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18 pages, 13475 KiB

Open AccessArticle

Weak Hypotensive Effect of Chronic Administration of the Dual FAAH/MAGL Inhibitor JZL195 in Spontaneously Hypertensive Rats as Revealed by Area under the Curve Analysis

by Marek Toczek, Piotr Ryszkiewicz, Patryk Remiszewski, Eberhard Schlicker, Anna Krzyżewska, Hanna Kozłowska and Barbara Malinowska

Int. J. Mol. Sci. 2023, 24(13), 10942; https://doi.org/10.3390/ijms241310942 - 30 Jun 2023

Cited by 3 | Viewed by 1530

Abstract

The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading [...] Read more.

The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then evaluated by the area under the curve (AUC). Single administration of JZL195 induced dose-dependent weak hypotensive and bradycardic responses in SHR but not in WKY. Similarly, its chronic application revealed only a slight hypotensive potential which, however, effectively prevented the progression of hypertension and did not undergo tolerance. In addition, multiple JZL195 administrations slightly decreased heart rate only in WKY and prevented the gradual weight gain in both groups. JZL195 did not affect organ weights, blood glucose level, rectal temperature and plasma oxidative stress markers. In conclusion, chronic dual FAAH/MAGL inhibition prevents the progression of hypertension in SHR without affecting some basal functions of the body. In addition, our study clearly proves the suitability of AUC for the evaluation of weak blood pressure changes. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Hypertension)

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13 pages, 2497 KiB

Open AccessArticle

Indole Propionic Acid Increases T Regulatory Cells and Decreases T Helper 17 Cells and Blood Pressure in Mice with Salt-Sensitive Hypertension

by Gaurav Baranwal, Bethany L. Goodlett, Cristina M. Arenaz, Heidi A. Creed, Shobana Navaneethabalakrishnan, Joseph M. Rutkowski, Robert C. Alaniz and Brett M. Mitchell

Int. J. Mol. Sci. 2023, 24(11), 9192; https://doi.org/10.3390/ijms24119192 - 24 May 2023

Cited by 6 | Viewed by 2318

Abstract

Hypertension affects over a billion adults worldwide and is a major risk factor for cardiovascular disease. Studies have reported that the microbiota and its metabolites regulate hypertension pathophysiology. Recently, tryptophan metabolites have been identified to contribute to and inhibit the progression of metabolic [...] Read more.

Hypertension affects over a billion adults worldwide and is a major risk factor for cardiovascular disease. Studies have reported that the microbiota and its metabolites regulate hypertension pathophysiology. Recently, tryptophan metabolites have been identified to contribute to and inhibit the progression of metabolic disorders and cardiovascular diseases, including hypertension. Indole propionic acid (IPA) is a tryptophan metabolite with reported protective effects in neurodegenerative and cardiovascular diseases; however, its involvement in renal immunomodulation and sodium handling in hypertension is unknown. In the current study, targeted metabolomic analysis revealed decreased serum and fecal IPA levels in mice with L-arginine methyl ester hydrochloride (L-NAME)/high salt diet-induced hypertension (LSHTN) compared to normotensive control mice. Additionally, kidneys from LSHTN mice had increased T helper 17 (Th17) cells and decreased T regulatory (Treg) cells. Dietary IPA supplementation in LSHTN mice for 3 weeks resulted in decreased systolic blood pressure, along with increased total 24 h and fractional sodium excretion. Kidney immunophenotyping demonstrated decreased Th17 cells and a trend toward increased Treg cells in IPA-supplemented LSHTN mice. In vitro, naïve T cells from control mice were skewed into Th17 or Treg cells. The presence of IPA decreased Th17 cells and increased Treg cells after 3 days. These results identify a direct role for IPA in attenuating renal Th17 cells and increasing Treg cells, leading to improved sodium handling and decreased blood pressure. IPA may be a potential metabolite-based therapeutic option for hypertension. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Hypertension)

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14 pages, 4100 KiB

Open AccessArticle

The Effect of Hypertension on the Recovery of Renal Dysfunction following Reversal of Unilateral Ureteral Obstruction in the Rat

by Fayez T. Hammad, Loay Lubbad, Suhail Al-Salam, Javed Yasin, Mohamed Fizur Nagoor Meeran, Shreesh Ojha and Waheed F. Hammad

Int. J. Mol. Sci. 2023, 24(8), 7365; https://doi.org/10.3390/ijms24087365 - 17 Apr 2023

Cited by 1 | Viewed by 1533

Abstract

Both ureteral obstruction (UO) and hypertension are common conditions that affect kidney functions. Hypertension and chronic kidney disease are closely associated with an overlapping and intermingled cause-and-effect relationship. The effect of hypertension on the renal dysfunction following reversible UO has not been studied [...] Read more.

