Protective effects of a dual endothelin converting enzyme/neutral endopeptidase inhibitor on the development of pulmonary hypertension secondary to cardiac dysfunction in the rat

Q3 · MEDICINE

Article

Author: Jwu-Lai Yeh ; Chong-Chao Hsieh ; Zen-Kong Dai ; Arco Y. Jeng ; Bin-Nan Wu ; Mian-Shin Tan ; Shah-Hwa Chou ; Jiunn-Ren Wu ; Ing-Jun Chen ; Chee-Yin Chai

AbstractEndothelium‐derived nitric oxide (NO) and endothelin (ET)‐1 interact to regulate the vascular tone in pulmonary hypertension (PH). We investigated the protective effects of an orally active, dual endothelin converting enzyme (ECE)/neutral endopeptidase (NEP) inhibitor/CGS 26393 on pulmonary vascular remodeling and pulmonary expressions of ET‐1 and endothelial nitric oxide synthase (eNOS) during the development of PH secondary to cardiac dysfunction. Significant increases in the mean pulmonary arterial pressure, pulmonary arteriolar medial thickness, and pulmonary expression of ET‐1 were seen in rats subjected to aortic banding for 4 weeks, compared with sham‐operated rats. Treatment with CGS 26393 (30 mg/kg, twice daily, p.o.) began on 1 day after aortic banding. CGS 26393 treated rats had lower mean pulmonary arterial pressure (15 ± 1 mmHg, mean ± SEM, P < 0.05) compared to vehicle‐treated rats (37 ± 1 mmHg). It also normalized pulmonary arteriolar medial thickness and reduced the levels of pulmonary ET‐1 and big ET‐1 by 55% (P < 0.05) and 28% (P < 0.01), respectively, when compared with vehicle‐treated animals. Meanwhile, the expressions of eNOS mRNA and eNOS protein and cGMP levels in the lung of CGS 26393‐treated rats were increased by 62% (P < 0.05), 100% (P < 0.05), and 32% (P < 0.01), respectively, compared to the vehicle‐treated rats. These results suggest that CGS 26393 could offer preventive effects on the development of PH by ameliorating pulmonary remodeling, decreasing ET‐1 production, and up‐regulating eNOS and cGMP in aorta‐banded rats. However, the molecular mechanisms by which treatment with CGS 26393 results in altered expressions of eNOS and cGMP awaits further investigation. Pediatr Pulmonol. 2010;45:1076–1085. © 2010 Wiley‐Liss, Inc.

01 Nov 2007·Vascular PharmacologyQ3 · MEDICINE

Big ET-1 processing into vasoactive peptides in arteries and veins

Q3 · MEDICINE

Article

Author: Catherine Rondelli ; Chuck Smark ; Stephanie W. Watts ; Keshari Thakali ; Gregory D. Fink

The endothelin (ET) peptides are more potent in contracting veins than arteries. The precursor big ET-1 is metabolized by endothelin converting enzyme [ECE; to ET-1 (1-21)], matrix metalloproteases [MMPs; to ET-1 (1-32)] and chymase [to ET-1(1-31)]. We hypothesized that arteries and veins were differently dependent in conversion of big ET-1 to vasoconstrictors. Immunohistochemical, western, zymographic and isometric contractile assays in rat aorta and vena cava were used. Big ET-1 contracted aorta [60+/-17% phenylephrine contraction] but was more efficacious in vena cava [478+/-61% norepinephrine contraction]. ECE and its product ET-1(1-21) were detected in aorta and vena cava, and the ECE inhibitors phosphoramidon and CGS-26393 reduced big ET-1-induced contraction. ET-1 (1-32) contracted aorta and vena cava but inhibition of MMPs with minocycline or GM6001 did not reduce big ET-1-induced contraction; zymography confirmed active tissue MMPs. Aorta and vena cava contracted to the product of chymase, ET-1 (1-31). Chymase was detected in aorta and only weakly in vena cava. Inhibition of chymase (chymostatin, 100 muM) reduced arterial (19% control) but not venous constriction to big ET-1. These results suggest at least one potential significant difference - the role of chymase - in in vitro enzymatic processing of big ET-1 in arteries and veins.

01 Sep 2002·Clinical ScienceQ2 · MEDICINE

Oral administration of an inhibitor of endothelin-converting enzyme attenuates cerebral vasospasm following experimental subarachnoid haemorrhage in rabbits

Q2 · MEDICINE

Article

Author: JENG, Arco Y. ; LIN, Chih-Lung ; YEN, Chun-Po ; KASSELL, Neal F. ; KWAN, Aij-Lie ; SAVAGE, Paula ; HOWNG, Shen-Long ; WINARDI, Daniel ; Wu, Shu-Chuan ; CHANG, Chih-Zen ; LEE, Kevin S.

Increasing evidence has implicated endothelin-1 (ET-1), a potent vasoconstrictive peptide, in the pathophysiology of cerebral vasospasm after subarachnoid haemorrhage (SAH). Endothelin-converting enzyme-1 (ECE-1), the protease involved in the final step of post-translational processing of ET-1, cleaves the inactive precursor big ET-1 at the Trp21–Val 22 peptide bond. In our previous study, we found that an inhibitor of ECE-1, CGS 26303, could prevent and reverse the arterial narrowing after SAH in rabbits. CGS 26393, a prodrug of CGS 26303, is an orally active, long-acting inhibitor of ECE-1. The present study examined the effects of CGS 26393 on the prevention and reversal of cerebral vasospasm after SAH. New Zealand white rabbits were subjected to experimental SAH by injecting autologous blood into the cisterna magna. In the prevention study, the drug was given orally 1h before the induction of SAH. All drug treatments in the reversal study were initiated at 23h after induction of SAH. One of three dosages (3, 10 or 30mg/kg) of CGS 26393 or vehicle was administrated orally twice daily, and all animals were sacrificed by perfusion and fixation 48h after SAH. Basilar arteries were removed and sectioned, and cross-sectional areas were measured. Cerebrospinal fluid (CSF) was collected prior to perfusion. Oral administration of CGS 26393 attenuated SAH-induced cerebral vasospasm in a dose-dependent manner in both the prevention and reversal groups. These effects achieved statistical significance at all dosages when compared with the SAH-only or SAH plus vehicle groups. Moreover, the attenuation of vasospasm following oral administration of CGS 26393 was more efficacious than that obtained with bolus injections of CGS 26303. The levels of free CGS 26303 in the CSF were increased in a dose-dependent manner in all three CGS 26393-treated groups. This study provides the first evidence that oral administration of an inhibitor of ECE-1, CGS 26393, is capable of preventing and reversing cerebral vasospasm following SAH. These findings also reinforce evidence demonstrating that treatment with an ECE-1 inhibitor is a potentially viable therapeutic approach for reducing cerebral vasospasm after SAH.

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