Anti-thrombotic effects of nebivolol and carvedilol: Involvement of β2 receptors and COX-2/PGI2 pathways

Kozlovski, Valery I; Łomnicka, Magdalena; Bartuś, Magdalena; Sternak, Magdalena; Chłopicki, Stefan

doi:10.1016/j.pharep.2015.03.008

Cited by 8 publications

(4 citation statements)

References 34 publications

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“…Consistent with this finding, inhibition of both enzymes significantly decreased the vasodilator effect of this compound. Our results are in agreement with those of previous studies, which indicated that this compound acts on vascular endothelium, provoking NO release [58,59] and enhancing NO bioavailability [45]. Carvedilol, a third-generation and nonselective β-adrenoceptor antagonist, is a licensed drug used for treating patients suffering from heart failure, hypertension, and myocardial ischaemia [60,61].…”

Section: Discussionsupporting

confidence: 92%

“…Kozlovski et al showed that coronary vasodilation elicited by both nebivolol and carvedilol does not involve direct activation of beta-2 adrenoceptors, however, they suggested that their metabolites do activate this type of receptors [59]. Considering that it has been suggested that activation of beta-2 adrenoceptors stimulates the NO/cGMP pathway [55,57], it is feasible to hypothesize that the metabolites of these compounds and isoxsuprine interact with these receptors, consequently activating both, the NO/cGMP and/or the H 2 S/K ATP pathways.…”

Section: Discussionmentioning

confidence: 99%

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Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels

et al. 2019

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Recently, our research group demonstrated that uvaol and ursolic acid increase NO and H2S production in aortic tissue. Molecular docking studies showed that both compounds bind with high affinity to endothelial NO synthase (eNOS) and cystathionine gamma-lyase (CSE). The aim of this study was to identify hits with high binding affinity for the triterpene binding-allosteric sites of eNOS and CSE and to evaluate their vasodilator effect. Additionally, the mechanism of action of the most potent compound was explored. A high-throughput virtual screening (HTVS) of 107,373 compounds, obtained from four ZINC database libraries, was performed employing the crystallographic structures of eNOS and CSE. Among the nine top-scoring ligands, isoxsuprine showed the most potent vasodilator effect. Pharmacological evaluation, employing the rat aorta model, indicated that the vasodilation produced by this compound involved activation of the NO/cGMP and H2S/KATP signaling pathways and blockade of α1-adrenoceptors and L-type voltage-dependent Ca2+ channels. Incubation of aorta homogenates in the presence of isoxsuprine caused 2-fold greater levels of H2S, which supported our preliminary in silico data. This study provides evidence to propose that the vasodilator effect of isoxsuprine involves various mechanisms, which highlights its potential to treat a wide variety of cardiovascular diseases.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels

et al. 2019

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“…This may be another aspect of nebivolol's improvements on endothelial dysfunction that consequently affects thrombogenesis. A few earlier studies tried to investigate the antithrombotic effects of nebivolol, some of them suggesting a connection with NO release, but the exact mechanism is so far unclear. The concept should perhaps be further investigated, as it could be relevant in treating hypertension complicated by atherosclerosis or heart failure.…”

Section: Discussionmentioning

confidence: 99%

Nebivolol in the treatment of arterial hypertension

Olawi

Krüger

Grimm

et al. 2019

Basic Clin Pharma Tox

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This MiniReview reports the current knowledge about the treatment of arterial hypertension with the third‐generation beta‐adrenoceptor antagonist (BAA) nebivolol. Furthermore, it reviews the advantages of nebivolol compared to the earlier generation of BAAs with respect to their different pharmacological properties. Beta‐adrenoceptor antagonists are a class of drugs applied for several different conditions, including hypertension and heart failure. They differ significantly in their pharmacological properties, including varying β1/β2‐selectivity and/or exertion of additive effects on the heart and circulation. Although these drugs have been a part of hypertensive therapy for about 40 years, the outcome of large clinical trials has put the role of BAAs into question. However, most of these results were based on first‐ and second‐generation BAAs and cannot be translated directly into third‐generation drugs. The third‐generation BAA nebivolol has the highest β1‐selectivity seen so far, together with additional vasodilating and anti‐oxidative properties. It is currently applied in the treatment of hypertension and congestive heart failure. Nebivolol has a unique pharmacological profile, despite showing similar blood pressure‐lowering effects, and has certain advantages in the treatment of hypertension compared to the previous generations of BAAs. This includes significant improvements in endothelial dysfunction, central haemodynamics and the degree of erectile dysfunction in men, a neutral/beneficial metabolic profile and lastly a more favourable side effect profile. It is widely beneficial for, for example, sexually active men and patients with comorbidities such as type II diabetes mellitus, metabolic syndrome and chronic obstructive lung disorders. Whether the advantages translate to an improved long‐term clinical outcome remains to be clarified, and ongoing prospective studies will show this in the future.

