s):  
Thayalini Ramaesh ◽  
James J. Logie ◽  
Antonia K. Roseweir ◽  
Robert P. Millar ◽  
Brian R. Walker ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Ex Vivo ◽  
Umbilical Vein ◽  
Biologically Active ◽  
Trophoblast Invasion ◽  
In Vitro Assays ◽  
Dependent Manner ◽  
Inhibition Of Proliferation

Recent studies suggest that kisspeptin (a neuropeptide central to the regulation of gonadotrophin secretion) has diverse roles in human physiology, including a putative role in implantation and placental function. Kisspeptin and its receptor are present in human blood vessels, where they mediate vasoconstriction, and kisspeptin is known to inhibit tumor metastasis and trophoblast invasion, both processes involving angiogenesis. We hypothesized that kisspeptin contributes to the regulation of angiogenesis in the reproductive system. The presence of the kisspeptin receptor was confirmed in human placental blood vessels and human umbilical vein endothelial cells (HUVEC) using immunochemistry. The ability of kisspeptin-10 (KP-10) (a shorter biologically active processed peptide) to inhibit angiogenesis was tested in explanted human placental arteries and HUVEC using complementary ex vivo and in vitro assays. KP-10 inhibited new vessel sprouting from placental arteries embedded in Matrigel and tube-like structure formation by HUVEC, in a concentration-dependent manner. KP-10 had no effect on HUVEC viability or apoptosis but induced concentration-dependent inhibition of proliferation and migration. In conclusion, KP-10 has antiangiogenic effects and, given its high expression in the placenta, may contribute to the regulation of angiogenesis in this tissue.

Nanostructured Lipid Carriers for Intranasal Administration of Olanzapine in the management of Schizophrenia

2021 ◽  
Vol 14 ◽  
Author(s):  
Sarbjot Kaur ◽  
Ujjwal Nautiyal ◽  
Pooja A. Chawla ◽  
Viney Chawla
Keyword(s):  
Drug Delivery ◽  
Ex Vivo ◽  
In Vitro Release ◽  
Nanostructured Lipid Carriers ◽  
Polydispersity Index ◽  
Poloxamer 407 ◽  
Ex Vivo Permeation ◽  
Permeation Studies ◽  
Vitro Release

Background: Background: Olanzapine belongs to a new class of dual spectrum antipsychotic agents. It is known to show promise in managing both the positive and negative symptoms of schizophrenia. Drug delivery systems based on nanostructured lipid carriers (NLC) are expected to provide rapid nose-to-brain transport of this drug and improved distribution into and within the brain. Objective: The present study deals with the preparation and evaluation of olanzapine loaded NLC via the intranasal route for schizophrenia. Methods: Olanzapine-NLC were formulated through the solvent injection method using isopropyl alcohol as the solvent, stearic acid as solid lipid, and oleic acid as liquid lipid, chitosan as a coating agent, and Poloxamer 407 as a surfactant. NLC were characterized for particle size, polydispersity index, entrapment efficiency, pH, viscosity, X-ray diffraction studies, in-vitro mucoadhesion study, in- vitro release and ex-vivo permeation studies. The shape and surface morphology of the prepared NLC was determined through transmission electron microscopy. To detect the interaction of the drug with carriers, compatibility studies were also carried out. Results: Average size and polydispersity index of developed formulation S6 was 227.0±6.3 nm and 0.460 respectively. The encapsulation efficiency of formulation S6 was found to be 87.25 %. The pH, viscosity, in-vitro mucoadhesion study, and in- vitro release of optimized olanzapine loaded NLC were recorded as 5.7 ± 0.05, 78 centipoise, 15±2 min, and 91.96 % respectively. In ex-vivo permeation studies, the percent drug permeated after 210 min was found to be 84.03%. Conclusion: These results reveal potential application of novel olanzapine-NLC in intranasal drug delivery system for treatment of schizophrenia.

