NO production and potassium channels activation induced by Crotalus durissus cascavella underlie mesenteric artery relaxation

Santos, Suelen Silva; Jesus, Rafael L C de; Simões, Letícia Oliveira; Vasconcelos, Walma Pereira de; Medeiros, Isac A.; Veras, Robson Cavalcante; Casais-e-Silva, Luciana Lyra; Silva, D.F.

doi:10.1016/j.toxicon.2017.04.010

Cited by 9 publications

(3 citation statements)

References 45 publications

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“…It is important to stress that there are other snake venoms compounds such as natriuretic peptides, L-type calcium channels blockers, sarafatoxins, and vascular endothelial growth factors that display cardiovascular effects (reviewed in [ 163 , 164 , 165 , 166 ]). Two recent works have demonstrated the vasorelaxant effect (which is likely due to the inducing of NO production) of Montivipera bornmuelleri [ 167 ] and Crotalus durissus cascavella [ 168 ] venoms, indicating their therapeutic potential in the treatment of cardiovascular diseases such as hypertension.…”

Section: Resultsmentioning

confidence: 99%

Revisiting the Therapeutic Potential of Bothrops jararaca Venom: Screening for Novel Activities Using Connectivity Mapping

Nicolau

Prorock

Bao

et al. 2018

Toxins

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Snake venoms are sources of molecules with proven and potential therapeutic applications. However, most activities assayed in venoms (or their components) are of hemorrhagic, hypotensive, edematogenic, neurotoxic or myotoxic natures. Thus, other relevant activities might remain unknown. Using functional genomics coupled to the connectivity map (C-map) approach, we undertook a wide range indirect search for biological activities within the venom of the South American pit viper Bothrops jararaca. For that effect, venom was incubated with human breast adenocarcinoma cell line (MCF7) followed by RNA extraction and gene expression analysis. A list of 90 differentially expressed genes was submitted to biosimilar drug discovery based on pattern recognition. Among the 100 highest-ranked positively correlated drugs, only the antihypertensive, antimicrobial (both antibiotic and antiparasitic), and antitumor classes had been previously reported for B. jararaca venom. The majority of drug classes identified were related to (1) antimicrobial activity; (2) treatment of neuropsychiatric illnesses (Parkinson’s disease, schizophrenia, depression, and epilepsy); (3) treatment of cardiovascular diseases, and (4) anti-inflammatory action. The C-map results also indicated that B. jararaca venom may have components that target G-protein-coupled receptors (muscarinic, serotonergic, histaminergic, dopaminergic, GABA, and adrenergic) and ion channels. Although validation experiments are still necessary, the C-map correlation to drugs with activities previously linked to snake venoms supports the efficacy of this strategy as a broad-spectrum approach for biological activity screening, and rekindles the snake venom-based search for new therapeutic agents.

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Section: Resultsmentioning

confidence: 99%

Revisiting the Therapeutic Potential of Bothrops jararaca Venom: Screening for Novel Activities Using Connectivity Mapping

Nicolau

Prorock

Bao

et al. 2018

Toxins

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“…Vascular smooth muscle cells (VSMCs) are exposed to mechanical stress and the pressure of blood flow, and play an important role in maintaining vascular tone and resistance [ 21 ]. In addition, the endothelium regulates vascular tone by synthesizing and releasing an array of endothelium-derived relaxing factors, such as nitric oxide and endothelium-dependent hyperpolarization factors, as well as endothelium-derived contracting factors [ 22 , 23 ]. In the current study, when the endothelium of mesenteric artery rings was removed, the vasorelaxant effect of 7-HC was not significantly impaired, indicating that the vasorelaxant activity of 7-HC does not rely on the integrity of the endothelial layer.…”