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“…Although there is equivocal evidence that Ang-(1-7) has vasoprotective, cardioprotective, and anti-inflammatory effects, still it is not clear if all of the effects of ACE2 pathway are mediated by Ang-(1-7) and by MasR. Ang-(1-7), alamandine, and bradykinin could act in concert as Renin-Angiotensin-Aldosterone System in Heart Failure: Focus on Nonclassical Angiotensin… DOI: http://dx.doi.org/10.5772/intechopen.87239 their concentrations increase simultaneously with decreased ACE/ACE2 ratio and Ang-(1-7)-mediated effects in some systems are inhibited by B 2 receptor antagonists [50]. Although evidence supporting the protective role of ACE2/Ang-(1-7) axis is convincing, it is still not clear if ACE2 is the only enzyme that plays a key role in Ang-(1-7) generation in various pathologies.…”

Section: Classical (Ace/ang Ii/at 1 R) and Nonclassical (Ace2/ang-(1-mentioning

confidence: 99%

Renin-Angiotensin-Aldosterone System in Heart Failure: Focus on Nonclassical Angiotensin Pathways as Novel Upstream Targets Regulating Aldosterone

Tyrankiewicz¹,

Kij²,

Mohaissen³

et al. 2019

Aldosterone-Mineralocorticoid Receptor - Cell Biology to Translational Medicine

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Aldosterone plays an important role in the regulation of blood pressure, body fluid, and electrolyte homeostasis. Overactivation of aldosterone/ mineralocorticoid receptor (MR) pathway leads to hypertension, atherosclerosis, vascular damage, heart failure, and chronic kidney disease and is involved in many other diseases associated with endothelial dysfunction, inflammation, fibrosis, and metabolic disorders. Aldosterone is a final product of the renin-angiotensin-aldosterone system (RAAS), and its production is activated by angiotensin II, while angiotensin-(1-7) negatively regulates angiotensin II-mediated aldosterone production and in some experimental models inhibits aldosterone-induced damage in target tissues. In fact, the aldosterone/mineralocorticoid receptor-dependent pathway is regulated upstream by at least two major axes of RAAS: classical axis (ACE/Ang II) and nonclassical axis (ACE2/Ang-(1-7)). The relative balance between these two axes determines aldosterone production and activity. To better understand the regulation of aldosterone activity in physiology and diseases, it is important to analyze the role of aldosterone/mineralocorticoid receptor-dependent pathways in the context of upstream angiotensin pathways as some of the recently described mechanisms of RAAS represent possible novel upstream targets to inhibit aldosterone/mineralocorticoid receptor-dependent responses. In this review, we highlight the complexity of angiotensin pathways focusing on their role in various tissues in heart failure, with particular emphasis on nonclassical pathways including protective ACE2/Ang-(1-7) axis and detrimental Ang-(1-12)/chymase/Ang II axis.

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Anti-thrombotic effects of nebivolol and carvedilol: Involvement of β2 receptors and COX-2/PGI2 pathways

Abstract: We demonstrated for the first time that nebivolol and carvedilol, independently of their adrenergic receptor blocking activities, induced anti-thrombotic effects in vivo that involved β2 adrenoceptors and the activation of the COX-2/PGI2 pathway.

Cited by 8 publications

References 34 publications

Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels

Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels

Nebivolol in the treatment of arterial hypertension

Renin-Angiotensin-Aldosterone System in Heart Failure: Focus on Nonclassical Angiotensin Pathways as Novel Upstream Targets Regulating Aldosterone

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