DEVELOPMENT AND EVALUATION OF NANOPARTICULATE BASED IN-SITU GELLING SYSTEM FOR NASAL DRUG DELIVERY OF AN ANTI-EPILEPTIC DRUG

INDIAN DRUGS ◽  
2017 ◽  
Vol 54 (09) ◽  
pp. 83-85
Author(s):  
A Ambavkar ◽  
◽  
N. Desai
Keyword(s):  
Drug Release ◽  
Ex Vivo ◽  
Entrapment Efficiency ◽  
Poloxamer 407 ◽  
Nasal Drug Delivery ◽  
Anti Epileptic Drug ◽  
Nanolipid Carriers ◽  
In Situ Nasal Gel

The objective of the study was to develop and evaluate nanolipid carriers based in situ gel of Carbamazepine, for brain delivery through intranasal route. The non – invasive nasal route can provide rapid delivery of drugs directly to the central nervous system by bypassing the blood brain barrier. The nanolipid carriers of carbamazepine as in situ nasal gel can prolong the drug release for control of repetitive seizures and were prepared by Phase Inversion Temperature technique. The retention of the carriers in the nasal cavity was improved by using Poloxamer 407 as thermoresponsive and Carbopol 974P as mucoadhesive gelling polymers, respectively. The developed gel was evaluated for particle size, polydispersity index, zeta potential, morphology, entrapment efficiency, mucoadhesive and thermoresponsive behaviour, in vitro drug release, ex vivo permeation and nasociliotoxicity. The gel showed sustained release over prolonged periods and was found to be non-toxic to the sheep nasal mucosa.

scholarly journals Nanocrystals of Fusidic Acid for Dual Enhancement of Dermal Delivery and Antibacterial Activity: In Vitro, Ex Vivo and In Vivo Evaluation

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 199 ◽  
Author(s):  
Iman S. Ahmed ◽  
Osama S. Elnahas ◽  
Nouran H. Assar ◽  
Amany M. Gad ◽  
Rania El Hosary
Keyword(s):  
Fusidic Acid ◽  
Therapeutic Efficacy ◽  
Ex Vivo ◽  
Skin Permeation ◽  
Fold Increase ◽  
Spherical Particles ◽  
Resistant Bacteria ◽  
Infection Model

With the alarming rise in incidence of antibiotic-resistant bacteria and the scarcity of newly developed antibiotics, it is imperative that we design more effective formulations for already marketed antimicrobial agents. Fusidic acid (FA), one of the most widely used antibiotics in the topical treatment of several skin and eye infections, suffers from poor water-solubility, sub-optimal therapeutic efficacy, and a significant rise in FA-resistant Staphylococcus aureus (FRSA). In this work, the physico-chemical characteristics of FA were modified by nanocrystallization and lyophilization to improve its therapeutic efficacy through the dermal route. FA-nanocrystals (NC) were prepared using a modified nanoprecipitation technique and the influence of several formulation/process variables on the prepared FA-NC characteristics were optimized using full factorial statistical design. The optimized FA-NC formulation was evaluated before and after lyophilization by several in-vitro, ex-vivo, and microbiological tests. Furthermore, the lyophilized FA-NC formulation was incorporated into a cream product and its topical antibacterial efficacy was assessed in vivo using a rat excision wound infection model. Surface morphology of optimized FA-NC showed spherical particles with a mean particle size of 115 nm, span value of 1.6 and zeta potential of −11.6 mV. Differential scanning calorimetry and powder X-ray diffractometry confirmed the crystallinity of FA following nanocrystallization and lyophilization. In-vitro results showed a 10-fold increase in the saturation solubility of FA-NC while ex-vivo skin permeation studies showed a 2-fold increase in FA dermal deposition from FA-NC compared to coarse FA. Microbiological studies revealed a 4-fofd decrease in the MIC against S. aureus and S. epidermidis from FA-NC cream compared to commercial Fucidin cream. In-vivo results showed that FA-NC cream improved FA distribution and enhanced bacterial exposure in the infected wound, resulting in increased therapeutic efficacy when compared to coarse FA marketed as Fucidin cream.