Section: Discussionmentioning

confidence: 99%

7-Hydroxycoumarin Induces Vasorelaxation in Animals with Essential Hypertension: Focus on Potassium Channels and Intracellular Ca2+ Mobilization

et al. 2022

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Cardiovascular diseases (CVD) are the deadliest noncommunicable disease worldwide. Hypertension is the most prevalent risk factor for the development of CVD. Although there is a wide range of antihypertensive drugs, there still remains a lack of blood pressure control options for hypertensive patients. Additionally, natural products remain crucial to the design of new drugs. The natural product 7-hydroxycoumarin (7-HC) exhibits pharmacological properties linked to antihypertensive mechanisms of action. This study aimed to evaluate the vascular effects of 7-HC in an experimental model of essential hypertension. The isometric tension measurements assessed the relaxant effect induced by 7-HC (0.001 μM–300 μM) in superior mesenteric arteries isolated from hypertensive rats (SHR, 200–300 g). Our results suggest that the relaxant effect induced by 7-HC rely on K+-channels (KATP, BKCa, and, to a lesser extent, Kv) activation and also on Ca2+ influx from sarcolemma and sarcoplasmic reticulum mobilization (inositol 1,4,5-triphosphate (IP3) and ryanodine receptors). Moreover, 7-HC diminishes the mesenteric artery’s responsiveness to α1-adrenergic agonist challenge and improves the actions of the muscarinic agonist and NO donor. The present work demonstrated that the relaxant mechanism of 7-HC in SHR involves endothelium-independent vasorelaxant factors. Additionally, 7-HC reduced vasoconstriction of the sympathetic agonist while improving vascular endothelium-dependent and independent relaxation.

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“…Protein expression of BK Ca and K ATP channels, was enhanced when FA exerted vasodilatory effects. K + channels play a significant role in cellular signaling processes including the maintenance of the membrane potential of VSMCs to regulate contractile tone (Francis et al, 2010;Santos et al, 2017;Shieh et al, 2000). It has been reported that K ATP channels, which are broadly expressed in the vasculature, can finely regulate vascular smooth muscle (Yamamoto et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Vasodilatory effect of formaldehyde via the NO/cGMP pathway and the regulation of expression of KATP, BKCa and L-type Ca2+ channels

Zhao

et al. 2019

Toxicology Letters

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Formaldehyde (FA), a well-known toxic gas molecule similar to nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H 2 S), is widely produced endogenously via numerous biochemical pathways, and has a number of physiological roles in the biosystem. We attempted to investigate the vasorelaxant effects of FA and their underlying mechanisms. We found that FA induced vasorelaxant effects on rat aortic rings in a concentration-dependent manner. The NO/ cyclic guanosine 5′ monophosphate (cGMP) pathway was up-regulated when the rat aortas were treated with FA. The expression of large-conductance Ca 2+ -activated K + (BK Ca ) channel subunits α and β of the rat aortas was increased by FA. Similarly, the levels of ATP-sensitive K + (K ATP ) channel subunits K ir 6.1 and K ir 6.2 were also up-regulated when the rat aortas were incubated with FA. In contrast, levels of the L-type Ca 2+ channel (LTCC) subunits, Ca v 1.2 and Ca v 1.3, decreased dramatically with increasing concentrations of FA. We demonstrated that the regulation of FA on vascular contractility may be via the up-regulation of the NO/cGMP pathway and the modulation of ion channels, including the upregulated expression of the K ATP and BK Ca channels and the inhibited expression of LTCCs. Further study is needed to explore the in-depth mechanisms of FA induced vasorelaxation.

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NO production and potassium channels activation induced by Crotalus durissus cascavella underlie mesenteric artery relaxation

Cited by 9 publications

References 45 publications

Revisiting the Therapeutic Potential of Bothrops jararaca Venom: Screening for Novel Activities Using Connectivity Mapping

Revisiting the Therapeutic Potential of Bothrops jararaca Venom: Screening for Novel Activities Using Connectivity Mapping

7-Hydroxycoumarin Induces Vasorelaxation in Animals with Essential Hypertension: Focus on Potassium Channels and Intracellular Ca2+ Mobilization

Vasodilatory effect of formaldehyde via the NO/cGMP pathway and the regulation of expression of KATP, BKCa and L-type Ca2+ channels

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