Both ureteral obstruction (UO) and hypertension are common conditions that affect kidney functions. Hypertension and chronic kidney disease are closely associated with an overlapping and intermingled cause-and-effect relationship. The effect of hypertension on the renal dysfunction following reversible UO has not been studied previously. To study this effect, spontaneously hypertensive (G-HT, n = 10) and normotensive Wistar (G-NT, n = 10) rats underwent 48-h reversible left unilateral UO (UUO), and the effect of UUO was studied 96 h following UUO reversal. The glomerular filtration rate, renal blood flow, and renal tubular functions such as the fractional excretion of sodium in the post-obstructed left kidney (POK) in both groups were significantly altered compared with the non-obstructed right kidney (NOK). However, the alterations in the G-HT were significantly more exaggerated when compared with the G-NT. Similar findings were observed with the histological features, gene expression of kidney injury markers, pro-inflammatory, pro-fibrotic and pro-apoptotic cytokines, and pro-collagen, as well as tissue levels of apoptotic markers. We conclude that hypertension has significantly exaggerated the alterations in renal functions and other parameters of renal injury associated with UUO. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Hypertension)

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14 pages, 1807 KiB

Open AccessArticle

Losartan Potassium and Verapamil Hydrochloride Compound Transdermal Drug Delivery System: Formulation and Characterization

by Yu-si Chen, Yi-yang Sun, Zi-chen Qin, Sai-ya Zhang, Wen-bo Chen and Yan-qiang Liu

Int. J. Mol. Sci. 2022, 23(21), 13051; https://doi.org/10.3390/ijms232113051 - 27 Oct 2022

Cited by 7 | Viewed by 6593

Abstract

In this study, we developed a sustained-release transdermal delivery system containing losartan potassium (LP) and verapamil hydrochloride (VPH). LP and VPH have low bioavailability and long half-life. Therefore, the development of an optimum administration mode is necessary to overcome these drawbacks and enhance [...] Read more.

In this study, we developed a sustained-release transdermal delivery system containing losartan potassium (LP) and verapamil hydrochloride (VPH). LP and VPH have low bioavailability and long half-life. Therefore, the development of an optimum administration mode is necessary to overcome these drawbacks and enhance the antihypertensive effect. A transdermal diffusion meter was used to determine the optimal formulation of LP-VPH transdermal drug delivery systems (TDDS). Based on in vitro results, a sustained-release patch was prepared. Physical characteristics, including quality, stickiness, and appearance, were evaluated in vitro, while pharmacokinetics and skin irritation were evaluated in vivo. The results showed that 8.3% polyvinyl alcohol, 74.7% polyvinylpyrrolidone K30, 12% oleic acid-azone, and 5% polyacrylic acid resin II provided an optimized TDDS product for effective administration of LP and VPH. Furthermore, in vitro and in vivo release tests showed that the system continuously released LP and VPH for 24 h. The pharmacokinetic results indicated that although the maximum concentration was lower, both the area under the curve from 0–time and the mean residence time of the prepared patch were significantly higher than those of the oral preparations. Furthermore, the prepared LP-VPH transdermal patch showed good stability and no skin irritation. The developed LP-VPH TDDS showed a sustained-release effect and good characteristics and pharmacokinetics; therefore, it is an ideal formulation. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Hypertension)

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14 pages, 2297 KiB

Open AccessArticle

Of Mouse and Man: Cross-Species Characterization of Hypertensive Cardiac Remodeling

by Susanna T. E. Cooper, Joseph D. Westaby, Zoe H. R. Haines, Giles O. Malone, Mary N. Sheppard and Daniel N. Meijles

Int. J. Mol. Sci. 2022, 23(14), 7709; https://doi.org/10.3390/ijms23147709 - 12 Jul 2022

Cited by 7 | Viewed by 2318

Abstract

Hypertension is a major public health concern and poses a significant risk for sudden cardiac death (SCD). However, the characterisation of human tissues tends to be macroscopic, with little appreciation for the quantification of the pathological remodelling responsible for the advancement of the [...] Read more.

Hypertension is a major public health concern and poses a significant risk for sudden cardiac death (SCD). However, the characterisation of human tissues tends to be macroscopic, with little appreciation for the quantification of the pathological remodelling responsible for the advancement of the disease. While the components of hypertensive remodelling are well established, the timeline and comparative quantification of pathological changes in hypertension have not been shown before. Here, we sought to identify the phasing of cardiac remodelling with hypertension using post-mortem tissue from SCD patients with early and advanced hypertensive heart disease (HHD). In order to study and quantify the progression of phenotypic changes, human specimens were contrasted to a well-described angiotensin-II-mediated hypertensive mouse model. While cardiomyocyte hypertrophy is an early adaptive response in the mouse that stabilises in established hypertension and declines as the disease progresses, this finding did not translate to the human setting. In contrast, optimising fibrosis quantification methods and applying them to each setting identified perivascular fibrosis as the prevailing possible cause for overall disease progression. Indeed, assessing myocardial inflammation highlights CD45+ inflammatory cell infiltration that precedes fibrosis and is an early-phase event in response to elevated arterial pressures that may underscore perivascular remodelling. Along with aetiology insight, we highlight cross-species comparison for quantification of cardiac remodelling in human hypertension. As such, this platform could assist with the development of therapies specific to the disease phase rather than targeting global components of hypertension, such as blood pressure lowering. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Hypertension)

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Review

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16 pages, 2322 KiB

Open AccessReview

Advances in the Pathogenesis and Treatment of Resistant Hypertension

by Jill Dybiec, Julia Krzemińska, Ewa Radzioch, Magdalena Szlagor, Magdalena Wronka, Ewelina Młynarska, Jacek Rysz and Beata Franczyk

Int. J. Mol. Sci. 2023, 24(16), 12911; https://doi.org/10.3390/ijms241612911 - 18 Aug 2023

Cited by 6 | Viewed by 4511

Abstract

Hypertension is a prevalent chronic disease associated with an increased risk of cardiovascular (CV) premature death, and its severe form manifests as resistant hypertension (RH). The accurate prevalence of resistant hypertension is difficult to determine due to the discrepancy in data from various [...] Read more.