Comparative in-Vitro Evaluation of the Myeloid Toxicity of Pentostatin and the Novel PNP-Inhibitor Forodesine.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3766-3766
Author(s):  
Mario Schubert ◽  
Christian Wallenwein ◽  
Larissa Pietsch ◽  
Dan Ran ◽  
Isabel Taubert ◽  
...  
Keyword(s):  
Primary Cultures ◽  
Flow Cytometric Analysis ◽  
Chemotherapeutic Agents ◽  
Dose Effect ◽  
In Vitro Assays ◽  
In Vitro Toxicity ◽  
The Novel ◽  
Xtt Assay ◽  
Cd34 Cells

Abstract Abstract 3766 Poster Board III-702 Inhibitors of the purine metabolism show promising results in the treatment of lymphatic malignancies due to their suppressive effects on lymphogenesis. Their first representative, Pentostatin (Pento), an inhibitor of the deoxyadenosine deaminase, has been in clinical use for several decades. However, early clinical trials with higher dose ranges of the drug reported unforseen severe myelotoxic effects. Recently, Forodesine (Foro), a novel inhibitor of the nucleoside phosphorylase (PNP) has been introduced and is currently deployed in clinical phase I/II trials for the treatment of acute lymphatic leukemia (ALL). In order to systematically evaluate the myelotoxic effects of Pento and Foro, we have now examined their influence on the proliferation and differentiation of primitive and lineage committed hematopoietic progenitor cells (HPCs). In vitro dose/effect-curves for Foro, Pento, and Cytarabine (AraC) were generated for the leukemic cell line jurkat by 48 hours of co-incubation with the compounds. Adequate cytotoxic effects, measured in the XTT assay and by flow cytometric analysis, were observed in clinically relevant dose ranges. For the following studies, an equivalent IC60 dose of each chemotherapeutic agent was selected and CD34+ HPCs from either bone marrow, mobilized peripheral blood, or umbilical cord blood were incubated with the compounds for 48 hours. Subsequently, the rate of vital cells was determined by flow cytometry after stainig with Annexin-V and Propidium Iodide. Compared to the untreated control, the lowest amount of vital CD34+ cells was found in AraC-treated samples (30%); Foro and Pento yielded more vital cells (66% vs 61%). The combination of Foro and Pento unexpectedly had the least toxic effect on CD34+ cells (72%; n=5; p<0.05). Cells from those primary cultures were harvested and short- and long term in vitro assays for colony forming units were performed to evaluate the compounds' toxicity on primitive and lineage committed HPCs. The frequency of primitive myeloic progenitors (LTC-IC) was 2.3% in the untreated samples and diminished after treatment with AraC (1.2%) and Pento (1.9%) but surprisingly significantly increased after Foro-treatment (2.7%); the combination of Foro and Pento resulted in a LTC-IC frequency of 2.3% (p<0.01; n=5) suggesting that Foro may have attenuated the myelotoxicity of Pento. Similar effects of Foro were also observed in the short term colony forming assays where Foro seemed to have a protective effect on multipotent GEMM-progenitors: colony count increased 1.3-fold in comparison to the control; AraC yielded only 0.1-fold, Pento 0.8-fold and the combination of Pento and Foro reached 0.9-fold of the control (p<0.05; n=15). In summary, the novel PNP-inhibitor Forodesine has not only proven to have a low in vitro toxicity on lineage committed HPCs but, surprisingly, the frequency of primitive myeloic progenitors (LTC-IC) increased; clinical studies should therefore be performed to evaluate whether Forodesine, while adding to the therapeutic efficiency, may attenuate adverse effects in combination with other chemotherapeutic agents, such as Pentostatin. Disclosures: Schubert: Mundipharma Int. LTD: Research Funding.

scholarly journals DEVELOPMENT AND EVALUATION OF TRANSDERMAL FILM CONTAINING SOLID LIPID NANOPARTICLES OF RIVASTIGMINE TARTRATE

