Effects of a novel ACE inhibitor, 3-(3-thienyl)-L-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in L-NAME-induced hypertensive rats

Q: What are the key findings of this study?

TOP (20 mg/kg/day) reduced systolic blood pressure to 136 mmHg compared to ~187 mmHg in untreated L-NAME-induced hypertensive rats and 153.5 mmHg with captopril (40 mg/kg/day) at 5 weeks (P<0.05).

Q: What is the clinical evidence from this study?

Population: L-NAME-induced hypertension (n=36). Intervention: 3-(3-thienyl)-L-alanyl-ornithyl-proline (TOP) vs. Captopril 40 mg/kg per day orally and untreated L-NAME control. Primary outcome: Systolic blood pressure (SBP) at 5 weeks (p=<0.05).

Q: What does this research mean for the field?

The novel ACE inhibitor TOP (20 mg/kg/day) reduces systolic blood pressure and improves endothelial vasodilation and hepatotoxicity more effectively than captopril at half the dose in L-NAME-induced hypertensive rats. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

Investigate the effects of the novel ACE inhibitor 3-(3-thienyl)-L-alanyl-ornithyl-proline (TOP) on the nitric oxide pathway, vasodilation, and hepatotoxicity in L-NAME-induced hypertensive rats.

Mahesh Kumar Seth; M Ezaj Hussain; Santosh Pasha; Mohammad Fahim

doi:10.2147/dddt.s77761

April 1, 2016Drug Design Development and TherapyOpen Access

Effects of a novel ACE inhibitor, 3-(3-thienyl)-L-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in L-NAME-induced hypertensive rats

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Key result

TOP lowers systolic blood pressure by ~51 mmHg versus untreated hypertensive controls.

P<0.05
n=36

Why the study?

Does the novel peptidomimetic ACE inhibitor 3-(3-thienyl)-L-alanyl-ornithyl-proline (TOP) prevent hypertension, restore nitric oxide pathway activity, and reduce hepatotoxicity compared to captopril in L-NAME-induced hypertensive rats?

Key Points

Investigate the effects of the novel ACE inhibitor 3-(3-thienyl)-L-alanyl-ornithyl-proline (TOP) on the nitric oxide pathway, vasodilation, and hepatotoxicity in L-NAME-induced hypertensive rats.
Assigned rats across six groups: control, L-NAME, L-NAME + TOP (20 mg/kg), L-NAME + captopril (40 mg/kg), TOP alone, and captopril alone over a 5-week treatment period.
Measured systolic blood pressure, serum ACE activity, plasma nitric oxide levels, and eNOS mRNA expression in aorta, heart, and kidney tissues.
Evaluated acetylcholine-induced vasorelaxation in isolated aortic rings, alongside liver histopathology and serum markers (malondialdehyde, alanine aminotransferase, and aspartate aminotransferase).
Concomitant TOP reduced systolic blood pressure from ~187 mmHg in L-NAME rats to 136 mmHg, compared with 153.5 mmHg with captopril (P<0.05).
TOP restored plasma nitric oxide levels to 40±2.4 µM and serum ACE activity to 68.2±0.9 mU/L, whereas captopril resulted in 32±3.7 µM and 74.9±3.5 mU/L, respectively.
TOP reduced serum malondialdehyde to 0.405 µM and preserved normal liver histology, whereas captopril-treated rats exhibited periportal lymphocytic infiltration and an altered AST/ALT ratio (1.04 vs. 1.66 with TOP).

Structured PICO

Does the novel peptidomimetic ACE inhibitor 3-(3-thienyl)-L-alanyl-ornithyl-proline (TOP) prevent hypertension, restore nitric oxide pathway activity, and reduce hepatotoxicity compared to captopril in L-NAME-induced hypertensive rats?

P

Population

36 male Wistar rats (180-200 g) divided into six groups to evaluate L-NAME-induced hypertension over 5 weeks.

I

Intervention

3-(3-thienyl)-L-alanyl-ornithyl-proline (TOP) 20 mg/kg per day (also described as 10 mg/kg twice a day) dissolved in tap water and given orally via gavage for 5 weeks, alone or concomitantly with L-NAME (40 mg/kg/day).

C

Comparator

Captopril 40 mg/kg per day given orally via gavage for 5 weeks (with or without L-NAME 40 mg/kg/day), L-NAME alone (40 mg/kg/day), and untreated control.

O

Outcome

Systolic blood pressure (SBP) measured by noninvasive tail-cuff plethysmography at the end of the first, third, and fifth weeks, alongside serum ACE activity, plasma nitric oxide (NO) levels, eNOS mRNA expression, and in vitro aortic ring vasorelaxation at 5 weeks.surrogate

Main Result

Absolute Event Rate: 136% vs 187%

p-value: p=<0.05

In a rat model of L-NAME-induced hypertension, the novel peptidomimetic ACE inhibitor TOP at half the dose of captopril produced superior blood pressure reduction, nitric oxide restoration, and endothelial vasodilation without the hepatotoxicity observed with captopril.

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Implication

TOP supports further preclinical ACE inhibitor development; leaves open translation to human hypertension therapy.

Abstract

Nitric oxide (NO) is a widespread biological mediator involved in many physiological and pathological processes, eg, in the regulation of vascular tone and hypertension. Chronic inhibition of NO synthase by N(G)-nitro-l-arginine methyl ester (l-NAME) hydrochloride results in the development of hypertension accompanied by an increase in vascular responsiveness to adrenergic stimuli. Recently, we developed a novel sulfur-containing angiotensin-converting enzyme inhibitor: 3-(3-thienyl)-l-alanyl-ornithyl-proline (TOP). Our previous studies indicated a superior nature of the molecule as an antihypertensive agent in spontaneously hypertensive rats (showing the involvement of renin-angiotensin-aldosterone system) in comparison to captopril. The aim of the present study was to investigate the effect of TOP on NO pathway in l-NAME-induced hypertensive rats, and captopril was included as the standard treatment group. Treatment with both TOP (20 mg/kg) and captopril (40 mg/kg) prevented the development of hypertension in l-NAME model, but TOP showed better restoration of NO and normal levels of angiotensin-converting enzyme. In addition, in vitro vasorelaxation assay showed an improvement in endothelium-dependent vasodilation in both the cases. Further, the biochemical (malondialdehyde, alanine aminotransferase, and aspartate aminotransferase) and the histopathological effects of TOP on rat liver tissues revealed a protective nature of TOP in comparison to captopril in the l-NAME model. In conclusion, TOP at 50% lesser dose than captopril was found to be better in the l-NAME model.

Discussion

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Cite This Study

Seth et al. (2016) studied L-NAME-induced hypertension (n=36). 3-(3-thienyl)-L-alanyl-ornithyl-proline (TOP) vs. Captopril 40 mg/kg per day orally and untreated L-NAME control was evaluated on Systolic blood pressure (SBP) at 5 weeks (p=<0.05). TOP (20 mg/kg/day) reduced systolic blood pressure to 136 mmHg compared to ~187 mmHg in untreated L-NAME-induced hypertensive rats and 153.5 mmHg with captopril (40 mg/kg/day) at 5 weeks (P<0.05).

synapsesocial.com/papers/6a74f40f508d802509f54f86 https://doi.org/10.2147/dddt.s77761

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Effects of a novel ACE inhibitor, 3-(3-thienyl)-L-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in L-NAME-induced hypertensive rats

Key Points

Structured PICO

Main Result

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Effects of a novel ACE inhibitor, 3-(3-thienyl)-L-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in L-NAME-induced hypertensive rats

Key Points

Structured PICO

Main Result

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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