Hypertension is a prevalent chronic disease associated with an increased risk of cardiovascular (CV) premature death, and its severe form manifests as resistant hypertension (RH). The accurate prevalence of resistant hypertension is difficult to determine due to the discrepancy in data from various populations, but according to recent publications, it ranges from 6% to 18% in hypertensive patients. However, a comprehensive understanding of the pathogenesis and treatment of RH is essential. This review emphasizes the importance of identifying the causes of treatment resistance in antihypertensive therapy and highlights the utilization of appropriate diagnostic methods. We discussed innovative therapies such as autonomic neuromodulation techniques like renal denervation (RDN) and carotid baroreceptor stimulation, along with invasive interventions such as arteriovenous anastomosis as potential approaches to support patients with inadequate medical treatment and enhance outcomes in RH. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Hypertension)

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15 pages, 2322 KiB

Open AccessReview

Pathogenesis of Hypertension in Metabolic Syndrome: The Role of Fructose and Salt

by Manoocher Soleimani, Sharon Barone, Henry Luo and Kamyar Zahedi

Int. J. Mol. Sci. 2023, 24(5), 4294; https://doi.org/10.3390/ijms24054294 - 21 Feb 2023

Cited by 22 | Viewed by 7063

Abstract

Metabolic syndrome is manifested by visceral obesity, hypertension, glucose intolerance, hyperinsulinism, and dyslipidemia. According to the CDC, metabolic syndrome in the US has increased drastically since the 1960s leading to chronic diseases and rising healthcare costs. Hypertension is a key component of metabolic [...] Read more.

Metabolic syndrome is manifested by visceral obesity, hypertension, glucose intolerance, hyperinsulinism, and dyslipidemia. According to the CDC, metabolic syndrome in the US has increased drastically since the 1960s leading to chronic diseases and rising healthcare costs. Hypertension is a key component of metabolic syndrome and is associated with an increase in morbidity and mortality due to stroke, cardiovascular ailments, and kidney disease. The pathogenesis of hypertension in metabolic syndrome, however, remains poorly understood. Metabolic syndrome results primarily from increased caloric intake and decreased physical activity. Epidemiologic studies show that an enhanced consumption of sugars, in the form of fructose and sucrose, correlates with the amplified prevalence of metabolic syndrome. Diets with a high fat content, in conjunction with elevated fructose and salt intake, accelerate the development of metabolic syndrome. This review article discusses the latest literature in the pathogenesis of hypertension in metabolic syndrome, with a specific emphasis on the role of fructose and its stimulatory effect on salt absorption in the small intestine and kidney tubules. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Hypertension)

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13 pages, 1065 KiB

Open AccessReview

Current Knowledge about the New Drug Firibastat in Arterial Hypertension

by Emma Hansen, Daniela Grimm and Markus Wehland

Int. J. Mol. Sci. 2022, 23(3), 1459; https://doi.org/10.3390/ijms23031459 - 27 Jan 2022

Cited by 7 | Viewed by 4400

Abstract

Hypertension significantly increases the risk of cardiovascular disease. Currently, effective standard pharmacological treatment is available in the form of diuretics, ACE inhibitors, angiotensin II receptor blockers and calcium channel blockers. These all help to decrease blood pressure in hypertensive patients, each with their [...] Read more.

Hypertension significantly increases the risk of cardiovascular disease. Currently, effective standard pharmacological treatment is available in the form of diuretics, ACE inhibitors, angiotensin II receptor blockers and calcium channel blockers. These all help to decrease blood pressure in hypertensive patients, each with their own mechanism. Recently, firibastat, a new first-in-class antihypertensive drug has been developed. Firibastat is a prodrug that when crossing the blood-brain barrier, is cleaved into two active EC33 molecules. EC33 is the active molecule that inhibits the enzyme aminopeptidase A. Aminopeptidase A converts angiotensin II to angiotensin III. Angiotensin III usually has three central mechanisms that increase blood pressure, so by inhibiting this enzyme activity, a decrease in blood pressure is seen. Firibastat is an antihypertensive drug that affects the brain renin angiotensin system by inhibiting aminopeptidase A. Clinical trials with firibastat have been performed in animals and humans. No severe adverse effects related to firibastat treatment have been reported. Results from studies show that firibastat is generally well tolerated and safe to use in hypertensive patients. The aim of this review is to investigate the current knowledge about firibastat in the treatment of hypertension. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Hypertension)

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