BKCa Channel Activation Attenuates the Pathophysiological Progression of Monocrotaline-Induced Pulmonary Arterial Hypertension in Wistar Rats

Ferraz, Ana Paula Costa Rodrigues; Seara, Fernando A.C.; Baptista, Emanuelle F; Barenco, Thais S; Sottani, Thais B B; Souza, Natália Soares; Domingos, Ainá E.; Barbosa, Raiana Andrade Quintanilha; Takiya, Christina Maeda; Couto, Marcos Tadeu; Resende, Gabriel O.; Carvalho, Antônio Carlos Campos de; Ponte, Cristiano G.; Nascimento, José

doi:10.1007/s10557-020-07115-5

Cited by 8 publications

(6 citation statements)

References 56 publications

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“…After a stabilization period of 60 min at a rest tension of 1.0 g with periodic changes of solution (every 15 min), a stable contraction was achieved with 1 µM phenylephrine (PHE). Functional endothelial integrity was assessed by the ability of 10 µM acetylcholine to induce ≥70% relaxation in vessels precontracted with 1 µM PHE [27]. For vascular reactivity tests, the rings were preconstricted with 1 µM of PHE and after a stable response, the concentrations (µM) of 0.3, 1.0, 3.0, 10.0 and 30.0 of (−)-grandisin were subsequently added to the chamber and the level of relaxation measured.…”

Section: Pharmacological Evaluationmentioning

confidence: 99%

Piper tectoniifolium Kunth: A New Natural Source of the Bioactive Neolignan (−)-Grandisin

et al. 2022

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The Piper species are a recognized botanical source of a broad structural diversity of lignans and its derivatives. For the first time, Piper tectoniifolium Kunth is presented as a promising natural source of the bioactive (−)-grandisin. Phytochemical analyses of extracts from its leaves, branches and inflorescences showed the presence of the target compound in large amounts, with leaf extracts found to contain up to 52.78% in its composition. A new HPLC-DAD-UV method was developed and validated to be selective for the identification of (−)-grandisin being sensitive, linear, precise, exact, robust and with a recovery above 90%. The absolute configuration of the molecule was determined by X-ray diffraction. Despite the identification of several enantiomers in plant extracts, the major isolated substance was characterized to be the (−)-grandisin enantiomer. In vascular reactivity tests, it was shown that the grandisin purified from botanical extracts presented an endothelium-dependent vasorelaxant effect with an IC50 of 9.8 ± 1.22 μM and around 80% relaxation at 30 μM. These results suggest that P. tectoniifolium has the potential to serve as a renewable source of grandisin on a large scale and the potential to serve as template for development of new drugs for vascular diseases with emphasis on disorders related to endothelial disfunction.

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Section: Pharmacological Evaluationmentioning

confidence: 99%

Piper tectoniifolium Kunth: A New Natural Source of the Bioactive Neolignan (−)-Grandisin

et al. 2022

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“…Early studies showed that BK Ca channels were activated by stretch and arachidonic acid in rabbit PASMC [ 175 ]. Besides, their activation prevents the development of PH in rat [ 176 , 185 ]. However, the mechanosensitive part of the function of these K + channels has not been studied in detail in PA cells and further investigation needs to be done.…”

Section: Other Mechanosensitive Channelsmentioning

confidence: 99%

Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

et al. 2021

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A variety of cell types in pulmonary arteries (endothelial cells, fibroblasts, and smooth muscle cells) are continuously exposed to mechanical stimulations such as shear stress and pulsatile blood pressure, which are altered under conditions of pulmonary hypertension (PH). Most functions of such vascular cells (e.g., contraction, migration, proliferation, production of extracellular matrix proteins, etc.) depend on a key event, i.e., the increase in intracellular calcium concentration ([Ca2+]i) which results from an influx of extracellular Ca2+ and/or a release of intracellular stored Ca2+. Calcium entry from the extracellular space is a major step in the elevation of [Ca2+]i, involving a variety of plasmalemmal Ca2+ channels including the superfamily of stretch-activated channels (SAC). A common characteristic of SAC is that their gating depends on membrane stretch. In general, SAC are non-selective Ca2+-permeable cation channels, including proteins of the TRP (Transient Receptor Potential) and Piezo channel superfamily. As membrane mechano-transducers, SAC convert physical forces into biological signals and hence into a cell response. Consequently, SAC play a major role in pulmonary arterial calcium homeostasis and, thus, appear as potential novel drug targets for a better management of PH.

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“…As described in the previous sections, BKCa could represent a promising molecular target for pulmonary hypertension therapy. There are cardiovascular drugs that involve the activation of BKCa channels, for instance NO or NO donors [64,91], PDE inhibitors such as sildenafil [92,93] or PGI2 analogues [47,[94][95][96]. However, as BKCa is ubiquitously expressed throughout the vessels of the entire body, adverse side effects due to systemic vasodilation limit the use of systemically applied BKCa activators.…”

Section: Perspectivementioning

confidence: 99%

“…The increased presence of BKCa channels in IPAH points to the possible utility of BKCa openers for pharmacological interventions in PAH. Accordingly, a recent preclinical study reported attenuation of the disease progression in the MCT-induced rat PH model by a selective BKCa opener [ 64 ]. In this study, also the elevated inflammatory TNF-α level was reduced, suggesting a dual effect of the drug in this PH model.…”

Section: The Role Of the α-Subunit In The Pulmonary Circulationmentioning

confidence: 99%

Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation

et al. 2021

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Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell′s membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) channels assemble from pore forming and various modulatory and auxiliary subunits. They are of vital significance due to their very high unitary conductance and hence their ability to rapidly cause extreme changes in the membrane potential. The pathophysiology of lung diseases in general and pulmonary hypertension, in particular, show the implication of either decreased expression and partial inactivation of BKCa channel and its subunits or mutations in the genes encoding different subunits of the channel. Signaling molecules, circulating humoral molecules, vasorelaxant agents, etc., have an influence on the open probability of the channel in pulmonary arterial vascular cells. BKCa channel is a possible therapeutic target, aimed to cause vasodilation in constricted or chronically stiffened vessels, as shown in various animal models. This review is a comprehensive collation of studies on BKCa channels in the pulmonary circulation under hypoxia (hypoxic pulmonary vasoconstriction; HPV), lung pathology, and fetal to neonatal transition, emphasising pharmacological interventions as viable therapeutic options.

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BKCa Channel Activation Attenuates the Pathophysiological Progression of Monocrotaline-Induced Pulmonary Arterial Hypertension in Wistar Rats

Cited by 8 publications

References 56 publications

Piper tectoniifolium Kunth: A New Natural Source of the Bioactive Neolignan (−)-Grandisin

Piper tectoniifolium Kunth: A New Natural Source of the Bioactive Neolignan (−)-Grandisin

Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation

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