2017 ◽  
Vol 9 (6) ◽  
pp. 85
Author(s):  
G. Ravi ◽  
N. Vishal Gupta
Keyword(s):  
Tensile Strength ◽  
Drug Release ◽  
Ex Vivo ◽  
Skin Permeation ◽  
Cost Effective ◽  
In Vitro Drug Release ◽  
Drug Content ◽  
Study Results ◽  
Transdermal Film

Objective: The objective of present investigation was to develop rivastigmine tartrate transdermal film employing factorial design.Methods: The formulations were designed by Design-Expert software-version10. A series of films were prepared by solvent casting method using polymers, plasticizer, permeation enhancer and other solvents. Transdermal films were evaluated for flatness, drug content, tensile strength, in vitro drug release and ex vivo skin permeation study.Results: The flatness was found 100% (percentage) for all film formulations. The drug content of transdermal film was found in the range of 96.51±0.2 to 98.81±0.3%. The tensile strength of transdermal film was found in the range of 6.28±0.06 to 11.56±0.03 N/mm2 (newton/millimeter2) and in vitro drug release at 24th h (hour) was found in the range of 86.24±0.25 to 96.1±0.48%% for various formulations and ex vivo skin permeation study results at 24th h was found in the range of 85.83±0.74 to 97.36±0.93%.Conclusion: These results support the feasibility of developing transdermal film of rivastigmine tartrate for human applications. Thus, transdermal delivery of rivastigmine tartrate film is a safe, painless and cost effective drug delivery system for Alzheimer’s patients.

BPP-5a produces a potent and long-lasting NO-dependent antihypertensive effect

2011 ◽  
Vol 5 (6) ◽  
pp. 281-295 ◽  
Author(s):  
Danielle Ianzer ◽  
Carlos Henrique Xavier ◽  
Fabiana Costa Fraga ◽  
Roberto Queiroga Lautner ◽  
Juliano Rodrigo Guerreiro ◽  
...  
Keyword(s):  
Ace Inhibitor ◽  
Antihypertensive Effect ◽  
Ex Vivo ◽  
Cardiovascular Effects ◽  
Ace Inhibition ◽  
In Vitro Assays ◽  
Spontaneously Hypertensive ◽  
Angiotensin I Converting Enzyme ◽  
Animal Venoms

Background: The bradykinin potentiating peptides (BPPs) are oligopeptides found in different animal venoms. BPPs isolated from Bothrops jararaca venom were the first natural inhibitors described for somatic angiotensin I-converting enzyme (ACE). They were used in the structural modeling for captopril development, a classical ACE inhibitor widely used to treat human hypertension. Methods: We evaluated the effect of BPP-5a on cardiovascular parameters of conscious Wistar (WTs) and spontaneously hypertensive rats (SHRs). Results: In SHR, BPP-5a showed potent cardiovascular effects, at doses ranging from 0.47 to 710 nmol/kg. The maximal changes in mean arterial pressure (MAP) and heart rate (HR) were found at the dose of 2.37 nmol/kg (Δ MAP: −38 ± 4 mmHg, p < 0.01; Δ HR: −71 ± 17 bpm, p < 0.05). Reductions in MAP and HR occurred throughout 6 hours of post-injection period. In contrast to active site-directed ACE inhibitors, no ACE inhibition, evaluated by the Ang I pressor effect, or bradykinin potentiation was observed during the antihypertensive effect of the pentapeptide. In vitro assays showed no effects of BPP-5a upon argininosuccinate synthetase and B1, B2, AT1, AT2 or Mas receptors. Ex vivo assays showed that BPP-5a induced endothelium-dependent vasorelaxation in isolated aortic rings of SHRs and WTs. Conclusions: Although the BPP-5a is considered an ACE inhibitor, our results indicate that its antihypertensive effect is exerted via a unique target, a nitric-oxide-dependent mechanism.

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