New Developments in the Pharmacological Treatment of Hypertension: Dead-End or a Glimmer at the Horizon?

Paulis, Ludovít; Rajkovicova, Romana; Šimko, Fedor

doi:10.1007/s11906-015-0557-x

Cited by 31 publications

(27 citation statements)

References 107 publications

(108 reference statements)

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“…Aliskiren, the most recent new first-in-class drug for hypertension, was approved seven years ago, and the last new molecule, azilsartan, was approved three years ago. In contrast, in the same time period the FDA has approved five novel anticoagulants (with three different modes of action), four new antiplatelet agents (two different modes of action), and five new molecules for the treatment of pulmonary hypertension (four modes of action) [ 91 ]. Here we have provided a demonstration that pharmacologically inhibiting the PG transporter PGT reduces BP by two modes of action in hypertensive mice and rats.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice

et al. 2015

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Inhibiting the synthesis of endogenous prostaglandins with nonsteroidal anti-inflammatory drugs exacerbates arterial hypertension. We hypothesized that the converse, i.e., raising the level of endogenous prostaglandins, might have anti-hypertensive effects. To accomplish this, we focused on inhibiting the prostaglandin transporter PGT (SLCO2A1), which is the obligatory first step in the inactivation of several common PGs. We first examined the role of PGT in controlling arterial blood pressure blood pressure using anesthetized rats. The high-affinity PGT inhibitor T26A sensitized the ability of exogenous PGE2 to lower blood pressure, confirming both inhibition of PGT by T26A and the vasodepressor action of PGE2 T26A administered alone to anesthetized rats dose-dependently lowered blood pressure, and did so to a greater degree in spontaneously hypertensive rats than in Wistar-Kyoto control rats. In mice, T26A added chronically to the drinking water increased the urinary excretion and plasma concentration of PGE2 over several days, confirming that T26A is orally active in antagonizing PGT. T26A given orally to hypertensive mice normalized blood pressure. T26A increased urinary sodium excretion in mice and, when added to the medium bathing isolated mouse aortas, T26A increased the net release of PGE2 induced by arachidonic acid, inhibited serotonin-induced vasoconstriction, and potentiated vasodilation induced by exogenous PGE2. We conclude that pharmacologically inhibiting PGT-mediated prostaglandin metabolism lowers blood pressure, probably by prostaglandin-induced natriuresis and vasodilation. PGT is a novel therapeutic target for treating hypertension.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice

et al. 2015

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“…In a different approach, LCZ696 (brand name Entresto), which contains the AT1R antagonist valsartan ( 5 ) and the neutral endopeptidase (NEP, neprilysin) inhibitor sacubitril ( 6 ) in a complex, has been generated. This angiotensin receptor neprilysin inhibitor (ARNI) was approved for the treatment of heart failure in 2016 …”

Section: Introductionmentioning

confidence: 99%

“…This angiotensin receptor neprilysin inhibitor (ARNI) was approved for the treatment of heart failure in 2016. [25][26][27][28] Frequently, bioactive peptides are converted into fragments that exhibit very different biological effects as compared to the parent peptide. 29,30 An excellent example is degradation of the hypertensive peptide Ang II via the heptapeptide angiotensin III (Ang III) (Arg 2 -Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7 -Phe 8 ) to the cognitive enhancer angiotensin IV (Ang IV, Ang 3-8) (Val 3 -Tyr 4 -Ile 5 -His 6 -Pro 7 -Phe 8 ).…”

Section: Introductionmentioning

confidence: 99%

Small‐molecule AT2 receptor agonists

Hallberg

Sumners

Steckelings

et al. 2017

Medicinal Research Reviews

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The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (K = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.

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“…So, NPRA agonist like PL3994 which is under phase II trial of study causes increase in cGMP level leading to decrease in the blood pressure and induction of natriuresis (Paulis et al, 2015).…”

Section: Natriuretic Peptide Receptor a (Npra) Agonistmentioning

confidence: 99%

“…Macitentan and Ambrisentan are recently approved Endothelin A receptor (ET A ) antagonist for pulmonary hypertension which shows its effect by preventing the binding of ET1 to both ET A and ET B (Iglarz et al, 2008;Paulis et al, 2015).…”

Section: Endothelin a Receptor (Et A ) Antagonistmentioning

confidence: 99%

Nanocarriers as treatment modalities for hypertension

et al. 2017

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Hypertension, a worldwide epidemic at present, is not a disease in itself rather it is an important risk factor for serious cardiovascular disorders including myocardial infarction, stroke, heart failure, and peripheral artery disease. Though numerous drugs acting via different mechanism of action are available in the market as conventional formulations for the treatment of hypertension but they face substantial challenges regarding their bioavailability, dosing and associated adverse effects which greatly limit their therapeutic efficacies. Various studies have demonstrated that nanocarriers can significantly increase the drug bioavailability thereby reducing the frequency of dosing in addition to minimizing toxicity associated with high dose of the drug. The present review provides an insight into the challenges associated with the conventional antihypertensive formulations and need for oral nanoparticulate systems in order to overcome problems associated with conventional formulations. Hypertension has circadian pattern of blood pressure, therefore chronotherapeutics can play a decisive role for the treatment, and however, nanoparticulate system can play major role in hypertension management. Future prospective for particulate nanocarriers in drug delivery for hypertension includes chronotherapeutics and emerging technique like gene therapy which is also covered in the review.

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New Developments in the Pharmacological Treatment of Hypertension: Dead-End or a Glimmer at the Horizon?

Cited by 31 publications

References 107 publications

Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice

Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice

Small‐molecule AT2 receptor agonists

Nanocarriers as treatment modalities for hypertension

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